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Farcas A, Hindmarch C, Iftene F. BDNF gene Val66Met polymorphisms as a predictor for clinical presentation in schizophrenia - recent findings. Front Psychiatry 2023; 14:1234220. [PMID: 37886115 PMCID: PMC10598753 DOI: 10.3389/fpsyt.2023.1234220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Accepted: 09/25/2023] [Indexed: 10/28/2023] Open
Abstract
Schizophrenia is a highly heritable, severe psychiatric disorder that involves dysfunctions in thinking, emotions, and behavior, with a profound impact on a person's ability to function normally in their daily life. Research efforts continue to focus on elucidating possible genetic underlying mechanisms of the disorder. Although the genetic loci identified to date to be significantly associated with schizophrenia risk do not represent disease-causing factors, each one of them could be seen as a possible incremental contributor. Considering the importance of finding new and more efficient pharmacological approaches to target the complex symptomatology of this disorder, in this scoping review, we are focusing on the most recent findings in studies aiming to elucidate the contribution of one of the genetic factors involved - the BDNF gene Val66Met polymorphisms. Here we performed a systematic search in Pubmed, Embase, and Web of Science databases with the search terms: (BDNF gene polymorphism) AND (schizophrenia) for articles published in the last 5 years. To be selected for this review, articles had to report on studies where genotyping for the BDNF Val66Met polymorphism was performed in participants diagnosed with schizophrenia (or schizophrenia spectrum disorders or first-episode psychosis). The search provided 35 results from Pubmed, 134 results from Embase, and 118 results from the Web of Science database. Twenty-two articles were selected to be included in this review, all reporting on studies where an implication of the BDNF Val66Met polymorphisms in the disorder's pathophysiology was sought to be elucidated. These studies looked at BDNF gene Val66Met polymorphism variants, their interactions with other genes of interest, and different facets of the illness. The Met/Met genotype was found to be associated with higher PANSS positive scores. Furthermore, Met/Met homozygous individuals appear to present with worse cognitive function and lower levels of serum BDNF. In the Val/Val genotype carriers, increased BDNF levels were found to correlate with weight gain under Risperidone treatment. However, due to heterogeneous results, the diversity in study populations and studies' small sample sizes, generalizations cannot be made. Our findings emphasize the need for further research dedicated to clarifying the role of gene polymorphisms in antipsychotic treatment to enhance specificity and efficacy in the treatment of schizophrenia.
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Affiliation(s)
- Adriana Farcas
- Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
- Providence Care Hospital, Kingston, ON, Canada
| | - Charles Hindmarch
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
- Department of Medicine, Queen’s University, Kingston, ON, Canada
- Queen’s Cardiopulmonary Unit, Translational Institute of Medicine, Queen’s University, Kingston, ON, Canada
| | - Felicia Iftene
- Centre for Neuroscience Studies, Queen’s University, Kingston, ON, Canada
- Providence Care Hospital, Kingston, ON, Canada
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Zuo WF, Pang Q, Yao LP, Zhang Y, Peng C, Huang W, Han B. Gut microbiota: A magical multifunctional target regulated by medicine food homology species. J Adv Res 2023; 52:151-170. [PMID: 37269937 PMCID: PMC10555941 DOI: 10.1016/j.jare.2023.05.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 05/27/2023] [Accepted: 05/28/2023] [Indexed: 06/05/2023] Open
Abstract
BACKGROUND The relationship between gut microbiota and human health has gradually been recognized. Increasing studies show that the disorder of gut microbiota is related to the occurrence and development of many diseases. Metabolites produced by the gut microbiota are responsible for their extensive regulatory roles. In addition, naturally derived medicine food homology species with low toxicity and high efficiency have been clearly defined owing to their outstanding physiological and pharmacological properties in disease prevention and treatment. AIM OF REVIEW Based on supporting evidence, the current review summarizes the representative work of medicine food homology species targeting the gut microbiota to regulate host pathophysiology and discusses the challenges and prospects in this field. It aims to facilitate the understanding of the relationship among medicine food homology species, gut microbiota, and human health and further stimulate the advancement of more relevant research. KEY SCIENTIFIC CONCEPTS OF REVIEW As this review reveals, from the initial practical application to more mechanism studies, the relationship among medicine food homology species, gut microbiota, and human health has evolved into an irrefutable interaction. On the one hand, through affecting the population structure, metabolism, and function of gut microbiota, medicine food homology species maintain the homeostasis of the intestinal microenvironment and human health by affecting the population structure, metabolism, and function of gut microbiota. On the other hand, the gut microbiota is also involved in the bioconversion of the active ingredients from medicine food homology species and thus influences their physiological and pharmacological properties.
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Affiliation(s)
- Wei-Fang Zuo
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qiwen Pang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Lai-Ping Yao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yang Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Bednarova A, Habalova V, Krivosova M, Marcatili M, Tkac I. Association Study of BDNF, SLC6A4, and FTO Genetic Variants with Schizophrenia Spectrum Disorders. J Pers Med 2023; 13:jpm13040658. [PMID: 37109044 PMCID: PMC10141144 DOI: 10.3390/jpm13040658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Schizophrenia spectrum disorders (patients with a diagnosis of schizophrenia, schizotypal, and delusional disorders: F20-F29 according to International Classification of Diseases 10th revision (ICD-10)) are considered highly heritable heterogeneous psychiatric conditions. Their pathophysiology is multifactorial with involved dysregulated serotonergic neurotransmission and synaptic plasticity. The present study aimed to evaluate the association of SLC6A4 (5-HTTLPR), FTO (rs9939609), and BDNF (rs6265, rs962369) polymorphisms with schizophrenia spectrum disorders in Slovak patients. We analyzed the genotypes of 150 patients with schizophrenia, schizotypal, and delusional disorders and compared them with genotypes from 178 healthy volunteers. We have found a marginally protective effect of LS + SS genotypes of 5-HTTLPR variant of the serotonin transporter SLC6A4 gene against the development of schizophrenia spectrum disorders, but the result failed to remain significant after Bonferroni correction. Similarly, we have not proven any significant association between other selected genetic variants and schizophrenia and related disorders. Studies including a higher number of subjects are warranted to reliably confirm the presence or absence of the studied associations.
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Affiliation(s)
- Aneta Bednarova
- 2nd Department of Psychiatry, Faculty of Medicine, Pavol Jozef Safarik University, Louis Pasteur University Hospital, 041 90 Kosice, Slovakia
| | - Viera Habalova
- Department of Medical Biology, Faculty of Medicine, Pavol Jozef Safarik University, 040 11 Kosice, Slovakia
| | - Michaela Krivosova
- Biomedical Centre Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, 036 01 Martin, Slovakia
| | - Matteo Marcatili
- Department of Mental Health and Addiction, Fondazione IRCCS San Gerardo dei Tintori, 209 00 Monza, Italy
| | - Ivan Tkac
- 4th Department of Internal Medicine, Faculty of Medicine, Pavol Jozef Safarik University, Louis Pasteur University Hospital, 041 90 Kosice, Slovakia
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You H, Lu B. Diverse Functions of Multiple Bdnf Transcripts Driven by Distinct Bdnf Promoters. Biomolecules 2023; 13:655. [PMID: 37189402 PMCID: PMC10135494 DOI: 10.3390/biom13040655] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/01/2023] [Accepted: 04/04/2023] [Indexed: 05/17/2023] Open
Abstract
The gene encoding brain-derived neurotrophic factor (Bdnf) consists of nine non-coding exons driven by unique promoters, leading to the expression of nine Bdnf transcripts that play different roles in various brain regions and physiological stages. In this manuscript, we present a comprehensive overview of the molecular regulation and structural characteristics of the multiple Bdnf promoters, along with a summary of the current knowledge on the cellular and physiological functions of the distinct Bdnf transcripts produced by these promoters. Specifically, we summarized the role of Bdnf transcripts in psychiatric disorders, including schizophrenia and anxiety, as well as the cognitive functions associated with specific Bdnf promoters. Moreover, we examine the involvement of different Bdnf promoters in various aspects of metabolism. Finally, we propose future research directions that will enhance our understanding of the complex functions of Bdnf and its diverse promoters.
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Affiliation(s)
- He You
- School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China;
- School of Life Sciences, Tsinghua University, Beijing 100084, China
| | - Bai Lu
- School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China;
- Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Centre, 10 Marais Street, Stellenbosch 7600, South Africa
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Ghanbarzehi A, Sepehrinezhad A, Hashemi N, Karimi M, Shahbazi A. Disclosing common biological signatures and predicting new therapeutic targets in schizophrenia and obsessive-compulsive disorder by integrated bioinformatics analysis. BMC Psychiatry 2023; 23:40. [PMID: 36641432 PMCID: PMC9840830 DOI: 10.1186/s12888-023-04543-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 01/11/2023] [Indexed: 01/15/2023] Open
Abstract
Schizophrenia (SCZ) is a severe mental illness mainly characterized by a number of psychiatric symptoms. Obsessive-compulsive disorder (OCD) is a long-lasting and devastating mental disorder. SCZ has high co-occurrence with OCD resulting in the emergence of a concept entitled "schizo-obsessive disorder" as a new specific clinical entity with more severe psychiatric symptoms. Many studies have been done on SCZ and OCD, but the common pathogenesis between them is not clear yet. Therefore, this study aimed to identify shared genetic basis, potential biomarkers and therapeutic targets between these two disorders. Gene sets were extracted from the Geneweaver and Harmonizome databases for each disorder. Interestingly, the combination of both sets revealed 89 common genes between SCZ and OCD, the most important of which were BDNF, SLC6A4, GAD1, HTR2A, GRIN2B, DRD2, SLC6A3, COMT, TH and DLG4. Then, we conducted a comprehensive bioinformatics analysis of the common genes. Receptor activity as the molecular functions, neuron projection and synapse as the cellular components as well as serotonergic synapse, dopaminergic synapse and alcoholism as the pathways were the most significant commonalities in enrichment analyses. In addition, transcription factor (TFs) analysis predicted significant TFs such as HMGA1, MAPK14, HINFP and TEAD2. Hsa-miR-3121-3p and hsa-miR-495-3p were the most important microRNAs (miRNAs) associated with both disorders. Finally, our study predicted 19 existing drugs (importantly, Haloperidol, Fluoxetine and Melatonin) that may have a potential influence on this co-occurrence. To summarize, this study may help us to better understand and handle the co-occurrence of SCZ and OCD by identifying potential biomarkers and therapeutic targets.
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Affiliation(s)
- Abdolhakim Ghanbarzehi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Sepehrinezhad
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Neuroscience Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Nazanin Hashemi
- Department of Biotechnology, Bangalore University, Bangalore, Karnataka, India
| | - Minoo Karimi
- Department of Audiology, School of Rehabilitation, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Shahbazi
- Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Białoń M, Wąsik A. Advantages and Limitations of Animal Schizophrenia Models. Int J Mol Sci 2022; 23:5968. [PMID: 35682647 PMCID: PMC9181262 DOI: 10.3390/ijms23115968] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/17/2022] [Accepted: 05/23/2022] [Indexed: 12/16/2022] Open
Abstract
Mental illness modeling is still a major challenge for scientists. Animal models of schizophrenia are essential to gain a better understanding of the disease etiopathology and mechanism of action of currently used antipsychotic drugs and help in the search for new and more effective therapies. We can distinguish among pharmacological, genetic, and neurodevelopmental models offering various neuroanatomical disorders and a different spectrum of symptoms of schizophrenia. Modeling schizophrenia is based on inducing damage or changes in the activity of relevant regions in the rodent brain (mainly the prefrontal cortex and hippocampus). Such artificially induced dysfunctions approximately correspond to the lesions found in patients with schizophrenia. However, notably, animal models of mental illness have numerous limitations and never fully reflect the disease state observed in humans.
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Affiliation(s)
| | - Agnieszka Wąsik
- Department of Neurochemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, 31-343 Cracow, Poland;
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Pan L, Cao Z, Chen L, Qian M, Yan Y. Association of BDNF and MMP-9 single-nucleotide polymorphisms with the clinical phenotype of schizophrenia. Front Psychiatry 2022; 13:941973. [PMID: 36325525 PMCID: PMC9619044 DOI: 10.3389/fpsyt.2022.941973] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 10/03/2022] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVE Schizophrenia is a highly polygenic psychiatric disorder; however, the complex genetic architecture underlying the pathogenesis remains elusive. Brain-derived neurotrophic factor (BDNF), a neurotrophin, and matrix metalloproteinase 9 (MMP-9), a gelatinase B, are the promising candidate genes for schizophrenia. To shed new light on the relationship between the single-nucleotide polymorphisms (SNPs) of BDNF and MMP-9 and the clinical variability of schizophrenia phenotype, this study aims to evaluate the relationship, and provide more definitive evidence for the relationship with various clinical features of schizophrenia. METHODS A case-control association study was performed, and one hundred and five subjects of Chinese Han population were enrolled, including 55 schizophrenia patients (SP) and 50 healthy controls (HC). The BDNF rs6265 196 G > A and MMP-9 rs3918242 -1562C > T SNPs were genotyped using PCR-RFLP assay. The Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptoms of patients with schizophrenia. RESULTS Compared with HC, the frequency of SP carrying BDNF rs6265 GG/GA genotype was significantly higher than HC, and the frequency of SP carrying BDNF rs6265 AA genotype was significantly lower than HC (p < 0.01). With regards to MMP-9 rs3918242 -1562C > T SNP, no significant difference was observed between the control and SP. BDNF GG genotype showed significantly higher PANSS and positive symptoms score than GA and AA genotypes (P < 0.01). MMP-9 CC genotype showed significantly higher PANSS and general score than CT and TT genotypes (P < 0.05). CONCLUSION BDNF rs6265 196 G > A and MMP-9 rs3918242-1562C > T SNPs are related to the clinical features of schizophrenia and could be a useful biomarker for the changes, remission or deterioration of clinical status of schizophrenia.
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Affiliation(s)
- Lihong Pan
- Pudong Nanhui Mental Health Center, Shanghai, China
| | - Zhonghai Cao
- People's Hospital of Datong County, Datong, China
| | - Lianghu Chen
- Pudong Nanhui Mental Health Center, Shanghai, China
| | - Min Qian
- Pudong Nanhui Mental Health Center, Shanghai, China
| | - Yuzhong Yan
- Department of Research, Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
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Chen Y, Xiao N, Chen Y, Chen X, Zhong C, Cheng Y, Du B, Li P. Semen Sojae Praeparatum alters depression-like behaviors in chronic unpredictable mild stress rats via intestinal microbiota. Food Res Int 2021; 150:110808. [PMID: 34863499 DOI: 10.1016/j.foodres.2021.110808] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 10/26/2021] [Accepted: 11/06/2021] [Indexed: 10/19/2022]
Abstract
A large number of Chinese medical books present that Semen Sojae Praeparatum, a fermented food, possesses antidepressant effect, but the mechanism of this antidepressant effect remains largely unknown. This study aimed to explore the effect of Semen Sojae Praeparatum on rats with chronic unpredictable mild stress (CUMS)-induced depression. The results showed that Semen Sojae Praeparatum improved depression-like behaviors (negative preference of sugar water and increased swimming immobility time and time spent in the dark zone) and effectively reduced cell morphological changes in the dentate gyrus of the hippocampus in CUMS rats. In addition, Semen Sojae Praeparatum significantly promoted the contents of norepinephrine (NE), 5-hydroxytryptamine (5-HT), brain-derived neurotrophic factor (BDNF), and gamma-aminobutyric acid (GABA) in the hippocampus and the content of BDNF in the serum (p < 0.05). 16S rRNA sequencing analysis results showed that Semen Sojae Praeparatum increased the abundance of genus Ruminococcaceae_UCG-008 and decreased those of genera Lactobacillus and Bacteroides. Genus Ruminococcaceae_UCG-008 was positively correlated with GABA and BDNF levels in the hippocampus; genus Lactobacillus had a positive correlation with 5-HT; and genus Bacteroides had negative correlations with 5-HT, BDNF, and NE. In addition, Semen Sojae Praeparatum considerably decreased the concentration of short-chain fatty acids (SCFAs). These results indicated that Semen Sojae Praeparatum fermented by Rhizopus chinensis 12 and Bacillus sp. DU-106 alleviated the neurotransmitter levels and structural changes in the neuronal morphology of the hippocampus associated with the modulation of gut microbiota and SCFAs. Therefore, this study confirmed that Semen Sojae Praeparatum could alter depression and provide a theoretical basis for the investigation of the relationship between the microbiota-gut-brain axis and antidepressant.
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Affiliation(s)
- Yanlan Chen
- College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Nan Xiao
- College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Yuxin Chen
- College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Xinye Chen
- College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Chunfei Zhong
- College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Yuying Cheng
- College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Bing Du
- College of Food Science, South China Agricultural University, Guangzhou 510642, China
| | - Pan Li
- College of Food Science, South China Agricultural University, Guangzhou 510642, China.
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Yu W, Fang H, Zhang L, Hu M, He S, Li H, Zhu H. Reversible Changes in BDNF Expression in MK-801-Induced Hippocampal Astrocytes Through NMDAR/PI3K/ERK Signaling. Front Cell Neurosci 2021; 15:672136. [PMID: 34054433 PMCID: PMC8160225 DOI: 10.3389/fncel.2021.672136] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 04/19/2021] [Indexed: 01/03/2023] Open
Abstract
Dizocilpine (MK-801), a non-competitive N-methyl-D-aspartic acid receptor (NMDA-R) antagonist, can induce schizophrenia-like symptoms in healthy individuals, implicating NMDA-R hypofunction in disease pathogenesis. Brain-derived neurotrophic factor (BDNF) is also implicated in schizophrenia, and expression is regulated by NMDA-R activity, suggesting a functional link. We previously found that BDNF signaling was upregulated by MK-801 in cultured hippocampal astrocytes, but the underlying mechanism is not clear. To address this issue, the levels of BDNF expression and secretion were evaluated in hippocampal astrocytes incubated with MK-801 by ELISA and qPCR, with and without NMDA co-incubation or pretreatment of either the ERK1/2 inhibitor, PD98059 or the PI3K inhibitor, LY294002. The apoptosis, viability, and proliferation of the astrocytes were also examined. In the current study, we demonstrate that MK-801 treatment (20 μM for 5 days) enhances the proliferation of rat cultured hippocampal astrocytes. Expression of BDNF mRNA was enhanced after 24 h in MK-801, but returned to near baseline over the next 24 h in the continued presence of MK-801. However, two successive 24-h treatments enhanced BDNF expression. These application regimens had no effect on apoptosis or proliferation rate. Co-addition of NMDA significantly inhibited MK-801-induced upregulation of BDNF. Similarly, MK-801-induced BDNF upregulation was blocked by pretreatment with inhibitors of PI3K and ERK1/2, but not by inhibitors of p38 and JNK. These findings suggested that astrocytes may contribute to the acute neurological and behavioral response to MK-801 treatment via a transient increase in BDNF expression involving NMDA-R–PI3K–ERK signaling.
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Affiliation(s)
- Wenjuan Yu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongwei Fang
- Department of Anesthesiology and Intensive Care Unit, Dongfang Hospital, Tongji University, Shanghai, China
| | - Lei Zhang
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Miaowen Hu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sidi He
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huafang Li
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Clinical Research Center for Mental Health, Shanghai, China.,Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China
| | - Hao Zhu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Martínez-Torres NI, Vázquez-Hernández N, Martín-Amaya-Barajas FL, Flores-Soto M, González-Burgos I. Ibotenic acid induced lesions impair the modulation of dendritic spine plasticity in the prefrontal cortex and amygdala, a phenomenon that underlies working memory and social behavior. Eur J Pharmacol 2021; 896:173883. [PMID: 33513334 DOI: 10.1016/j.ejphar.2021.173883] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 01/08/2023]
Abstract
The lesions induced by Ibotenic acid (IA) emulate some of the symptoms associated with schizophrenia, such as impaired working memory that is predominantly organized by the medial prefrontal cortex (mPFC), or difficulties in social interactions that aremainly organized by the amygdala (AMG). The plastic capacity of dendritic spines in neurons of the mPFC and AMG is modulated by molecules that participate in the known deterioration of working memory, although the influence of these on the socialization of schizophrenic patients is unknown. Here, the effect of a neonatal IA induced lesion on social behavior and working memory was evaluated in adult rats, along with the changes in cytoarchitecture of dendritic spines and their protein content, specifically the postsynaptic density protein 95 (PSD-95), Synaptophysin (Syn), AMPA receptors, and brain-derived neurotrophic factor (BDNF). Both working memory and social behavior were impaired, and the density of the spines, as well as their PSD-95, Syn, AMPA receptor and BDNF content was lower in IA lesioned animals. The proportional density of thin, mushroom, stubby and wide spines resulted in plastic changes that suggest the activation of compensatory processes in the face of the adverse effects of the lesion. In addition, the reduction in the levels of the modulating factors also suggests that the signaling pathways in which such factors are implicated would be altered in the brains of patients with schizophrenia. Accordingly, the experimental study of such signaling pathways is likely to aid the development of more effective pharmacological strategies for the treatment of schizophrenia.
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Affiliation(s)
- Néstor I Martínez-Torres
- División de Neurociencias, Centro de Investigación Biomédica de Occidente, Guadalajara, Jal., Mexico; Centro Universitario del Norte, Universidad de Guadalajara, Colotlán, Jal., Mexico
| | - Nallely Vázquez-Hernández
- División de Neurociencias, Centro de Investigación Biomédica de Occidente, Guadalajara, Jal., Mexico
| | | | - Mario Flores-Soto
- División de Neurociencias, Centro de Investigación Biomédica de Occidente, Guadalajara, Jal., Mexico
| | - Ignacio González-Burgos
- División de Neurociencias, Centro de Investigación Biomédica de Occidente, Guadalajara, Jal., Mexico.
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11
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Quan R, Wu Z, Guo W, He L, Fang P, Gong P. The BDNF Val66Met polymorphism impacts victim's moral emotions following interpersonal transgression. Scand J Psychol 2020; 62:7-12. [PMID: 32815193 DOI: 10.1111/sjop.12678] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/30/2020] [Indexed: 11/30/2022]
Abstract
Immoral behaviors make individuals abominate and punish transgressors. Inspired by the associations between the Val66Met polymorphism of brain-derived neurotropic factor (BDNF) gene and emotional responses following negative events, we investigated whether this polymorphism was also associated moral emotions such as punishment and forgiveness following interpersonal transgression. To do so, we categorized 340 individuals according to the BDNF Val66Met and assessed moral emotions by using 12 hypothetic scenarios in different conditions of intention and interpersonal consequence. The results indicated that this polymorphism was significantly associated with moral aversion and punishment towards transgressors. Victims with the Val/Val genotype expressed less aversion and punishment than the Met carriers, regardless of intention and interpersonal consequence. Moreover, this polymorphism was associated with forgiveness. Victims with the Val/Val genotype expressed more forgiveness than the Met carriers. Taken together, these findings highlight the importance of the BDNF Val66Met to moral emotions.
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Affiliation(s)
- Rui Quan
- College of Life Science, Northwest University, Xi'an, 710069, China
| | - Zhenzhen Wu
- College of Life Science, Northwest University, Xi'an, 710069, China
| | - Wenxuan Guo
- College of Life Science, Northwest University, Xi'an, 710069, China
| | - Linlin He
- College of Life Science, Northwest University, Xi'an, 710069, China
| | - Pengpeng Fang
- College of Life Science, Northwest University, Xi'an, 710069, China
| | - Pingyuan Gong
- College of Life Science, Northwest University, Xi'an, 710069, China.,College of Medicine, Northwest University, Xi'an, 710069, China.,Shaanxi Key Laboratory for Animal Conservation, Northwest University, Xi'an, 710069, China.,Institute of Population and Health, Northwest University, Xi'an, 710069, China
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12
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Abstract
The brain-derived neurotrophic factor (BDNF) is a secretory growth factor that promotes neuronal proliferation and survival, synaptic plasticity and long-term potentiation in the central nervous system. Brain-derived neurotrophic factor biosynthesis and secretion are chrono-topically regulated processes at the cellular level, accounting for specific localizations and functions. Given its role in regulating brain development and activity, BDNF represents a potentially relevant gene for schizophrenia, and indeed BDNF and its non-synonymous functional variant, rs6265 (C → T, Val → Met) have been widely studied in psychiatric genetics. Human and animal studies have indicated that brain-derived neurotrophic factor is relevant for schizophrenia-related phenotypes, and that: (1) fine-tuned regulation of brain-derived neurotrophic factor secretion and activity is necessary to guarantee brain optimal development and functioning; (2) the Val → Met substitution is associated with impaired activity-dependent secretion of brain-derived neurotrophic factor; (3) disruption of brain-derived neurotrophic factor signaling is associated with altered synaptic plasticity and neurodevelopment. However, genome-wide association studies failed to associate the BDNF locus with schizophrenia, even though a sub-threshold association exists. Here, we will review studies focused on the relationship between the genetic variation of BDNF and schizophrenia, trying to fill the gap between genetic risk per se and insights from molecular biology. A deeper understanding of brain-derived neurotrophic factor biology and of the epigenetic regulation of brain-derived neurotrophic factor and its interactome during development may help clarifying the potential role of this gene in schizophrenia, thus informing development of brain-derived neurotrophic factor-based strategies of prevention and treatment of this disorder.
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Rodrigues-Amorim D, Rivera-Baltanás T, Vallejo-Curto MDC, Rodriguez-Jamardo C, de las Heras E, Barreiro-Villar C, Blanco-Formoso M, Fernández-Palleiro P, Álvarez-Ariza M, López M, García-Caballero A, Olivares JM, Spuch C. Proteomics in Schizophrenia: A Gateway to Discover Potential Biomarkers of Psychoneuroimmune Pathways. Front Psychiatry 2019; 10:885. [PMID: 31849731 PMCID: PMC6897280 DOI: 10.3389/fpsyt.2019.00885] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2019] [Accepted: 11/11/2019] [Indexed: 12/17/2022] Open
Abstract
Schizophrenia is a severe and disabling psychiatric disorder with a complex and multifactorial etiology. The lack of consensus regarding the multifaceted dysfunction of this ailment has increased the need to explore new research lines. This research makes use of proteomics data to discover possible analytes associated with psychoneuroimmune signaling pathways in schizophrenia. Thus, we analyze plasma of 45 patients [10 patients with first-episode schizophrenia (FES) and 35 patients with chronic schizophrenia] and 43 healthy subjects by label-free liquid chromatography-tandem mass spectrometry. The analysis revealed a significant reduction in the levels of glia maturation factor beta (GMF-β), the brain-derived neurotrophic factor (BDNF), and the 115-kDa isoform of the Rab3 GTPase-activating protein catalytic subunit (RAB3GAP1) in patients with schizophrenia as compared to healthy volunteers. In conclusion, GMF-β, BDNF, and 115-kDa isoform of RAB3GAP1 showed significantly reduced levels in plasma of patients with schizophrenia, thus making them potential biomarkers in schizophrenia.
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Affiliation(s)
- Daniela Rodrigues-Amorim
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - Tania Rivera-Baltanás
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - María del Carmen Vallejo-Curto
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - Cynthia Rodriguez-Jamardo
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - Elena de las Heras
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - Carolina Barreiro-Villar
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - María Blanco-Formoso
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - Patricia Fernández-Palleiro
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - María Álvarez-Ariza
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - Marta López
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - Alejandro García-Caballero
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
- Department of Psychiatry, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - José Manuel Olivares
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
| | - Carlos Spuch
- Translational Neuroscience Research Group, Galicia Sur Health Research Institute, University of Vigo, CIBERSAM, Vigo, Spain
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Arabska J, Margulska A, Strzelecki D, Wysokiński A. Does metabolic status affect serum levels of BDNF and MMP-9 in patients with schizophrenia? Nord J Psychiatry 2019; 73:515-521. [PMID: 31464540 DOI: 10.1080/08039488.2019.1658126] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The purpose of the article: Brain-derived neurotrophic factor (BDNF) and matrix metalloproteinase-9 (MMP-9) are involved in the processes of neurogenesis, synaptic plasticity, learning and memory. Growing number of studies shows a relationship between BDNF or MMP-9 and schizophrenia. Also, BDNF and MMP-9 levels may be affected by metabolic parameters, such as obesity or dyslipidemia. Our hypothesis is that alterations of BDNF or MMP-9 levels in schizophrenia might be secondary to metabolic abnormalities, often found among schizophrenia patients. Materials and methods: We have compared BDNF and MMP-9 between patients with schizophrenia (n = 64, age 49 ± 8.2 y) and healthy controls (n = 32, age 51 ± 8.9 y) in the context of cardio-metabolic parameters. Serum levels of BDNF and MMP-9 were measured using ELISA test, body composition parameters were determined using bioelectric impedance analysis. Results and conclusions: Our results showed significantly lowered serum BDNF concentration in the schizophrenia group (schizophrenia: 23.8 ± 7.83 ng/mL, control: 27.69 ± 8.11 ng/mL, p = 0.03). Serum MMP-9 concentration in schizophrenia group did not differ compared with the control group (schizophrenia: 456.8 ± 278.4 ng/mL, control: 341.5 ± 162.4 ng/mL, p = 0.07). After adjusting for age, all anthropometric parameters, body composition and laboratory tests BDNF were still significantly lower in the schizophrenia group. However, MMP-9 became significantly elevated in the schizophrenia group after adjusting for several anthropometric and body composition covariates. Our results confirmed reduced serum BDNF concentration in patients with schizophrenia. Also, this reduction seems to be independent of metabolic abnormalities. On the other hand, our hypothesis that MMP-9 level in schizophrenia is altered due to metabolic abnormalities might be true.
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Affiliation(s)
- Jaśmina Arabska
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz , Lodz , Poland
| | - Aleksandra Margulska
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz , Lodz , Poland
| | - Dominik Strzelecki
- Department of Affective and Psychotic Disorders, Medical University of Lodz , Lodz , Poland
| | - Adam Wysokiński
- Department of Old Age Psychiatry and Psychotic Disorders, Medical University of Lodz , Lodz , Poland
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15
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Yu W, Zhu M, Fang H, Zhou J, Ye L, Bian W, Wang Y, Zhu H, Xiao J, Zhu H, Li H. Risperidone Reverses the Downregulation of BDNF in Hippocampal Neurons and MK801-Induced Cognitive Impairment in Rats. Front Behav Neurosci 2019; 13:163. [PMID: 31396062 PMCID: PMC6664152 DOI: 10.3389/fnbeh.2019.00163] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 07/02/2019] [Indexed: 12/22/2022] Open
Abstract
MK-801, also known as dizocilpine, is a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that induces schizophrenia-like symptoms. Our previous study showed that brain-derived neurotrophic factor (BDNF) signaling was upregulated in cultured hippocampal astrocytes in response to MK-801. However, dysfunctional NMDA receptors are mainly expressed in neurons. The effects of MK-801 on neuron-derived BDNF expression and of risperidone on MK-801-induced cognitive impairment and changes in BDNF expression are unclear. To address this issue, we examined BDNF expression in the hippocampus of rats that received repeated injections of MK-801 (0.5 mg/kg body weight for 6 days) and in primary cultured hippocampal neurons incubated with 20 μM MK-801 for 24 h. BDNF expression and cognitive function were also evaluated in rats receiving intraperitoneal injections of risperidone (1 mg/kg body weight) once daily for 7 days and in hippocampal neurons incubated with 10 μM risperidone following MK801 treatment. MK-801 treatment decreased BDNF expression in the rat hippocampus as well as the expression and secretion of BDNF in hippocampal neurons in vitro. However, risperidone reversed the effects of MK801 on BDNF level and improved cognitive function in rats treated with MK801. These findings suggest that risperidone may alleviate cognitive impairment caused by MK801 via upregulation of BNDF signaling in the hippocampus.
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Affiliation(s)
- Wenjuan Yu
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Zhu
- Department of Pharmacy, South Campus, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hongwei Fang
- Department of Anesthesiology and Intensive Care Unit, Dongfang Hospital, Tongji University, Shanghai, China
| | - Jie Zhou
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Le Ye
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenyu Bian
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan Wang
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Zhu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Xiao
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Zhu
- Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huafang Li
- Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Shanghai Key Laboratory of Psychotic Disorders, Shanghai, China.,Clinical Research Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Fletcher JL, Murray SS, Xiao J. Brain-Derived Neurotrophic Factor in Central Nervous System Myelination: A New Mechanism to Promote Myelin Plasticity and Repair. Int J Mol Sci 2018; 19:ijms19124131. [PMID: 30572673 PMCID: PMC6321406 DOI: 10.3390/ijms19124131] [Citation(s) in RCA: 71] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 12/18/2018] [Accepted: 12/18/2018] [Indexed: 12/27/2022] Open
Abstract
Brain-derived neurotrophic factor (BDNF) plays vitally important roles in neural development and plasticity in both health and disease. Recent studies using mutant mice to selectively manipulate BDNF signalling in desired cell types, in combination with animal models of demyelinating disease, have demonstrated that BDNF not only potentiates normal central nervous system myelination in development but enhances recovery after myelin injury. However, the precise mechanisms by which BDNF enhances myelination in development and repair are unclear. Here, we review some of the recent progress made in understanding the influence BDNF exerts upon the myelinating process during development and after injury, and discuss the cellular and molecular mechanisms underlying its effects. In doing so, we raise new questions for future research.
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Affiliation(s)
- Jessica L Fletcher
- Department of Anatomy and Neuroscience, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3010, VIC, Australia.
| | - Simon S Murray
- Department of Anatomy and Neuroscience, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3010, VIC, Australia.
| | - Junhua Xiao
- Department of Anatomy and Neuroscience, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, 3010, VIC, Australia.
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17
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Arumugam V, John VS, Augustine N, Jacob T, Joy SM, Sen S, Sen T. The impact of antidepressant treatment on brain-derived neurotrophic factor level: An evidence-based approach through systematic review and meta-analysis. Indian J Pharmacol 2018; 49:236-242. [PMID: 29033483 PMCID: PMC5637134 DOI: 10.4103/ijp.ijp_700_16] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVES: Antidepressant treatment alters brain-derived neurotrophic factor (BDNF) levels, but it is not well established whether BDNF can be used as a marker to prove the efficacy of antidepressant treatment. The present systematic review and meta-analysis aim at assessing the influence of antidepressant treatment on BDNF level and the Hamilton Depression Rating Scale (HDRS) score, thereby to establish the rationale of utilizing BDNF as a predictive biomarker and HDRS score as an indicator for antidepressant treatment efficacy. MATERIALS AND METHODS: Search was conducted in PubMed, Science Direct, and Cochrane databases using the key words “BDNF” and “Depression” and “Antidepressants.” On the basis of the inclusion and exclusion criteria, studies were filtered and finally 6 randomized controlled trials were shortlisted. RESULTS: Comparison of serum BDNF level before and after antidepressant treatment was performed and the result showed that antidepressant treatment does not significantly affect the BDNF levels (confidence interval [CI]: −0.483 to 0.959; standard mean difference [SMD]: 0.238, P = 0.518). Egger's regression test (P = 0.455) and heterogeneity test (I2 = 88.909%) were done. Similarly, comparison of HDRS scores before and after antidepressant treatment indicated improvement in HDRS score suggesting positive outcome (CI: 1.719 to 3.707; SMD: 2.713, P < 0.001). Egger's regression test (P = 0.1417) and heterogeneity test (I2 = 89.843%) were performed. Publication bias was observed by funnel plot. CONCLUSION: Changes in BDNF levels do not occur uniformly for all the antidepressants. Hence, to use BDNF as a biomarker, it needs to be seen whether the same is true for all antidepressants.
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Affiliation(s)
- Vijayakumar Arumugam
- Department of Pharmacy Practice, Drug and Poison Information Center, KMCH College of Pharmacy, Coimbatore, Tamil Nadu, India
| | - Vini Susan John
- Department of Pharmacy Practice, Drug and Poison Information Center, KMCH College of Pharmacy, Coimbatore, Tamil Nadu, India
| | - Nisha Augustine
- Department of Pharmacy Practice, Drug and Poison Information Center, KMCH College of Pharmacy, Coimbatore, Tamil Nadu, India
| | - Taniya Jacob
- Department of Pharmacy Practice, Drug and Poison Information Center, KMCH College of Pharmacy, Coimbatore, Tamil Nadu, India
| | - Sagar Maliakkal Joy
- Department of Pharmacy Practice, Drug and Poison Information Center, KMCH College of Pharmacy, Coimbatore, Tamil Nadu, India
| | - Suchandra Sen
- Department of Pharmacy Practice, Drug and Poison Information Center, KMCH College of Pharmacy, Coimbatore, Tamil Nadu, India
| | - Tuhinadri Sen
- Department of Pharmaceutical Technology, Division of Pharmacology, Jadavpur University, Kolkata, West Bengal, India
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18
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Sangiovanni E, Brivio P, Dell'Agli M, Calabrese F. Botanicals as Modulators of Neuroplasticity: Focus on BDNF. Neural Plast 2017; 2017:5965371. [PMID: 29464125 PMCID: PMC5804326 DOI: 10.1155/2017/5965371] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 11/09/2017] [Accepted: 12/02/2017] [Indexed: 12/19/2022] Open
Abstract
The involvement of brain-derived neurotrophic factor (BDNF) in different central nervous system (CNS) diseases suggests that this neurotrophin may represent an interesting and reliable therapeutic target. Accordingly, the search for new compounds, also from natural sources, able to modulate BDNF has been increasingly explored. The present review considers the literature on the effects of botanicals on BDNF. Botanicals considered were Bacopa monnieri (L.) Pennell, Coffea arabica L., Crocus sativus L., Eleutherococcus senticosus Maxim., Camellia sinensis (L.) Kuntze (green tea), Ginkgo biloba L., Hypericum perforatum L., Olea europaea L. (olive oil), Panax ginseng C.A. Meyer, Rhodiola rosea L., Salvia miltiorrhiza Bunge, Vitis vinifera L., Withania somnifera (L.) Dunal, and Perilla frutescens (L.) Britton. The effect of the active principles responsible for the efficacy of the extracts is reviewed and discussed as well. The high number of articles published (more than one hundred manuscripts for 14 botanicals) supports the growing interest in the use of natural products as BDNF modulators. The studies reported strengthen the hypothesis that botanicals may be considered useful modulators of BDNF in CNS diseases, without high side effects. Further clinical studies are mandatory to confirm botanicals as preventive agents or as useful adjuvant to the pharmacological treatment.
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Affiliation(s)
- Enrico Sangiovanni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Paola Brivio
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Mario Dell'Agli
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Francesca Calabrese
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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19
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Codella R, Terruzzi I, Luzi L. Sugars, exercise and health. J Affect Disord 2017; 224:76-86. [PMID: 27817910 DOI: 10.1016/j.jad.2016.10.035] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Revised: 10/19/2016] [Accepted: 10/23/2016] [Indexed: 11/17/2022]
Abstract
BACKGROUND There is a direct link between a variety of addictions and mood states to which exercise could be relieving. Sugar addiction has been recently counted as another binge/compulsive/addictive eating behavior, differently induced, leading to a high-significant health problem. Regularly exercising at moderate intensity has been shown to efficiently and positively impact upon physiological imbalances caused by several morbid conditions, including affective disorders. Even in a wider set of physchiatric diseases, physical exercise has been prescribed as a complementary therapeutic strategy. METHOD A comprehensive literature search was carried out in the Cochrane Library and MEDLINE databases (search terms: sugar addiction, food craving, exercise therapy, training, physical fitness, physical activity, rehabilitation and aerobic). RESULTS Seeking high-sugar diets, also in a reward- or craving-addiction fashion, can generate drastic metabolic derangements, often interpolated with affective disorders, for which exercise may represent a valuable, universal, non-pharmachological barrier. LIMITATIONS More research in humans is needed to confirm potential exercise-mechanisms that may break the bond between sugar over-consumption and affective disorders. CONCLUSIONS The purpose of this review is to address the importance of physical exercise in reversing the gloomy scenario of unhealthy diets and sedentary lifestyles in our modern society.
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Affiliation(s)
- Roberto Codella
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy; Metabolism Research Center, IRCCS Policlinico San Donato, San Donato Milanese, Italy
| | - Ileana Terruzzi
- Diabetes Research Institute, Metabolism, Nutrigenomics and Cellular Differentiation Unit, San Raffaele Scientific Institute, Milan, Italy
| | - Livio Luzi
- Department of Biomedical Sciences for Health, Università degli Studi di Milano, Milan, Italy; Metabolism Research Center, IRCCS Policlinico San Donato, San Donato Milanese, Italy.
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20
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López Hill X, Richeri A, Scorza MC. Clozapine blockade of MK-801-induced learning/memory impairment in the mEPM: Role of 5-HT1A receptors and hippocampal BDNF levels. Physiol Behav 2017; 179:346-352. [DOI: 10.1016/j.physbeh.2017.07.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 07/05/2017] [Accepted: 07/08/2017] [Indexed: 12/22/2022]
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Cheah SY, McLeay R, Wockner LF, Lawford BR, Young RM, Morris CP, Voisey J. Expression and methylation of BDNF in the human brain in schizophrenia. World J Biol Psychiatry 2017; 18:392-400. [PMID: 27712141 DOI: 10.1080/15622975.2016.1245443] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To examine the combined effect of the BDNF Val66Met (rs6265) polymorphism and BDNF DNA methylation on transcriptional regulation of the BDNF gene. METHODS DNA methylation profiles were generated for CpG sites proximal to Val66Met, within BDNF promoter I and exon V for prefrontal cortex samples from 25 schizophrenia and 25 control subjects. Val66Met genotypes and BDNF mRNA expression data were generated by transcriptome sequencing. Expression, methylation and genotype data were correlated and examined for association with schizophrenia. RESULTS There was 43% more of the BDNF V-VIII-IX transcript in schizophrenia samples. BDNF mRNA expression and DNA methylation of seven CpG sites were not associated with schizophrenia after accounting for age and PMI effects. BDNF mRNA expression and DNA methylation were not altered by Val66Met after accounting for age and PMI effects. DNA methylation of one CpG site had a marginally significant positive correlation with mRNA expression in schizophrenia subjects. CONCLUSIONS Schizophrenia risk was not associated with differential BDNF mRNA expression and DNA methylation. A larger age-matched cohort with comprehensive clinical history is required to accurately identify the effects of genotype, mRNA expression and DNA methylation on schizophrenia risk.
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Affiliation(s)
- Sern-Yih Cheah
- a School of Biomedical Sciences, Institute of Health and Biomedical Innovation , Queensland University of Technology , Kelvin Grove , Queensland , Australia
| | - Robert McLeay
- a School of Biomedical Sciences, Institute of Health and Biomedical Innovation , Queensland University of Technology , Kelvin Grove , Queensland , Australia
| | - Leesa F Wockner
- b Queensland Institute of Medical Research, Royal Brisbane Hospital , Brisbane , Queensland , Australia
| | - Bruce R Lawford
- a School of Biomedical Sciences, Institute of Health and Biomedical Innovation , Queensland University of Technology , Kelvin Grove , Queensland , Australia.,c Discipline of Psychiatry , Royal Brisbane and Women's Hospital , Herston , Queensland , Australia
| | - Ross McD Young
- a School of Biomedical Sciences, Institute of Health and Biomedical Innovation , Queensland University of Technology , Kelvin Grove , Queensland , Australia
| | - Charles P Morris
- a School of Biomedical Sciences, Institute of Health and Biomedical Innovation , Queensland University of Technology , Kelvin Grove , Queensland , Australia
| | - Joanne Voisey
- a School of Biomedical Sciences, Institute of Health and Biomedical Innovation , Queensland University of Technology , Kelvin Grove , Queensland , Australia
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22
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Zhang C, Fang X, Yao P, Mao Y, Cai J, Zhang Y, Chen M, Fan W, Tang W, Song L. Metabolic adverse effects of olanzapine on cognitive dysfunction: A possible relationship between BDNF and TNF-alpha. Psychoneuroendocrinology 2017; 81:138-143. [PMID: 28477447 DOI: 10.1016/j.psyneuen.2017.04.014] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Revised: 04/17/2017] [Accepted: 04/21/2017] [Indexed: 11/15/2022]
Abstract
OBJECTIVE There is accumulating evidence indicating that long-term treatment with second-generation antipsychotics (SGAs) results in metabolic syndrome (MetS) and cognitive impairment. This evidence suggests an intrinsic link between antipsychotic-induced MetS and cognitive dysfunction in schizophrenia patients. Olanzapine is a commonly prescribed SGA with a significantly higher MetS risk than that of most antipsychotics. In this study, we hypothesized that olanzapine-induced MetS may exacerbate cognitive dysfunction in patients with schizophrenia. METHODS A sample of 216 schizophrenia patients receiving long-term olanzapine monotherapy were divided into two groups, MetS and non-MetS, based on the diagnostic criteria of the National Cholesterol Education Program's Adult Treatment Panel III. We also recruited 72 healthy individuals for a control group. Cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Plasma brain-derived neurotrophic factor (BDNF) and tumor necrosis factor-alpha (TNF-alpha) were measured by an enzyme-linked immunosorbent assay for 108 patients and 47 controls. RESULTS Among the 216 schizophrenia patients receiving olanzapine monotherapy, MetS was found in 95/216 (44%). Patients with MetS had more negative symptoms, higher total scores in PANSS (Ps<0.05) and lower immediate memory, attention, delayed memory and total scores in RBANS (Ps<0.01). Stepwise multivariate linear regression analysis revealed that increased glucose was the independent risk factor for cognitive dysfunction (t=-2.57, P=0.01). Patients with MetS had significantly lower BDNF (F=6.49, P=0.012) and higher TNF-alpha (F=5.08, P=0.026) levels than those without MetS. There was a negative correlation between the BDNF and TNF-alpha levels in the patients (r=-0.196, P=0.042). CONCLUSION Our findings provide evidence suggesting that the metabolic adverse effects of olanzapine may aggravate cognitive dysfunction in patients with schizophrenia through an interaction between BDNF and TNF-alpha.
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Affiliation(s)
- Chen Zhang
- Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Xinyu Fang
- Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Peifen Yao
- Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yemeng Mao
- Department of Pharmacology, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Cai
- Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yi Zhang
- Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meijuan Chen
- Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weixing Fan
- Department of Psychiatry, Jinhua Second Hospital, Jinhua, Zhejiang, China
| | - Wei Tang
- Department of Psychiatry, Wenzhou Kanging Hospital, Wenzhou, Zhejiang, China
| | - Lisheng Song
- Schizophrenia Program, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Kabir ZD, Martínez-Rivera A, Rajadhyaksha AM. From Gene to Behavior: L-Type Calcium Channel Mechanisms Underlying Neuropsychiatric Symptoms. Neurotherapeutics 2017; 14:588-613. [PMID: 28497380 PMCID: PMC5509628 DOI: 10.1007/s13311-017-0532-0] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The L-type calcium channels (LTCCs) Cav1.2 and Cav1.3, encoded by the CACNA1C and CACNA1D genes, respectively, are important regulators of calcium influx into cells and are critical for normal brain development and plasticity. In humans, CACNA1C has emerged as one of the most widely reproduced and prominent candidate risk genes for a range of neuropsychiatric disorders, including bipolar disorder (BD), schizophrenia (SCZ), major depressive disorder, autism spectrum disorder, and attention deficit hyperactivity disorder. Separately, CACNA1D has been found to be associated with BD and autism spectrum disorder, as well as cocaine dependence, a comorbid feature associated with psychiatric disorders. Despite growing evidence of a significant link between CACNA1C and CACNA1D and psychiatric disorders, our understanding of the biological mechanisms by which these LTCCs mediate neuropsychiatric-associated endophenotypes, many of which are shared across the different disorders, remains rudimentary. Clinical studies with LTCC blockers testing their efficacy to alleviate symptoms associated with BD, SCZ, and drug dependence have provided mixed results, underscoring the importance of further exploring the neurobiological consequences of dysregulated Cav1.2 and Cav1.3. Here, we provide a review of clinical studies that have evaluated LTCC blockers for BD, SCZ, and drug dependence-associated symptoms, as well as rodent studies that have identified Cav1.2- and Cav1.3-specific molecular and cellular cascades that underlie mood (anxiety, depression), social behavior, cognition, and addiction.
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Affiliation(s)
- Zeeba D Kabir
- Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA
- Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA
| | - Arlene Martínez-Rivera
- Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA
- Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA
| | - Anjali M Rajadhyaksha
- Pediatric Neurology, Pediatrics, Weill Cornell Medicine, New York, NY, USA.
- Weill Cornell Autism Research Program, Weill Cornell Medicine, New York, NY, USA.
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
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Tatham EL, Hall GBC, Clark D, Foster J, Ramasubbu R. The 5-HTTLPR and BDNF polymorphisms moderate the association between uncinate fasciculus connectivity and antidepressants treatment response in major depression. Eur Arch Psychiatry Clin Neurosci 2017; 267:135-147. [PMID: 27277475 DOI: 10.1007/s00406-016-0702-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 05/23/2016] [Indexed: 12/13/2022]
Abstract
Symptom improvement in depression due to antidepressant treatment is highly variable and clinically unpredictable. Linking neuronal connectivity and genetic risk factors in predicting antidepressant response has clinical implications. Our investigation assessed whether indices of white matter integrity, serotonin transporter-linked polymorphism (5-HTTLPR) and brain-derived neurotrophic factor (BDNF) val66met polymorphism predicted magnitude of depression symptom change following antidepressant treatment. Fractional anisotropy (FA) was used as an indicator of white matter integrity and was assessed in the uncinate fasciculus and superior longitudinal fasciculus using tract-based spatial statistics (TBSS) and probabilistic tractography. Forty-six medication-free patients with major depressive disorder participated in a diffusion tensor imaging scan prior to completing an 8-week treatment regime with citalopram or quetiapine XR. Indexed improvements in Hamilton Depression Rating Scale score from baseline to 8-week endpoint were used as an indicator of depression improvement. Carriers of the BDNF met allele exhibited lower FA values in the left uncinate fasciculus relative to val/val individuals [F(1, 40) = 7.314, p = 0.009]. Probabilistic tractography identified that higher FA in the left uncinate fasciculus predicted percent change in depression severity, with BDNF moderating this association [F(3, 30) = 3.923, p = 0.018]. An interaction between FA in the right uncinate fasciculus and 5-HTTLPR also predicted percent change in depression severity [F(5, 25) = 5.315, p = 0.002]. Uncorrected TBSS results revealed significantly higher FA in hippocampal portions of the cingulum bundle in responders compared to non-responders (p = 0.016). The predictive value of prefrontal and amygdala/hippocampal WM connectivity on antidepressant treatment response may be influenced by 5-HTTLPR and BDNF polymorphisms in MDD.
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Affiliation(s)
- Erica L Tatham
- McMaster Integrative Neuroscience Discovery and Study, McMaster University, Hamilton, ON, Canada
| | - Geoff B C Hall
- Department of Psychology, Neuroscience and Behaviour, McMaster University, Hamilton, ON, Canada
| | - Darren Clark
- Department of Psychiatry and Clinical Neurosciences, Mathison Centre for Mental Health Research and Education, University of Calgary, TRW Building, Room 4D64, 3280 Hospital Drive NW, Calgary, AB, T2N4Z6, Canada
| | - Jane Foster
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada
| | - Rajamannar Ramasubbu
- Department of Psychiatry and Clinical Neurosciences, Mathison Centre for Mental Health Research and Education, University of Calgary, TRW Building, Room 4D64, 3280 Hospital Drive NW, Calgary, AB, T2N4Z6, Canada.
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de Castro-Catala M, van Nierop M, Barrantes-Vidal N, Cristóbal-Narváez P, Sheinbaum T, Kwapil TR, Peña E, Jacobs N, Derom C, Thiery E, van Os J, van Winkel R, Rosa A. Childhood trauma, BDNF Val66Met and subclinical psychotic experiences. Attempt at replication in two independent samples. J Psychiatr Res 2016; 83:121-129. [PMID: 27596955 DOI: 10.1016/j.jpsychires.2016.08.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 08/19/2016] [Accepted: 08/19/2016] [Indexed: 02/06/2023]
Abstract
Childhood trauma exposure is a robust environmental risk factor for psychosis. However, not all exposed individuals develop psychotic symptoms later in life. The Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265) has been suggested to moderate the psychosis-inducing effects of childhood trauma in clinical and nonclinical samples. Our study aimed to explore the interaction effect between childhood trauma and the BDNF Val66Met polymorphism on subclinical psychotic experiences (PEs). This was explored in two nonclinical independent samples: an undergraduate and technical-training school student sample (n = 808, sample 1) and a female twin sample (n = 621, sample 2). Results showed that childhood trauma was strongly associated with positive and negative PEs in nonclinical individuals. A BDNF Val66Met x childhood trauma effect on positive PEs was observed in both samples. These results were discordant in terms of risk allele: while in sample 1 Val allele carriers, especially males, were more vulnerable to the effects of childhood trauma regarding PEs, in sample 2 Met carriers presented higher PEs scores when exposed to childhood trauma, compared with Val carriers. Moreover, in sample 2, a significant interaction was also found in relation to negative PEs. Our study partially replicates previous findings and suggests that some individuals are more prone to develop PEs following childhood trauma because of a complex combination of multiple factors. Further studies including genetic, environmental and epigenetic factors may provide insights in this field.
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Affiliation(s)
- Marta de Castro-Catala
- Secció de Zoologia i Antropologia Biològica, Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
| | - Martine van Nierop
- KU Leuven, Department of Neuroscience, Research Group Psychiatry, Centre for Contextual Psychiatry, Leuven, Belgium
| | - Neus Barrantes-Vidal
- Departament de Psicologia Clínica i de la Salut, Facultat de Psicologia, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain; Department of Psychology, University of North Carolina at Greensboro, Greensboro, NC, United States; Sant Pere Claver - Fundació Sanitària, Barcelona, Spain; Centre for Biomedical Research Network on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain
| | - Paula Cristóbal-Narváez
- Departament de Psicologia Clínica i de la Salut, Facultat de Psicologia, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
| | - Tamara Sheinbaum
- Departament de Psicologia Clínica i de la Salut, Facultat de Psicologia, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain
| | - Thomas R Kwapil
- Department of Psychology, University of North Carolina at Greensboro, Greensboro, NC, United States
| | - Elionora Peña
- Secció de Zoologia i Antropologia Biològica, Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain
| | - Nele Jacobs
- KU Leuven, Department of Neuroscience, Research Group Psychiatry, Centre for Contextual Psychiatry, Leuven, Belgium; Faculty of Psychology, Open University of the Netherlands, Heerlen, The Netherlands
| | - Catherine Derom
- Centre of Human Genetics, University Hospital Leuven, Department of Human Genetics, Leuven, Belgium
| | - Evert Thiery
- Department of Neurology, Ghent University Hospital, Ghent, Belgium
| | - Jim van Os
- Department of Psychosis Studies, Institute of Psychiatry, King's College London, King's Health Partners, London, United Kingdom; Maastricht University Medical Centre, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht, The Netherlands
| | - Ruud van Winkel
- KU Leuven, Department of Neuroscience, Research Group Psychiatry, Centre for Contextual Psychiatry, Leuven, Belgium; University Psychiatric Center, Katholieke Universiteit Leuven, Belgium
| | - Araceli Rosa
- Secció de Zoologia i Antropologia Biològica, Departament de Biologia Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; Centre for Biomedical Research Network on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
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Guo J, Ji Y, Ding Y, Jiang W, Sun Y, Lu B, Nagappan G. BDNF pro-peptide regulates dendritic spines via caspase-3. Cell Death Dis 2016; 7:e2264. [PMID: 27310873 PMCID: PMC5143394 DOI: 10.1038/cddis.2016.166] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2015] [Revised: 04/11/2016] [Accepted: 05/05/2016] [Indexed: 01/18/2023]
Abstract
The precursor of brain-derived neurotrophic factor (BDNF) (proBDNF) is enzymatically cleaved, by either intracellular (furin/PC1) or extracellular proteases (tPA/plasmin/MMP), to generate mature BDNF (mBDNF) and its pro-peptide (BDNF pro-peptide). Little is known about the function of BDNF pro-peptide. We have developed an antibody that specifically detects cleaved BDNF pro-peptide, but not proBDNF or mBDNF. Neuronal depolarization elicited a marked increase in extracellular BDNF pro-peptide, suggesting activity-dependent regulation of its extracellular levels. Exposure of BDNF pro-peptide to mature hippocampal neurons in culture dramatically reduced dendritic spine density. This effect was mediated by caspase-3, as revealed by studies with pharmacological inhibitors and genetic knockdown. BDNF pro-peptide also increased the number of ‘elongated' mitochondria and cytosolic cytochrome c, suggesting the involvement of mitochondrial-caspase-3 pathway. These results, along with BDNF pro-peptide effects recently reported on growth cones and long-term depression (LTD), suggest that BDNF pro-peptide is a negative regulator of neuronal structure and function.
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Affiliation(s)
- J Guo
- Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China.,Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - Y Ji
- Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China
| | - Y Ding
- Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China
| | - W Jiang
- Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China
| | - Y Sun
- Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China
| | - B Lu
- School of Medicine, Tsinghua University, Beijing 100084, China
| | - G Nagappan
- Neurodegeneration Discovery Performance Unit, GlaxoSmithKline, R&D China, Shanghai 201203, China
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Armbruster D, Müller-Alcazar A, Strobel A, Lesch KP, Kirschbaum C, Brocke B. BDNF val(66)met genotype shows distinct associations with the acoustic startle reflex and the cortisol stress response in young adults and children. Psychoneuroendocrinology 2016; 66:39-46. [PMID: 26773399 DOI: 10.1016/j.psyneuen.2015.12.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 12/17/2015] [Accepted: 12/17/2015] [Indexed: 12/28/2022]
Abstract
Brain Derived Neurotrophic Factor (BDNF) is a crucial regulator of neuronal development, organization and function and the val(66)met polymorphism in the BDNF gene has been associated with several (endo-) phenotypes of cognitive and affective processing. The BDNF met allele is considered a risk factor for anxiety and fear related phenotypes although findings are not entirely consistent. Here, the impact of BDNF val(66)met on two parameters of anxiety and stress was investigated in a series of studies. Acoustic startle responses were assessed in three adult samples (N1=117, N2=104, N3=116) as well as a children sample (N4=123). Cortisol increase in response to the Trier Social Stress Test (TSST) was measured in one adult sample (N3) and in the children sample (N4). The BDNF met allele was associated with enhanced cortisol responses in young adults (p=0.039) and children (p=0.013). On the contrary, BDNF met allele carriers showed a reduced acoustic startle response which reached significance in most samples (N1: p=0.004; N2: p=0.045; N3: n.s., N4: p=0.043) pointing to differential effects of BDNF val(66)met on distinct endophenotypes of anxiety and stress-related responses. However, small effect sizes suggest substantial additional genetic as well as environmental contributors.
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Affiliation(s)
- Diana Armbruster
- Institute of Psychology II, Technische Universität Dresden, Dresden, Germany.
| | - Anett Müller-Alcazar
- MSH Medical School Hamburg, University of Applied Science and Medical University, Hamburg, Germany
| | - Alexander Strobel
- Institute of Psychology II, Technische Universität Dresden, Dresden, Germany
| | - Klaus-Peter Lesch
- Division of Molecular Psychiatry, Laboratory of Translational Neurobiology, Department of Psychiatry, Psychosomatics, and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany
| | - Clemens Kirschbaum
- Institute of Psychology I, Technische Universität Dresden, Dresden, Germany
| | - Burkhard Brocke
- Institute of Psychology II, Technische Universität Dresden, Dresden, Germany
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Çöpoğlu ÜS, Igci M, Bozgeyik E, Kokaçya MH, İğci YZ, Dokuyucu R, Ari M, Savaş HA. DNA Methylation of BDNF Gene in Schizophrenia. Med Sci Monit 2016; 22:397-402. [PMID: 26851233 PMCID: PMC4749043 DOI: 10.12659/msm.895896] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background Although genetic factors are risk factors for schizophrenia, some environmental factors are thought to be required for the manifestation of disease. Epigenetic mechanisms regulate gene functions without causing a change in the nucleotide sequence of DNA. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that regulates synaptic transmission and plasticity. It has been suggested that BDNF may play a role in the pathophysiology of schizophrenia. It is established that methylation status of the BDNF gene is associated with fear learning, memory, and stressful social interactions. In this study, we aimed to investigate the DNA methylation status of BDNF gene in patients with schizophrenia. Material/Methods The study included 49 patients (33 male and 16 female) with schizophrenia and 65 unrelated healthy controls (46 male and 19 female). Determination of methylation pattern of CpG islands was based on the principle that bisulfite treatment of DNA results in conversion of unmethylated cytosine residues into uracil, whereas methylated cytosine residues remain unmodified. Methylation-specific PCR was performed with primers specific for either methylated or unmethylated DNA. Results There was no significant difference in methylated or un-methylated status for BDNF promoters between schizophrenia patients and controls. The mean duration of illness was significantly lower in the hemi-methylated group compared to the non-methylated group for BDNF gene CpG island-1 in schizophrenia patients. Conclusions Although there were no differences in BDNF gene methylation status between schizophrenia patients and healthy controls, there was an association between duration of illness and DNA methylation.
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Affiliation(s)
- Ümit Sertan Çöpoğlu
- Department of Psychiatry, School of Medicine, Mustafa Kemal University, Hatay, Turkey
| | - Mehri Igci
- Department Medical Biology, School of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Esra Bozgeyik
- Department Medical Biology, School of Medicine, Gaziantep University, Gaziantep, Turkey
| | - M Hanifi Kokaçya
- Department of Psychiatry, School of Medicine, Mustafa Kemal University, Hatay, Turkey
| | - Yusuf Ziya İğci
- Department Medical Biology, School of Medicine, Gaziantep University, Gaziantep, Turkey
| | - Recep Dokuyucu
- Department of Physiology, School of Medicine, Mustafa Kemal University, Hatay, Turkey
| | - Mustafa Ari
- Department of Physiology, Mustafa Kemal University, School of Medicine, Hatay, Turkey
| | - Haluk A Savaş
- Department Psychiatry, School of Medicine, Gaziantep University, Gaziantep, Turkey
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Reactive Transformation and Increased BDNF Signaling by Hippocampal Astrocytes in Response to MK-801. PLoS One 2015; 10:e0145651. [PMID: 26700309 PMCID: PMC4689377 DOI: 10.1371/journal.pone.0145651] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 12/07/2015] [Indexed: 11/26/2022] Open
Abstract
MK-801, also known as dizocilpine, is a noncompetitive N-methyl-D-aspartic acid (NMDA) receptor antagonist that induces schizophrenia-like symptoms. While astrocytes have been implicated in the pathophysiology of psychiatric disorders, including schizophrenia, astrocytic responses to MK-801 and their significance to schizotypic symptoms are unclear. Changes in the expression levels of glial fibrillary acid protein (GFAP), a marker of astrocyte activation in response to a variety of pathogenic stimuli, were examined in the hippocampus of rats treated with the repeated MK-801 injection (0.5 mg/10ml/kg body weight for 6 days) and in primary cultured hippocampal astrocytes incubated with MK-801 (5 or 20 μM for 24 h). Moreover, the expression levels of BDNF and its receptors TrkB and p75 were examined in MK-801-treated astrocyte cultures. MK-801 treatment enhanced GFAP expression in the rat hippocampus and also increased the levels of GFAP protein and mRNA in hippocampal astrocytes in vitro. Treatment of cultured hippocampal astrocytes with MK-801 enhanced protein and mRNA levels of BDNF, TrkB, and p75. Collectively, our results suggest that hippocampal astrocytes may contribute to the pathophysiology of schizophrenia symptoms associated with NMDA receptor hypofunction by reactive transformation and altered BDNF signaling.
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Andrews JL, Newell KA, Matosin N, Huang XF, Fernandez-Enright F. Alterations of p75 neurotrophin receptor and Myelin transcription factor 1 in the hippocampus of perinatal phencyclidine treated rats. Prog Neuropsychopharmacol Biol Psychiatry 2015; 63:91-7. [PMID: 26071990 DOI: 10.1016/j.pnpbp.2015.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 05/19/2015] [Accepted: 06/04/2015] [Indexed: 11/28/2022]
Abstract
Postnatal administration of phencyclidine (PCP) in rodents causes major disturbances to neurological processes resulting in severe modifications to normal behavioral traits into adulthood. It is routinely used to model psychiatric disorders such as schizophrenia, producing many of the dysfunctional processes in the brain that are present in this devastating disorder, including elevated levels of apoptosis during neurodevelopment and disruptions to myelin and plasticity processes. Lingo-1 (or Leucine-rich repeat and immunoglobulin domain-containing protein) is responsible for negatively regulating neurite outgrowth and the myelination of axons. Recent findings using a postmortem human brain cohort showed that Lingo-1 signaling partners in the Nogo receptor (NgR)/p75/TNF receptor orphan Y (TROY) signaling complex, and downstream signaling partners With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1), play a significant part in schizophrenia pathophysiology. Here we have examined the implication of Lingo-1 and its signaling partners in a neurodevelopmental model of schizophrenia using PCP to determine if these pathways are altered in the hippocampus throughout different stages of neurodevelopment. Male Sprague-Dawley rats were injected subcutaneously with PCP (10mg/kg) or saline solution on postnatal days (PN) 7, 9, and 11. Rats (n=6/group) were sacrificed at PN12, 5weeks, or 14weeks. Relative expression levels of Lingo-1 signaling proteins were examined in the hippocampus of the treated rats. p75 and Myt1 were decreased (0.001≤p≤0.011) in the PCP treated rats at PN12. There were no significant changes in any of the tested proteins at 5weeks (p>0.05). At 14weeks, p75, TROY, and Myt1 were increased in the PCP treated rats (0.014≤p≤0.022). This is the first report of an alteration in Lingo-1 signaling proteins in the rat hippocampus, both directly after PCP treatment in early development and in adulthood. Based on our results, we propose that components of the Lingo-1 signaling pathways may be involved in the acute neurotoxicity induced by perinatal administration of PCP in rats early in development and suggest that this may have implications for the hippocampal deficits seen in schizophrenia.
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Affiliation(s)
- Jessica L Andrews
- Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522 Australia; Schizophrenia Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010 Australia.
| | - Kelly A Newell
- Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522 Australia; Schizophrenia Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010 Australia.
| | - Natalie Matosin
- Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522 Australia; Schizophrenia Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010 Australia.
| | - Xu-Feng Huang
- Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522 Australia; Schizophrenia Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010 Australia.
| | - Francesca Fernandez-Enright
- Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522 Australia; Schizophrenia Research Institute, 405 Liverpool Street, Darlinghurst, New South Wales 2010 Australia; School of Psychology, Faculty of Social Sciences, University of Wollongong, Wollongong, New South Wales 2522 Australia.
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Simchon Tenenbaum Y, Weizman A, Rehavi M. The Impact of Chronic Early Administration of Psychostimulants on Brain Expression of BDNF and Other Neuroplasticity-Relevant Proteins. J Mol Neurosci 2015; 57:231-42. [PMID: 26152882 DOI: 10.1007/s12031-015-0611-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 06/26/2015] [Indexed: 01/08/2023]
Abstract
ABSRACT Frequently, healthy individuals, children, and students are using stimulants to treat attention deficit hyperactivity disorder (ADHD)-like symptoms or to enhance cognitive capacity, attention and concentration. Methylphenidate, the most common treatment for ADHD, similarly to cocaine, blocks the dopamine reuptake, leading to increase in dopamine level in the synaptic cleft. Brain-derived neurotrophic factor (BDNF) and other neuroplasticity-relevant proteins have a major role in cellular plasticity during development and maturation of the brain. Young Sprague Dawley rats (postnatal days (PND) 14) were treated chronically with either cocaine or methylphenidate. The rats were examined behaviorally and biochemically at several time points (PND 35, 56, 70, and 90). We found age-dependent, but stimulant-independent, alterations in the mRNA expression levels of microtubule-associated protein tau, doublecortin, and synaptophysin. The PND 90 rats, treated with methylphenidate at an early age, exhibited increased BDNF protein levels in the prefrontal cortex compared to the saline-treated group. Despite the treatment effects at the biochemical level, cocaine and methylphenidate treatments at an early age had only minor effects on the behavioral parameters measured at older ages. The biochemical alterations may reflect neuroprotective or neuroplastic effects of chronic methylphenidate treatment at an early age.
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Affiliation(s)
- Yaarit Simchon Tenenbaum
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, 69978, Tel-Aviv, Israel
| | - Abraham Weizman
- Research Unit, Geha Mental Health Center and Felsenstein Medical Research Center, Petah-Tikva, Israel
| | - Moshe Rehavi
- Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, 69978, Tel-Aviv, Israel. .,The Dr. Miriam and Sheldon G. Adelson Chair and Center for the Biology of Addictive Diseases, Tel-Aviv, Israel.
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Wu JQ, Chen DC, Tan YL, Tan SP, Hui L, Lv MH, Soares JC, Zhang XY. Altered BDNF is correlated to cognition impairment in schizophrenia patients with tardive dyskinesia. Psychopharmacology (Berl) 2015; 232:223-32. [PMID: 24994553 DOI: 10.1007/s00213-014-3660-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2014] [Accepted: 06/03/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND Long-term antipsychotic treatment for schizophrenia is often associated with the emergence of tardive dyskinesia (TD), which is linked to greater cognitive impairment. Brain-derived neurotrophic factor (BDNF) plays a critical role in cognitive function, and schizophrenia patients with TD have lower BDNF levels than those without TD. OBJECTIVE This study examines the BDNF levels, the cognitive function, and the association of BDNF with cognitive function in schizophrenia patients with or without TD. METHODS We recruited 83 male chronic patients with (n=35) and without TD (n=48) meeting DSM-IV criteria for schizophrenia and 52 male control subjects. We examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and BDNF levels for all subjects. Positive and Negative Symptom Scale (PANSS) and the Abnormal Involuntary Movement Scale (AIMS) were assessed in patients. RESULTS BDNF levels were lower in patients with than those without TD (p<0.05). RBANS total score (p<0.01) and subscales of immediate memory, visuospatial/constructional performance, and attention were lower in patients with than those without TD (all p<0.05). BDNF levels were positively associated with immediate memory in patients without TD, but negatively in TD patients (both p<0.05). Multiple regression analysis confirmed that in either TD or non-TD group, BDNF was an independent contributor to immediate memory (both p<0.05). CONCLUSIONS BDNF may be involved in the pathophysiology of TD. While the associations between BDNF and cognition in both TD and non-TD patients suggest a close relationship between BDNF and cognition, the different directions may implicate distinct mechanisms between TD and non-TD patients.
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Affiliation(s)
- Jing Qin Wu
- School of Biomedical Sciences and Pharmacy, Faculty of Health, The University of Newcastle, University Drive, Callaghan, NSW, 2308, Australia
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Sun QQ, Zhang Z, Sun J, Nair AS, Petrus DP, Zhang C. Functional and structural specific roles of activity-driven BDNF within circuits formed by single spiny stellate neurons of the barrel cortex. Front Cell Neurosci 2014; 8:372. [PMID: 25414642 PMCID: PMC4222225 DOI: 10.3389/fncel.2014.00372] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2014] [Accepted: 10/21/2014] [Indexed: 11/13/2022] Open
Abstract
Brain derived neurotrophic factor (BDNF) plays key roles in several neurodevelopmental disorders and actions of pharmacological treatments. However, it is unclear how specific BDNF’s effects are on different circuit components. Current studies have largely focused on the role of BDNF in modification of synaptic development. The precise roles of BDNF in the refinement of a functional circuit in vivo remain unclear. Val66Met polymorphism of BDNF may be associated with increased risk for cognitive impairments and is mediated at least in part by activity-dependent trafficking and/or secretion of BDNF. Using mutant mice that lacked activity-driven BDNF expression (bdnf-KIV), we previously reported that experience regulation of the cortical GABAergic network is mediated by activity-driven BDNF expression. Here, we demonstrate that activity-driven BDNF’s effects on circuits formed by the layer IV spiny stellate cells are highly specific. Structurally, dendritic but not axonal morphology was altered in the mutant. Physiologically, GABAergic but not glutamatergic synapses were severely affected. The effects on GABA transmission occurs via presynaptic alteration of calcium-dependent release probability. These results suggest that neuronal activity through activity-driven BDNF expression, can selectively regulate specific features of layer IV circuits in vivo. We postulate that the role of activity-dependent BDNF is to modulate the computational ability of circuits that relate to the gain control (i.e., feed-forward inhibition); whereas the basic wiring of circuits relevant to the sensory pathway is spared. Gain control modulation within cortical circuits has broad impact on cognitive processing and brain state-transitions. Cognitive behavior and mode is determined by brain states, thus the studying of circuit alteration by endogenous BDNF provides insights into the cellular and molecular mechanisms of diseases mediated by BDNF.
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Affiliation(s)
- Qian-Quan Sun
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY USA
| | - Zhi Zhang
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY USA
| | - June Sun
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY USA
| | - Anand S Nair
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY USA
| | - Dan P Petrus
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY USA
| | - Chunzhao Zhang
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY USA
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Papathanassoglou EDE, Miltiadous P, Karanikola MN. May BDNF Be Implicated in the Exercise-Mediated Regulation of Inflammation? Critical Review and Synthesis of Evidence. Biol Res Nurs 2014; 17:521-39. [DOI: 10.1177/1099800414555411] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Exercise attenuates inflammation and enhances levels of brain-derived neurotrophic factor (BDNF). Exercise also enhances parasympathetic tone, although its role in activating the cholinergic anti-inflammatory pathway is unclear. The physiological pathways of exercise’s effect on inflammation are obscure. Aims: To critically review the evidence on the role of BDNF in the anti-inflammatory effects of exercise and its potential involvement in the cholinergic anti-inflammatory pathway. Methods: Critical literature review of studies published in MEDLINE, PubMed, CINAHL, Embase, and Cochrane databases. Results: BDNF is critically involved in the bidirectional signaling between immune and neurosensory cells and in the regulation of parasympathetic system responses. BDNF is also intricately involved in the inflammatory response: inflammation induces BDNF production, and, in turn, BDNF exerts pro- and/or anti-inflammatory effects. Although exercise modulates BDNF and its receptors in lymphocytes, data on BDNF’s immunoregulatory/anti-inflammatory effects in relation to exercise are scarce. Moreover, BDNF increases cholinergic activity and is modulated by parasympathetic system activation. However, its involvement in the cholinergic anti-inflammatory pathway has not been investigated. Conclusion: Converging lines of evidence implicate BDNF in exercise-mediated regulation of inflammation; however, data are insufficient to draw concrete conclusions. We suggest that there is a need to investigate BDNF as a potential modulator/mediator of the anti-inflammatory effects of exercise and of the cholinergic anti-inflammatory pathway during exercise. Such research would have implications for a wide range of inflammatory diseases and for planning targeted exercise protocols.
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Hill RA, Klug M, Kiss Von Soly S, Binder MD, Hannan AJ, van den Buuse M. Sex-specific disruptions in spatial memory and anhedonia in a "two hit" rat model correspond with alterations in hippocampal brain-derived neurotrophic factor expression and signaling. Hippocampus 2014; 24:1197-211. [PMID: 24802968 DOI: 10.1002/hipo.22302] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2014] [Indexed: 01/01/2023]
Abstract
Post-mortem studies have demonstrated reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of schizophrenia and major depression patients. The "two hit" hypothesis proposes that two or more major disruptions at specific time points during development are involved in the pathophysiology of these mental illnesses. However, the role of BDNF in these "two hit" effects is unclear. Our aim was to behaviorally characterize a "two hit" rat model of developmental stress accompanied by an in-depth assessment of BDNF expression and signalling. Wistar rats were exposed to neonatal maternal separation (MS) stress and/or adolescent/young-adult corticosterone (CORT) treatment. In adulthood, models of cognitive and negative symptoms of mental illness were analyzed. The hippocampus was then dissected into dorsal (DHP) and ventral (VHP) regions and analyzed by qPCR for exon-specific BDNF gene expression or by Western blot for BDNF protein expression and downstream signaling. Male "two hit" rats showed marked disruptions in short-term spatial memory (Y-maze) which were absent in females. However, female "two hit" rats showed signs of anhedonia (sucrose preference test), which were absent in males. Novel object recognition and anxiety (elevated plus maze) were unchanged by either of the two "hits". In the DHP, MS caused a male-specific increase in BDNF Exons I, II, IV, VII, and IX mRNA but a decrease in mature BDNF and phosphorylated TrkB (pTrkB) protein expression in adulthood. In the VHP, BDNF transcript expression was unchanged; however, in female rats only, MS significantly decreased mature BDNF and pTrkB protein expression in adulthood. These data demonstrate that MS causes region-specific and sex-specific long-term effects on BDNF expression and signaling and, importantly, mRNA expression does not always infer protein expression. Alterations to BDNF signaling may mediate the sex-specific effects of developmental stress on anhedonic behaviors.
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Affiliation(s)
- Rachel A Hill
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
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Ray MT, Shannon Weickert C, Webster MJ. Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders. Transl Psychiatry 2014; 4:e389. [PMID: 24802307 PMCID: PMC4035720 DOI: 10.1038/tp.2014.26] [Citation(s) in RCA: 124] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Accepted: 03/09/2014] [Indexed: 02/07/2023] Open
Abstract
Abnormalities in brain-derived neurotrophic factor (BDNF)/trkB signaling have been implicated in the etiology of schizophrenia and mood disorders. Patients with schizophrenia, bipolar disorder (BPD) and major depression (MDD) have reduced levels of neurotrophins in their brains when compared with normal unaffected individuals; however, only a few brain areas have been examined to date. Owing to the broad range of symptoms manifested in these disorders, we hypothesized that multiple associative areas of the neocortex may be implicated and that the degree of change in BDNF and trkB-TK+ mRNA expression and the cortical region or layers involved may vary according to Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis. We compared BDNF and trkB-TK+ mRNA levels across all layers of the prefrontal cortex (dorsolateral prefrontal cortex, DLPFC), orbital frontal cortex (OFC), anterior cingulate cortex (ACC), inferior temporal gyrus (ITG) and superior temporal gyrus (STG) in four groups: schizophrenia, BPD, MDD and unaffected controls (n=60). BDNF mRNA levels were significantly decreased in layers IV and V of DLPFC in schizophrenia patients, in layer VI of ACC in schizophrenia and MDD and in layer VI of ITG in schizophrenia, BPD and MDD. BDNF mRNA levels were also significantly decreased in layer V and/or VI of STG in schizophrenia, BPD and MDD. TrkB-TK+ mRNA levels were only significantly decreased in the cortical layer VI of OFC in BPD. The shared and distinct patterns of neurotrophin transcript reductions, with some specific to each group, may compromise the function and plasticity of distinct cortical areas to various degrees in the different groups and contribute to the range and overlap of symptoms manifested across the diagnoses.
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Affiliation(s)
- M T Ray
- Stanley Medical Research Institute, Laboratory of Brain Research, Rockville, MD, USA,Trinity Washington University, NE Washington, DC, USA
| | - C Shannon Weickert
- Schizophrenia Research Institute, Sydney, NSW, Australia,Neuroscience Research Australia, Randwick, NSW, Australia,School of Psychiatry, University of New South Wales, Sydney, NSW, Australia
| | - M J Webster
- Stanley Medical Research Institute, Laboratory of Brain Research, Rockville, MD, USA,Stanley Laboratory of Brain Research, 9800 Medical Center Drive, Rockville, MD 20850, USA. E-mail:
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Romano E, De Angelis F, Ulbrich L, De Jaco A, Fuso A, Laviola G. Nicotine exposure during adolescence: cognitive performance and brain gene expression in adult heterozygous reeler mice. Psychopharmacology (Berl) 2014; 231:1775-87. [PMID: 24337025 DOI: 10.1007/s00213-013-3388-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 11/30/2013] [Indexed: 12/11/2022]
Abstract
RATIONALE We have recently reported nicotine-induced stimulation of reelin and glutamic acid decarboxylase 67 (GAD67) mRNA expression levels in the brain of heterozygous reeler mice (HRM), a putative animal model for the study of symptoms relevant to major behavioral disorders. OBJECTIVES We aimed to evaluate long-term behavioral effects and brain molecular changes as a result of adaptations to nicotine exposure in the developing HRM males. METHODS Adolescent mice (pnd 37-42) were exposed to oral nicotine (10 mg/l) in a 6-day free-choice drinking schedule. As expected, no differences in total nicotine intake between WT (wild-type) mice and HRM were found. RESULTS Long-term behavioral effects and brain molecular changes, as a consequence of nicotine exposure during adolescence, were only evidenced in HRM. Indeed, HRM perseverative exploratory behavior and poor cognitive performance were modulated to WT levels by subchronic exposure to nicotine during development. Furthermore, the expected reduction in the expression of mRNA of reelin and GAD67 in behaviorally relevant brain areas of HRM appeared persistently restored by nicotine. For brain-derived neurotrophic factor (BDNF) mRNA expression, no genotype-dependent changes appeared. However, expression levels were increased by previous nicotine in brains from both genotypes. The mRNA encoding for nicotine receptor subunits (α7, β2 and α4) did not differ between genotypes and as a result of previous nicotine exposure. CONCLUSION These findings support the hypothesis of pre-existing vulnerability (based on haploinsufficiency of reelin) to brain and behavioral disorders and regulative short- and long-term effects associated with nicotine modulation.
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Affiliation(s)
- Emilia Romano
- Section of Behavioural Neuroscience, Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161, Rome, Italy
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Fernandez-Enright F, Andrews JL, Newell KA, Pantelis C, Huang XF. Novel implications of Lingo-1 and its signaling partners in schizophrenia. Transl Psychiatry 2014; 4:e348. [PMID: 24448210 PMCID: PMC3905231 DOI: 10.1038/tp.2013.121] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2013] [Revised: 11/04/2013] [Accepted: 11/10/2013] [Indexed: 02/06/2023] Open
Abstract
Myelination and neurite outgrowth both occur during brain development, and their disturbance has been previously been implicated in the pathophysiology of schizophrenia. Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) is a potent negative regulator of axonal myelination and neurite extension. As co-factors of Lingo-1 signaling (Nogo receptor (NgR), With No Lysine (K) (WNK1) and Myelin transcription factor 1 (Myt1)) have been implicated in the genetics of schizophrenia, we explored for the first time the role of Lingo-1 signaling pathways in this disorder. Lingo-1 protein, together with its co-receptor and co-factor proteins NgR, tumor necrosis factor (TNF) receptor orphan Y (TROY), p75, WNK1 and Myt1, have never been explored in the pathogenesis of schizophrenia. We examined protein levels of Lingo-1, NgR, TROY, p75, WNK1, Myt1 and myelin basic protein (MBP) (as a marker of myelination) within the post-mortem dorsolateral prefrontal cortex (DLPFC) (37 schizophrenia patients versus 37 matched controls) and hippocampus (Cornu Ammonis, CA1 and CA3) (20 schizophrenia patients versus 20 matched controls from the same cohort). Both of these brain regions are highly disrupted in the schizophrenia pathophysiology. There were significant increases in Lingo-1 (P<0.001) and Myt1 (P=0.023) and a reduction in NgR (P<0.001) in the DLPFC in schizophrenia subjects compared with controls. There were also increases in both TROY (P=0.001) and WNK1 (P=0.011) in the CA1 of schizophrenia subjects and, in contrast to the DLPFC, there was an increase in NgR (P=0.006) in the CA3 of schizophrenia subjects compared with controls. No significant difference was reported for MBP levels (P>0.05) between the schizophrenia and control groups in the three tested regions. This is the first time that a study has shown altered Lingo-1 signaling in the schizophrenia brain. Our novel findings may present a direct application for the use of a Lingo-1 antagonist to complement current and future schizophrenia therapies.
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Affiliation(s)
- F Fernandez-Enright
- Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia,Schizophrenia Research Institute, Darlinghurst, NSW, Australia,Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Northfields Avenue, Wollongong 2522, NSW, Australia. E-mail:
| | - J L Andrews
- Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia,Schizophrenia Research Institute, Darlinghurst, NSW, Australia
| | - K A Newell
- Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia,Schizophrenia Research Institute, Darlinghurst, NSW, Australia
| | - C Pantelis
- Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne and Melbourne Health, Melbourne, VIC, Australia
| | - X F Huang
- Centre for Translational Neuroscience, Illawarra Health and Medical Research Institute, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia,Schizophrenia Research Institute, Darlinghurst, NSW, Australia
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Yanev S, Aloe L, Fiore M, Chaldakov GN. Neurotrophic and metabotrophic potential of nerve growth factor and brain-derived neurotrophic factor: Linking cardiometabolic and neuropsychiatric diseases. World J Pharmacol 2013; 2:92-99. [DOI: 10.5497/wjp.v2.i4.92] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 09/20/2013] [Accepted: 10/16/2013] [Indexed: 02/06/2023] Open
Abstract
One of biggest recent achievements of neurobiology is the study on neurotrophic factors. The neurotrophins are exciting examples of these factors. They belong to a family of proteins consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), NT-4/5, NT-6, and NT-7. Today, NGF and BDNF are well recognized to mediate a dizzying number of trophobiological effects, ranging from neurotrophic through immunotrophic and epitheliotrophic to metabotrophic effects. These are implicated in the pathogenesis of various diseases. In the same vein, recent studies in adipobiology reveal that this tissue is the body’s largest endocrine and paracrine organ producing multiple signaling proteins collectively termed adipokines, with NGF and BDNF being also produced from adipose tissue. Altogether, neurobiology and adipobiology contribute to the improvement of our knowledge on diseases beyond obesity such as cardiometabolic (atherosclerosis, type 2 diabetes, and metabolic syndrome) and neuropsychiatric (e.g., Alzheimer’s disease and depression) diseases. The present review updates evidence for (1) neurotrophic and metabotrophic potentials of NGF and BDNF linking the pathogenesis of these diseases, and (2) NGF- and BDNF-mediated effects in ampakines, NMDA receptor antagonists, antidepressants, selective deacetylase inhibitors, statins, peroxisome proliferator-activated receptor gamma agonists, and purinergic P2X3 receptor up-regulation. This may help to construct a novel paradigm in the field of translational pharmacology of neuro-metabotrophins, particularly NGF and BDNF.
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Thomas J, Garg ML, Smith DW. Altered expression of histone and synaptic plasticity associated genes in the hippocampus of streptozotocin-induced diabetic mice. Metab Brain Dis 2013; 28:613-8. [PMID: 23832395 DOI: 10.1007/s11011-013-9418-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2013] [Accepted: 06/25/2013] [Indexed: 02/04/2023]
Abstract
Accumulating evidence indicates that hyper-glycaemia is deleterious to brain function, in particular to the hippocampus. It is thought this hippocampal dysfunction may contribute to hyperglycaemia related cognitive impairment, such as that which manifests with diabetes. In the present study, we investigated the effects of diabetes-related hyperglycaemia on hippocampal gene expression, in order to identify potential mechanisms that might be associated with the cognitive dysfunction that develops with diabetes mellitus. Genome-wide gene expression profiling was carried out on the hippocampi from streptozotocin (STZ)-induced diabetic mice, and from vehicle treated control mice. Genes of interest that satisfied expression fold-change and statistical criteria, and that were considered to be potentially associated with cognitive function, were further tested by real time, quantitative polymerase chain reaction (qPCR) analysis. We found that STZ-induced diabetes resulted in decreased hippocampal expression of genes involved in epigenetic regulation and synaptic plasticity, for example, histone deacetylases and glycogen synthase kinase 3 beta (HDACs and GSK3β). We also found increased expression of genes involved in signalling cascades related to cell growth, cell survival and energy metabolism, such as neurotropic tyrosine kinase receptor type 2, apolipoprotein E, and protein tyrosine phosphatase receptor type (Ntrk2, APOE, PTPRT). To our knowledge this is the first study to demonstrate a gene expression profile implicating epigenetic modifications and alterations of synaptic plasticity associated genes in diabetes mellitus. The present study will improve our understanding of the neural mechanisms that might underpin diabetes-related cognitive dysfunction.
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Affiliation(s)
- Jency Thomas
- University of Newcastle, Callaghan, NSW, Australia
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Lifestyle modification and behavior therapy effectively reduce body weight and increase serum level of brain-derived neurotrophic factor in obese non-diabetic patients with schizophrenia. Psychiatry Res 2013; 209:150-4. [PMID: 23219101 DOI: 10.1016/j.psychres.2012.11.020] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Revised: 09/30/2012] [Accepted: 11/12/2012] [Indexed: 12/21/2022]
Abstract
The goal of the study was to elucidate the relationship between serum circulating brain-derived neurotrophic factor (BDNF) and body weight reduction via lifestyle modification and behavior therapy in obese non-diabetic patients with chronic schizophrenia. Thirty-three obese non-diabetic subjects with schizophrenia treated with stable antipsychotic medication in a day-care unit for at least 3 months were recruited. Thirty age-, body weight-matched subjects without psychiatric disorders were enrolled as controls. All participants underwent a 10-week weight reduction program, including lifestyle modification, psychosocial treatment, behavior therapy and exercise in the day-care unit. Blood biochemistry, serum BDNF, adipokine (adiponectin), inflammatory markers (C-reactive protein, tumor necrosis factor-alpha and interleukin-6) and oral glucose tolerance test were evaluated before and after the program. Serum BDNF concentrations were significantly lower among patients with schizophrenia compared to control subjects. Serum BDNF levels were significantly increased following the weight reduction program. Elevations in serum BDNF levels were positively correlated with body weight and body mass index reduction. Altogether, our results demonstrate that a non-pharmacological weight reduction program effectively reduces body weight with significant elevation of serum BDNF levels in obese non-diabetic patients with schizophrenia.
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Abstract
Major depression is characterized by low mood, a reduced ability to experience pleasure and frequent cognitive, physiological and high anxiety symptoms. It is also the leading cause of years lost due to disability worldwide in women and men, reflecting a lifelong trajectory of recurring episodes, increasing severity and progressive treatment resistance. Yet, antidepressant drugs at best treat only one out of every two patients and have not fundamentally changed since their discovery by chance >50 yr ago. This status quo may reflect an exaggerated emphasis on a categorical disease classification that was not intended for biological research and on oversimplified gene-to-disease models for complex illnesses. Indeed, genetic, molecular and cellular findings in major depression suggest shared risk and continuous pathological changes with other brain-related disorders. So, an alternative is that pathological findings in major depression reflect changes in vulnerable brain-related biological modules, each with their own aetiological factors, pathogenic mechanisms and biological/environment moderators. In this model, pathological entities have low specificity for major depression and instead co-occur, combine and interact within individual subjects across disorders, contributing to the expression of biological endophenotypes and potentially clinical symptom dimensions. Here, we discuss current limitations in depression research, review concepts of gene-to-disease biological scales and summarize human post-mortem brain findings related to pyramidal neurons, γ-amino butyric acid neurons, astrocytes and oligodendrocytes, as prototypical brain circuit biological modules. Finally we discuss nested aetiological factors and implications for dimensional pathology. Evidence suggests that a focus on local cell circuits may provide an appropriate integration point and a critical link between underlying molecular mechanisms and neural network dysfunction in major depression.
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Baudry M, Bi X, Aguirre C. Progesterone-estrogen interactions in synaptic plasticity and neuroprotection. Neuroscience 2013; 239:280-94. [PMID: 23142339 PMCID: PMC3628409 DOI: 10.1016/j.neuroscience.2012.10.051] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Revised: 10/23/2012] [Accepted: 10/26/2012] [Indexed: 01/01/2023]
Abstract
17ß-Estradiol and progesterone exert a number of physiological effects throughout the brain due to interactions with several types of receptors belonging to the traditional family of intracellular hormonal receptors as well as to membrane-bound receptors. In particular, both hormones elicit rapid modifications of neuronal excitability that have been postulated to underlie their effects on synaptic plasticity and learning and memory. Likewise, both hormones have been shown to be neuroprotective under certain conditions, possibly due to the activation of pro-survival pathways and the inhibition of pro-apoptotic cascades. Because of the similarities in their cellular effects, there have been a number of questions raised by numerous observations that progesterone inhibits the effects of estrogen. In this manuscript, we first review the interactions between 17ß-estradiol (E2) and progesterone (P4) in synaptic plasticity, and conclude that, while E2 exerts a clear and important role in long-term potentiation of synaptic transmission in hippocampal neurons, the role of P4 is much less clear, and could be accounted by the direct or indirect regulation of GABAA receptors. We then discuss the neuroprotective roles of both hormones, in particular against excitotoxicity. In this case, the neuroprotective effects of these hormones are very similar to those of the neurotrophic factor BDNF. Interestingly, P4 antagonizes the effects of E2, possibly through the regulation of estrogen receptors or of proteins associated with the receptors or interactions with signaling pathways activated by E2. Overall, this review emphasizes the existence of common molecules and pathways that participate in the regulation of both synaptic plasticity and neurodegeneration.
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Affiliation(s)
- M Baudry
- GCBS and COMP, Western University of Health Sciences, Pomona, CA, USA.
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Singer W, Panford-Walsh R, Knipper M. The function of BDNF in the adult auditory system. Neuropharmacology 2013; 76 Pt C:719-28. [PMID: 23688926 DOI: 10.1016/j.neuropharm.2013.05.008] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 05/03/2013] [Accepted: 05/06/2013] [Indexed: 02/06/2023]
Abstract
The inner ear of vertebrates is specialized to perceive sound, gravity and movements. Each of the specialized sensory organs within the cochlea (sound) and vestibular system (gravity, head movements) transmits information to specific areas of the brain. During development, brain-derived neurotrophic factor (BDNF) orchestrates the survival and outgrowth of afferent fibers connecting the vestibular organ and those regions in the cochlea that map information for low frequency sound to central auditory nuclei and higher-auditory centers. The role of BDNF in the mature inner ear is less understood. This is mainly due to the fact that constitutive BDNF mutant mice are postnatally lethal. Only in the last few years has the improved technology of performing conditional cell specific deletion of BDNF in vivo allowed the study of the function of BDNF in the mature developed organ. This review provides an overview of the current knowledge of the expression pattern and function of BDNF in the peripheral and central auditory system from just prior to the first auditory experience onwards. A special focus will be put on the differential mechanisms in which BDNF drives refinement of auditory circuitries during the onset of sensory experience and in the adult brain. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.
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Affiliation(s)
- Wibke Singer
- University of Tübingen, Department of Otolaryngology, Head and Neck Surgery, Tübingen Hearing Research Centre (THRC), Molecular Physiology of Hearing, Elfriede-Aulhorn-Straße 5, 72076 Tübingen, Germany
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Nicotine restores Wt-like levels of reelin and GAD67 gene expression in brain of heterozygous reeler mice. Neurotox Res 2013; 24:205-15. [PMID: 23385624 DOI: 10.1007/s12640-013-9378-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 01/15/2013] [Accepted: 01/21/2013] [Indexed: 12/11/2022]
Abstract
Important reduction of reelin, a neural development- and plasticity-associated protein, and glutamic acid decarboxylase (GAD67) are reported in brains of schizophrenic patients. These individuals are consistently engaged in tobacco smoking and nicotine is thought to alleviate negative behavioral symptoms or cognitive alterations. In mouse brain, nicotine has been shown to reduce GAD67 promoter methylation and increase its transcription. We assessed the effects of administration of nicotine (1 mg/kg s.c.) for 6 days, in male mice heterozygous for reelin (HRM), a putative model for symptoms related to schizophrenia. Expression of reelin, GAD67 and brain-derived neurotrophic factor (BDNF) was measured in different brain areas. RNA expression analysis evidenced genotype-related changes, with a marked reduction in reelin and GAD67 gene expression in prefrontal cortex, hippocampus, cerebellum, and striatum from HRM. Nicotine treatment selectively reversed the HRM-related phenotype in most brain areas and increased BDNF gene expression in cortex and hippocampus of both genotypes. Locomotor performance in their home cage revealed that HRM subjects were characterized by general hyperactivity; with nicotine administration restoring WT-like levels of locomotion. These findings are interpreted within the hypothesis of pre-existing vulnerability (based on haploinsufficiency of reelin) to brain and behavioral disorders and regulative effects associated with nicotine exposure.
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Pandya CD, Kutiyanawalla A, Pillai A. BDNF-TrkB signaling and neuroprotection in schizophrenia. Asian J Psychiatr 2013; 6:22-8. [PMID: 23380313 PMCID: PMC3565158 DOI: 10.1016/j.ajp.2012.08.010] [Citation(s) in RCA: 77] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2012] [Accepted: 08/20/2012] [Indexed: 01/18/2023]
Abstract
Neurotrophins such as brain-derived neurotropic factor (BDNF), play critical role in neuronal survival, synaptic plasticity and cognitive functions. BDNF is known to mediate its action through various intracellular signaling pathways triggered by activation of tyrosine kinase receptor B (TrkB). Evidence from clinical as well pre-clinical studies indicate alterations in BDNF signaling in schizophrenia. Moreover, several antipsychotic drugs have time-dependent effects on BDNF levels in both schizophrenia subjects and animal models of schizophrenia. Given the emerging interest in neuroplasticity in schizophrenia understanding the neuroprotective and cell survival roles of BDNF signaling will enhance our knowledge of its diverse effects, which may lead to more effective treatments for schizophrenia. This article will present an overview of recent findings on the role of BDNF signaling in the pathophysiology and treatment of schizophrenia, with a special focus on its neuroprotective effects.
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Affiliation(s)
- Chirayu D Pandya
- Department of Psychiatry and Health Behavior, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA 30912, USA
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Zheng F, Zhou X, Moon C, Wang H. Regulation of brain-derived neurotrophic factor expression in neurons. INTERNATIONAL JOURNAL OF PHYSIOLOGY, PATHOPHYSIOLOGY AND PHARMACOLOGY 2012; 4:188-200. [PMID: 23320132 PMCID: PMC3544221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 12/22/2012] [Indexed: 06/01/2023]
Abstract
Brain-derived neurotrophic factor (BDNF) plays critical roles in many aspects of brain functions, including cell survival, differentiation, development, learning and memory. Aberrant BDNF expression has also been implicated in numerous neurological disorders. Thus, significant effort has been made to understand how BDNF transcription as well as translation is regulated. Interestingly, the BDNF gene structure suggests that multiple promoters control its transcription, leading to the existence of distinct mRNA species. Further, the long- and short-tail of the 3'un-translated region may dictate different sub-cellular BDNF mRNA targeting and translational responses following neuronal stimulation. This review aims to summarize the main findings that demonstrate how neuronal activities specifically up-regulate the transcription and translation of unique BDNF transcripts. We also discuss some of the recent reports that emphasize the epigenetic regulation of BDNF transcription.
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Affiliation(s)
- Fei Zheng
- Department of Biochemistry, St. Jude Children’s Research HospitalMemphis, TN38105, USA
| | - Xianju Zhou
- Department of Neurology, Changzhou No. 2 People’s Hospital, The affiliated Hospital of Nanjing Medical University29 Xinglong Alley, Changzhou, 213003, People’s Republic of China
| | - Changjong Moon
- College of Veterinary Medicine, Chonnam National University and Animal Medical InstituteGwangju 500-757, South Korea
| | - Hongbing Wang
- Department of Physiology, Neuroscience Program, Michigan State UniversityEast Lansing, MI 48824, USA
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Nurjono M, Lee J, Chong SA. A Review of Brain-derived Neurotrophic Factor as a Candidate Biomarker in Schizophrenia. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2012; 10:61-70. [PMID: 23431036 PMCID: PMC3569148 DOI: 10.9758/cpn.2012.10.2.61] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Accepted: 04/26/2012] [Indexed: 12/21/2022]
Abstract
Brain-derived neurotrophic factor (BDNF), a neurotrophin known to be responsible for development, regeneration, survival and maintenance of neurons has been implicated in the pathophysiology of schizophrenia. This review seeks to complement previous reviews on biological roles of BDNF and summarizes evidence on the involvement of BDNF in the pathophysiology of schizophrenia with an emphasis on clinical relevance. The expressions of BDNF were altered in patients with schizophrenia and were found to be correlated with psychotic symptomatology. Antipsychotics appeared to have differential effects on expression of BDNF but did not restore BDNF expression of patients with schizophrenia to normal levels. In addition, evidence suggests that BDNF is involved in the major neurotransmitter systems and is associated with disruptions in brain structure, neurodevelopmental process, cognitive function, metabolic and immune systems commonly associated with schizophrenia. Besides that, BDNF has been demonstrated to be tightly regulated with estrogen which has also been previously implicated in schizophrenia. Evidence gathered in this review confirms the relevance of BDNF in the pathophysiology of schizophrenia and the potential utility of BDNF as a suitable biomarker for diagnostic and prognostic purposes for disease outcome and other co-morbidities. However, further investigations are warranted to examine the specificity of BDNF in schizophrenia compared to other neurodegenerative disorders and other neuropsychiatric illness. Longitudinal prospective studies will also be of added advantage for evaluation of prognostic utility of BDNF in schizophrenia.
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Affiliation(s)
- Milawaty Nurjono
- Research Division, Institute of Mental Health/Woodbridge Hospital, Singapore
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Lack of brain-derived neurotrophic factor hampers inner hair cell synapse physiology, but protects against noise-induced hearing loss. J Neurosci 2012; 32:8545-53. [PMID: 22723694 DOI: 10.1523/jneurosci.1247-12.2012] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The precision of sound information transmitted to the brain depends on the transfer characteristics of the inner hair cell (IHC) ribbon synapse and its multiple contacting auditory fibers. We found that brain derived neurotrophic factor (BDNF) differentially influences IHC characteristics in the intact and injured cochlea. Using conditional knock-out mice (BDNF(Pax2) KO) we found that resting membrane potentials, membrane capacitance and resting linear leak conductance of adult BDNF(Pax2) KO IHCs showed a normal maturation. Likewise, in BDNF(Pax2) KO membrane capacitance (ΔC(m)) as a function of inward calcium current (I(Ca)) follows the linear relationship typical for normal adult IHCs. In contrast the maximal ΔC(m), but not the maximal size of the calcium current, was significantly reduced by 45% in basal but not in apical cochlear turns in BDNF(Pax2) KO IHCs. Maximal ΔC(m) correlated with a loss of IHC ribbons in these cochlear turns and a reduced activity of the auditory nerve (auditory brainstem response wave I). Remarkably, a noise-induced loss of IHC ribbons, followed by reduced activity of the auditory nerve and reduced centrally generated wave II and III observed in control mice, was prevented in equally noise-exposed BDNF(Pax2) KO mice. Data suggest that BDNF expressed in the cochlea is essential for maintenance of adult IHC transmitter release sites and that BDNF upholds opposing afferents in high-frequency turns and scales them down following noise exposure.
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Neto FL, Borges G, Torres-Sanchez S, Mico JA, Berrocoso E. Neurotrophins role in depression neurobiology: a review of basic and clinical evidence. Curr Neuropharmacol 2012; 9:530-52. [PMID: 22654714 PMCID: PMC3263450 DOI: 10.2174/157015911798376262] [Citation(s) in RCA: 110] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2010] [Revised: 08/18/2010] [Accepted: 08/09/2010] [Indexed: 01/02/2023] Open
Abstract
Depression is a neuropsychiatric disorder affecting a huge percentage of the active population especially in developed countries. Research has devoted much of its attention to this problematic and many drugs have been developed and are currently prescribed to treat this pathology. Yet, many patients are refractory to the available therapeutic drugs, which mainly act by increasing the levels of the monoamines serotonin and noradrenaline in the synaptic cleft. Even in the cases antidepressants are effective, it is usually observed a delay of a few weeks between the onset of treatment and remission of the clinical symptoms. Additionally, many of these patients who show remission with antidepressant therapy present a relapse of depression upon treatment cessation. Thus research has focused on other possible molecular targets, besides monoamines, underlying depression. Both basic and clinical evidence indicates that depression is associated with
several structural and neurochemical changes where the levels of neurotrophins, particularly of brain-derived neurotrophic factor (BDNF), are altered. Antidepressants, as well as other therapeutic strategies, seem to restore these levels. Neuronal atrophy, mostly detected in limbic structures that regulate mood and cognition, like the hippocampus, is observed in depressed patients and in animal behavioural paradigms for depression. Moreover, chronic antidepressant treatment enhances adult hippocampal neurogenesis, supporting the notion that this event underlies antidepressants effects. Here we review some of the preclinical and clinical studies, aimed at disclosing the role of neurotrophins in the pathophysiological
mechanisms of depression and the mode of action of antidepressants, which favour the neurotrophic/neurogenic hypothesis.
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Affiliation(s)
- Fani L Neto
- Instituto de Histologia e Embriologia, Faculdade de Medicina e IBMC, Universidade do Porto, 4200-319, Porto, Portugal
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