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1
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Liu Y, Whitfield TW, Bell GW, Guo R, Flamier A, Young RA, Jaenisch R. Exploring the complexity of MECP2 function in Rett syndrome. Nat Rev Neurosci 2025:10.1038/s41583-025-00926-1. [PMID: 40360671 DOI: 10.1038/s41583-025-00926-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/23/2025] [Indexed: 05/15/2025]
Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder that is mainly caused by mutations in the methyl-DNA-binding protein MECP2. MECP2 is an important epigenetic regulator that plays a pivotal role in neuronal gene regulation, where it has been reported to function as both a repressor and an activator. Despite extensive efforts in mechanistic studies over the past two decades, a clear consensus on how MECP2 dysfunction impacts molecular mechanisms and contributes to disease progression has not been reached. Here, we review recent insights from epigenomic, transcriptomic and proteomic studies that advance our understanding of MECP2 as an interacting hub for DNA, RNA and transcription factors, orchestrating diverse processes that are crucial for neuronal function. By discussing findings from different model systems, we identify crucial epigenetic details and cofactor interactions, enriching our understanding of the multifaceted roles of MECP2 in transcriptional regulation and chromatin structure. These mechanistic insights offer potential avenues for rational therapeutic design for RTT.
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Affiliation(s)
- Yi Liu
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | | | - George W Bell
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | - Ruisi Guo
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
| | - Anthony Flamier
- Department of Neuroscience, Université de Montréal, Montreal, Quebec, Canada
- CHU Sainte-Justine Research Center, Montreal, Quebec, Canada
| | - Richard A Young
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Rudolf Jaenisch
- Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
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2
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Haimson B, Mizrahi A. Integrating innate and learned behavior through brain circuits. Trends Neurosci 2025; 48:319-329. [PMID: 40169295 DOI: 10.1016/j.tins.2025.03.002] [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: 12/14/2024] [Revised: 02/28/2025] [Accepted: 03/07/2025] [Indexed: 04/03/2025]
Abstract
Understanding how innate predispositions and learned experiences interact to shape behavior is a central question in systems neuroscience. Traditionally, innate behaviors, that is, those present without prior learning and governed by evolutionarily conserved neural circuits, have been studied separately from learned behaviors, which depend on experience and neural plasticity. This division has led to a compartmentalized view of behavior and neural circuit organization. Increasing evidence suggests that innate and learned behaviors are not independent, but rather deeply intertwined, with plasticity evident even in circuits classically considered 'innate'. In this opinion, we highlight examples across species that illustrate the dynamic interaction between these behavioral domains and discuss the implications for unifying theoretical and empirical frameworks. We argue that a more integrative approach, namely one that acknowledges the reciprocal influences of innate and learned processes, is essential for advancing our understanding of how neuronal activity drives complex behaviors.
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Affiliation(s)
- Baruch Haimson
- The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Adi Mizrahi
- The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, Jerusalem, Israel; Department of Life Sciences, The Hebrew University of Jerusalem, Israel.
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3
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Nowlan AC, Choe J, Tromblee H, Kelahan C, Hellevik K, Shea SD. Multisensory integration of social signals by a pathway from the basal amygdala to the auditory cortex in maternal mice. Curr Biol 2025; 35:36-49.e4. [PMID: 39631401 PMCID: PMC11809444 DOI: 10.1016/j.cub.2024.10.078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Revised: 10/03/2024] [Accepted: 10/30/2024] [Indexed: 12/07/2024]
Abstract
Social encounters are inherently multisensory events, yet how and where social cues of distinct sensory modalities merge and interact in the brain is poorly understood. When their pups wander away from the nest, mother mice use a combination of vocal and olfactory signals emitted by the pups to locate and retrieve them. Previous work revealed the emergence of multisensory interactions in the auditory cortex (AC) of both dams and virgins who cohabitate with pups ("surrogates"). Here, we identify a neural pathway that relays information about odors to the AC to be integrated with responses to sound. We found that a scattered population of glutamatergic neurons in the basal amygdala (BA) projects to the AC and responds to odors, including the smell of pups. These neurons exhibit increased activity when the female is searching for pups that terminates upon contact. Finally, we show that selective optogenetic activation of BA-AC neurons modulates responses to pup calls, and that this modulation switches from predominantly suppressive to predominantly excitatory after maternal experience. This supports an underappreciated role for the amygdala in directly shaping sensory representations in an experience-dependent manner. We propose that the BA-AC pathway supports integration of olfaction and audition to facilitate maternal care and speculate that it may carry valence information to the AC.
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Affiliation(s)
- Alexandra C Nowlan
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
| | - Jane Choe
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
| | - Hoda Tromblee
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
| | - Clancy Kelahan
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
| | - Karin Hellevik
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
| | - Stephen D Shea
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
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Kuroda KO, Fukumitsu K, Kurachi T, Ohmura N, Shiraishi Y, Yoshihara C. Parental brain through time: The origin and development of the neural circuit of mammalian parenting. Ann N Y Acad Sci 2024; 1534:24-44. [PMID: 38426943 DOI: 10.1111/nyas.15111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/02/2024]
Abstract
This review consolidates current knowledge on mammalian parental care, focusing on its neural mechanisms, evolutionary origins, and derivatives. Neurobiological studies have identified specific neurons in the medial preoptic area as crucial for parental care. Unexpectedly, these neurons are characterized by the expression of molecules signaling satiety, such as calcitonin receptor and BRS3, and overlap with neurons involved in the reproductive behaviors of males but not females. A synthesis of comparative ecology and paleontology suggests an evolutionary scenario for mammalian parental care, possibly stemming from male-biased guarding of offspring in basal vertebrates. The terrestrial transition of tetrapods led to prolonged egg retention in females and the emergence of amniotes, skewing care toward females. The nocturnal adaptation of Mesozoic mammalian ancestors reinforced maternal care for lactation and thermal regulation via endothermy, potentially introducing metabolic gate control in parenting neurons. The established maternal care may have served as the precursor for paternal and cooperative care in mammals and also fostered the development of group living, which may have further contributed to the emergence of empathy and altruism. These evolution-informed working hypotheses require empirical validation, yet they offer promising avenues to investigate the neural underpinnings of mammalian social behaviors.
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Affiliation(s)
- Kumi O Kuroda
- RIKEN Center for Brain Science, Saitama, Japan
- School of Life Sciences and Technologies, Tokyo Institute of Technology, Kanagawa, Japan
| | - Kansai Fukumitsu
- RIKEN Center for Brain Science, Saitama, Japan
- Department of Physiology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Takuma Kurachi
- RIKEN Center for Brain Science, Saitama, Japan
- Department of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan
| | - Nami Ohmura
- RIKEN Center for Brain Science, Saitama, Japan
- Center for Brain, Mind and Kansei Sciences Research, Hiroshima University, Hiroshima, Japan
| | - Yuko Shiraishi
- RIKEN Center for Brain Science, Saitama, Japan
- Kawamura Gakuen Woman's University, Chiba, Japan
| | - Chihiro Yoshihara
- RIKEN Center for Brain Science, Saitama, Japan
- School of Life Sciences and Technologies, Tokyo Institute of Technology, Kanagawa, Japan
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Mykins M, Bridges B, Jo A, Krishnan K. Multidimensional Analysis of a Social Behavior Identifies Regression and Phenotypic Heterogeneity in a Female Mouse Model for Rett Syndrome. J Neurosci 2024; 44:e1078232023. [PMID: 38199865 PMCID: PMC10957218 DOI: 10.1523/jneurosci.1078-23.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 11/01/2023] [Accepted: 11/17/2023] [Indexed: 01/12/2024] Open
Abstract
Regression is a key feature of neurodevelopmental disorders such as autism spectrum disorder, Fragile X syndrome, and Rett syndrome (RTT). RTT is caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). It is characterized by an early period of typical development with subsequent regression of previously acquired motor and speech skills in girls. The syndromic phenotypes are individualistic and dynamic over time. Thus far, it has been difficult to capture these dynamics and syndromic heterogeneity in the preclinical Mecp2-heterozygous female mouse model (Het). The emergence of computational neuroethology tools allows for robust analysis of complex and dynamic behaviors to model endophenotypes in preclinical models. Toward this first step, we utilized DeepLabCut, a marker-less pose estimation software to quantify trajectory kinematics and multidimensional analysis to characterize behavioral heterogeneity in Het in the previously benchmarked, ethologically relevant social cognition task of pup retrieval. We report the identification of two distinct phenotypes of adult Het: Het that display a delay in efficiency in early days and then improve over days like wild-type mice and Het that regress and perform worse in later days. Furthermore, regression is dependent on age and behavioral context and can be detected in the initial days of retrieval. Together, the novel identification of two populations of Het suggests differential effects on neural circuitry, opens new avenues to investigate the underlying molecular and cellular mechanisms of heterogeneity, and designs better studies for stratifying therapeutics.
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Affiliation(s)
- Michael Mykins
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee
| | - Benjamin Bridges
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee
| | - Angela Jo
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee
| | - Keerthi Krishnan
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee
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Farhoomand F, Delaney KR. Long-term cortical plasticity following sensory deprivation is reduced in male Rett model mice. Somatosens Mot Res 2023; 40:133-140. [PMID: 36565289 DOI: 10.1080/08990220.2022.2158799] [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: 03/01/2022] [Accepted: 12/08/2022] [Indexed: 12/25/2022]
Abstract
PURPOSE/AIM Rett (RTT) syndrome, a neurodevelopmental disorder, results from loss-of-function mutations in methyl-CpG-binding protein 2. We studied activity-dependent plasticity induced by sensory deprivation via whisker trimming in early symptomatic male mutant mice to assess neural rewiring capability. METHODS One whisker was trimmed for 0-14 days and intrinsic optical imaging of the transient reduction of brain blood oxygenation resulting from neural activation by 1 second of wiggling of the whisker stump was compared to that of an untrimmed control whisker. RESULTS Cortical evoked responses to wiggling a non-trimmed whisker were constant for 14 days, reduced for a trimmed whisker by 49.0 ± 4.3% in wild type (n = 14) but by only 22.7 ± 4.6% in mutant (n = 18, p = 0.001). CONCLUSION As the reduction in neural activation following sensory deprivation in whisker barrel cortex is known to be dependent upon evoked and basal neural activity, impairment of cortical re-wiring following whisker trimming provides a paradigm suitable to explore mechanisms underlying deficiencies in the establishment and maintenance of synapses in RTT, which can be potentially targeted by therapeutics.
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Affiliation(s)
| | - Kerry R Delaney
- Department of Biology, University of Victoria, Victoria, B.C, Canada
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Rupert DD, Pagliaro AH, Choe J, Shea SD. Selective Deletion of Methyl CpG Binding Protein 2 from Parvalbumin Interneurons in the Auditory Cortex Delays the Onset of Maternal Retrieval in Mice. J Neurosci 2023; 43:6745-6759. [PMID: 37625856 PMCID: PMC10552946 DOI: 10.1523/jneurosci.0838-23.2023] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 08/05/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome. MECP2 codes for methyl CpG binding protein 2 (MECP2), a transcriptional regulator that activates genetic programs for experience-dependent plasticity. Many neural and behavioral symptoms of Rett syndrome may result from dysregulated timing and thresholds for plasticity. As a model of adult plasticity, we examine changes to auditory cortex inhibitory circuits in female mice when they are first exposed to pups; this plasticity facilitates behavioral responses to pups emitting distress calls. Brainwide deletion of Mecp2 alters expression of markers associated with GABAergic parvalbumin interneurons (PVins) and impairs the emergence of pup retrieval. We hypothesized that loss of Mecp2 in PVins disproportionately contributes to the phenotype. Here, we find that deletion of Mecp2 from PVins delayed the onset of maternal retrieval behavior and recapitulated the major molecular and neurophysiological features of brainwide deletion of Mecp2 We observed that when PVin-selective mutants were exposed to pups, auditory cortical expression of PVin markers increased relative to that in wild-type littermates. PVin-specific mutants also failed to show the inhibitory auditory cortex plasticity seen in wild-type mice on exposure to pups and their vocalizations. Finally, using an intersectional viral genetic strategy, we demonstrate that postdevelopmental loss of Mecp2 in PVins of the auditory cortex is sufficient to delay onset of maternal retrieval. Our results support a model in which PVins play a central role in adult cortical plasticity and may be particularly impaired by loss of Mecp2 SIGNIFICANCE STATEMENT Rett syndrome is a neurodevelopmental disorder that includes deficits in both communication and the ability to update brain connections and activity during learning (plasticity). This condition is caused by mutations in the gene MECP2 We use a maternal behavioral test in mice requiring both vocal perception and neural plasticity to probe the role of Mecp2 in social and sensory learning. Mecp2 is normally active in all brain cells, but here we remove it from a specific population (parvalbumin neurons). We find that this is sufficient to delay learned behavioral responses to pups and recreates many deficits seen in whole-brain Mecp2 deletion. Our findings suggest that parvalbumin neurons specifically are central to the consequences of loss of Mecp2 activity and yield clues as to possible mechanisms by which Rett syndrome impairs brain function.
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Affiliation(s)
- Deborah D Rupert
- Department of Neurobiology and Behavior and Medical Scientist Training Program, School of Medicine, Stony Brook University, Stony Brook, New York 11794-8434
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724
| | - Alexa H Pagliaro
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724
| | - Jane Choe
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724
| | - Stephen D Shea
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724
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8
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Mykins M, Layo-Carris D, Dunn LR, Skinner DW, McBryar AH, Perez S, Shultz TR, Willems A, Lau BYB, Hong T, Krishnan K. Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome. J Neurosci Res 2023; 101:1236-1258. [PMID: 37026482 PMCID: PMC10332853 DOI: 10.1002/jnr.25190] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 02/07/2023] [Accepted: 03/12/2023] [Indexed: 04/08/2023]
Abstract
Rett syndrome is characterized by an early period of typical development and then, regression of learned motor and speech skills in girls. Loss of MECP2 protein is thought to cause Rett syndrome phenotypes. The specific underlying mechanisms from typical developmental trajectory to regression features throughout life are unclear. Lack of established timelines to study the molecular, cellular, and behavioral features of regression in female mouse models is a major contributing factor. Due to random X-chromosome inactivation, female patients with Rett syndrome and female mouse models for Rett syndrome (Mecp2Heterozygous , Het) express a functional copy of wild-type MECP2 protein in approximately half of all cells. As MECP2 expression is regulated during early postnatal development and experience, we characterized the expression of wild-type MECP2 in the primary somatosensory cortex of female Het mice. Here, we report increased MECP2 levels in non-parvalbumin-positive neurons of 6-week-old adolescent Het relative to age-matched wild-type controls, while also displaying typical levels of perineuronal net expression in the barrel field subregion of the primary somatosensory cortex, mild tactile sensory perception deficits, and efficient pup retrieval behavior. In contrast, 12-week-old adult Het express MECP2 at levels similar to age-matched wild-type mice, show increased perineuronal net expression in the cortex, and display significant tactile sensory perception deficits. Thus, we have identified a set of behavioral metrics and the cellular substrates to study regression during a specific time in the female Het mouse model, which coincides with changes in wild-type MECP2 expression. We speculate that the precocious increase in MECP2 expression within specific cell types of adolescent Het may provide compensatory benefits at the behavioral level, while the inability to further increase MECP2 levels leads to regressive behavioral phenotypes over time.
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Affiliation(s)
- Michael Mykins
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - Dana Layo-Carris
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - Logan Reid Dunn
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - David Wilson Skinner
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - Alexandra Hart McBryar
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - Sarah Perez
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - Trinity Rose Shultz
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - Andrew Willems
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - Billy You Bun Lau
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - Tian Hong
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
| | - Keerthi Krishnan
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, USA
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9
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Haimson B, Mizrahi A. Plasticity in auditory cortex during parenthood. Hear Res 2023; 431:108738. [PMID: 36931020 DOI: 10.1016/j.heares.2023.108738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 02/09/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023]
Abstract
Most animals display robust parental behaviors that support the survival and well-being of their offspring. The manifestation of parental behaviors is accompanied by physiological and hormonal changes, which affect both the body and the brain for better care giving. Rodents exhibit a behavior called pup retrieval - a stereotyped sequence of perception and action - used to identify and retrieve their newborn pups back to the nest. Pup retrieval consists of a significant auditory component, which depends on plasticity in the auditory cortex (ACx). We review the evidence of neural changes taking place in the ACx of rodents during the transition to parenthood. We discuss how the plastic changes both in and out of the ACx support the encoding of pup vocalizations. Key players in the mechanism of this plasticity are hormones and experience, both of which have a clear dynamic signature during the transition to parenthood. Mothers, co caring females, and fathers have been used as models to understand parental plasticity at disparate levels of organization. Yet, common principles of cortical plasticity and the biological mechanisms underlying its involvement in parental behavior are just beginning to be unpacked.
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Affiliation(s)
- Baruch Haimson
- The Edmond and Lily Safra Center for Brain Sciences, and 2Department of Neurobiology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
| | - Adi Mizrahi
- The Edmond and Lily Safra Center for Brain Sciences, and 2Department of Neurobiology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
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10
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Xu P, Yue Y, Su J, Sun X, Du H, Liu Z, Simha R, Zhou J, Zeng C, Lu H. Pattern decorrelation in the mouse medial prefrontal cortex enables social preference and requires MeCP2. Nat Commun 2022; 13:3899. [PMID: 35794118 PMCID: PMC9259602 DOI: 10.1038/s41467-022-31578-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 06/21/2022] [Indexed: 11/08/2022] Open
Abstract
Sociability is crucial for survival, whereas social avoidance is a feature of disorders such as Rett syndrome, which is caused by loss-of-function mutations in MECP2. To understand how a preference for social interactions is encoded, we used in vivo calcium imaging to compare medial prefrontal cortex (mPFC) activity in female wild-type and Mecp2-heterozygous mice during three-chamber tests. We found that mPFC pyramidal neurons in Mecp2-deficient mice are hypo-responsive to both social and nonsocial stimuli. Hypothesizing that this limited dynamic range restricts the circuit's ability to disambiguate coactivity patterns for different stimuli, we suppressed the mPFC in wild-type mice and found that this eliminated both pattern decorrelation and social preference. Conversely, stimulating the mPFC in MeCP2-deficient mice restored social preference, but only if it was sufficient to restore pattern decorrelation. A loss of social preference could thus indicate impaired pattern decorrelation rather than true social avoidance.
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Affiliation(s)
- Pan Xu
- The GW Institute for Neuroscience, The George Washington University, Washington, DC, 20037, USA
- Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC, 20037, USA
- Institute of Basic Science, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China
- Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250000, China
| | - Yuanlei Yue
- The GW Institute for Neuroscience, The George Washington University, Washington, DC, 20037, USA
- Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC, 20037, USA
| | - Juntao Su
- The GW Institute for Neuroscience, The George Washington University, Washington, DC, 20037, USA
| | - Xiaoqian Sun
- Department of Computer Science, School of Engineering and Applied Science, The George Washington University, Washington, DC, 20037, USA
| | - Hongfei Du
- Department of Statistics, Columbian College of Art and Sciences, The George Washington University, Washington, DC, 20037, USA
| | - Zhichao Liu
- Department of Physics, Columbian College of Art and Sciences, The George Washington University, Washington, DC, 20037, USA
- School of Biological Information, Chongqing University of Posts and Telecommunications, Chongqing, 400065, China
| | - Rahul Simha
- Department of Computer Science, School of Engineering and Applied Science, The George Washington University, Washington, DC, 20037, USA
| | - Jianhui Zhou
- Department of Statistics, School of Arts and Sciences, University of Virginia, Charlottesville, VA, 22904, USA
| | - Chen Zeng
- Department of Statistics, Columbian College of Art and Sciences, The George Washington University, Washington, DC, 20037, USA
| | - Hui Lu
- The GW Institute for Neuroscience, The George Washington University, Washington, DC, 20037, USA.
- Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, DC, 20037, USA.
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Gilfarb RA, Leuner B. GABA System Modifications During Periods of Hormonal Flux Across the Female Lifespan. Front Behav Neurosci 2022; 16:802530. [PMID: 35783228 PMCID: PMC9245048 DOI: 10.3389/fnbeh.2022.802530] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 02/21/2022] [Indexed: 01/10/2023] Open
Abstract
The female lifespan is marked by periods of dramatic hormonal fluctuation. Changes in the ovarian hormones estradiol and progesterone, in addition to the progesterone metabolite allopregnanolone, are among the most significant and have been shown to have widespread effects on the brain. This review summarizes current understanding of alterations that occur within the GABA system during the major hormonal transition periods of puberty, the ovarian cycle, pregnancy and the postpartum period, as well as reproductive aging. The functional impacts of altered inhibitory activity during these times are also discussed. Lastly, avenues for future research are identified, which, if pursued, can broaden understanding of the GABA system in the female brain and potentially lead to better treatments for women experiencing changes in brain function at each of these hormonal transition periods.
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Affiliation(s)
- Rachel A. Gilfarb
- Neuroscience Graduate Program, The Ohio State University, Columbus, OH, United States
| | - Benedetta Leuner
- Department of Psychology, The Ohio State University, Columbus, OH, United States
- Department of Neuroscience, The Ohio State University, Columbus, OH, United States
- *Correspondence: Benedetta Leuner,
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12
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Zhang WJ, Shi LL, Zhang L. Dysregulated cortical synaptic plasticity under methyl-CpG binding protein 2 deficiency and its implication in motor impairments. World J Psychiatry 2022; 12:673-682. [PMID: 35663301 PMCID: PMC9150038 DOI: 10.5498/wjp.v12.i5.673] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/16/2021] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
Caused by the mutation of methyl-CpG binding protein 2 (MeCP2), Rett syndrome leads to a battery of severe neural dysfunctions including the regression of motor coordination and motor learning. Current understanding has revealed the motor cortex as the critical region mediating voluntary movement. In this review article, we will summarize major findings from human patients and animal models regarding the cortical synaptic plasticity under the regulation of MeCP2. We will also discuss how mutation of MeCP2 leads to the disruption of cortical circuitry homeostasis to cause motor deficits. Lastly, potential values of physical exercise and neuromodulation approaches to recover neural plasticity and motor function will be evaluated. All of this evidence may help to accelerate timely diagnosis and effective interventions for Rett syndrome patients.
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Affiliation(s)
- Wei-Jia Zhang
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Ling-Ling Shi
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou 510632, Guangdong Province, China
| | - Li Zhang
- GHM Institute of CNS Regeneration, Jinan University, Guangzhou 510632, Guangdong Province, China
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13
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Rupert DD, Shea SD. Parvalbumin-Positive Interneurons Regulate Cortical Sensory Plasticity in Adulthood and Development Through Shared Mechanisms. Front Neural Circuits 2022; 16:886629. [PMID: 35601529 PMCID: PMC9120417 DOI: 10.3389/fncir.2022.886629] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/30/2022] [Indexed: 11/13/2022] Open
Abstract
Parvalbumin-positive neurons are the largest class of GABAergic, inhibitory neurons in the central nervous system. In the cortex, these fast-spiking cells provide feedforward and feedback synaptic inhibition onto a diverse set of cell types, including pyramidal cells, other inhibitory interneurons, and themselves. Cortical inhibitory networks broadly, and cortical parvalbumin-expressing interneurons (cPVins) specifically, are crucial for regulating sensory plasticity during both development and adulthood. Here we review the functional properties of cPVins that enable plasticity in the cortex of adult mammals and the influence of cPVins on sensory activity at four spatiotemporal scales. First, cPVins regulate developmental critical periods and adult plasticity through molecular and structural interactions with the extracellular matrix. Second, they activate in precise sequence following feedforward excitation to enforce strict temporal limits in response to the presentation of sensory stimuli. Third, they implement gain control to normalize sensory inputs and compress the dynamic range of output. Fourth, they synchronize broad network activity patterns in response to behavioral events and state changes. Much of the evidence for the contribution of cPVins to plasticity comes from classic models that rely on sensory deprivation methods to probe experience-dependent changes in the brain. We support investigating naturally occurring, adaptive cortical plasticity to study cPVin circuits in an ethologically relevant framework, and discuss recent insights from our work on maternal experience-induced auditory cortical plasticity.
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Affiliation(s)
- Deborah D. Rupert
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States
- Medical Scientist Training Program, Stony Brook University, Stony Brook, NY, United States
| | - Stephen D. Shea
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States
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14
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Fuentes I, Morishita Y, Gonzalez-Salinas S, Champagne FA, Uchida S, Shumyatsky GP. Experience-Regulated Neuronal Signaling in Maternal Behavior. Front Mol Neurosci 2022; 15:844295. [PMID: 35401110 PMCID: PMC8987921 DOI: 10.3389/fnmol.2022.844295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 02/28/2022] [Indexed: 11/13/2022] Open
Abstract
Maternal behavior is shaped and challenged by the changing developmental needs of offspring and a broad range of environmental factors, with evidence indicating that the maternal brain exhibits a high degree of plasticity. This plasticity is displayed within cellular and molecular systems, including both intra- and intercellular signaling processes as well as transcriptional profiles. This experience-associated plasticity may have significant overlap with the mechanisms controlling memory processes, in particular those that are activity-dependent. While a significant body of work has identified various molecules and intracellular processes regulating maternal care, the role of activity- and experience-dependent processes remains unclear. We discuss recent progress in studying activity-dependent changes occurring at the synapse, in the nucleus, and during the transport between these two structures in relation to maternal behavior. Several pre- and postsynaptic molecules as well as transcription factors have been found to be critical in these processes. This role reflects the principal importance of the molecular and cellular mechanisms of memory formation to maternal and other behavioral adaptations.
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Affiliation(s)
- Ileana Fuentes
- Department of Genetics, Rutgers University, Piscataway, NJ, United States
| | | | | | - Frances A. Champagne
- Department of Psychology, University of Texas at Austin, Austin, TX, United States
| | - Shusaku Uchida
- SK Project, Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Gleb P. Shumyatsky
- Department of Genetics, Rutgers University, Piscataway, NJ, United States
- *Correspondence: Gleb P. Shumyatsky
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15
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Li W. Excitation and Inhibition Imbalance in Rett Syndrome. Front Neurosci 2022; 16:825063. [PMID: 35250460 PMCID: PMC8894599 DOI: 10.3389/fnins.2022.825063] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
A loss of the excitation/inhibition (E/I) balance in the neural circuit has emerged as a common neuropathological feature in many neurodevelopmental disorders. Rett syndrome (RTT), a prevalent neurodevelopmental disorder that affects 1:10,000-15,000 women globally, is caused by loss-of-function mutations in the Methyl-CpG-binding Protein-2 (Mecp2) gene. E/I imbalance is recognized as the leading cellular and synaptic hallmark that is fundamental to diverse RTT neurological symptoms, including stereotypic hand movements, impaired motor coordination, breathing irregularities, seizures, and learning/memory dysfunctions. E/I balance in RTT is not homogeneously altered but demonstrates brain region and cell type specificity instead. In this review, I elaborate on the current understanding of the loss of E/I balance in a range of brain areas at molecular and cellular levels. I further describe how the underlying cellular mechanisms contribute to the disturbance of the proper E/I ratio. Last, I discuss current pharmacologic innervations for RTT and their role in modifying the E/I balance.
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Affiliation(s)
- Wei Li
- Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL, United States
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16
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Abstract
Members of the order Rodentia are among the best-studied mammals for understanding the patterns, outcomes, and biological determinants of maternal and paternal caregiving. This research has provided a wealth of information but has historically focused on just a few rodents, mostly members of the two Myomorpha families that easily breed and can be studied within a laboratory setting (including laboratory rats, mice, hamsters, voles, gerbils). It is unclear how well this small collection of animals represents the over 2000 species of extant rodents. This chapter provides an overview of the hormonal and neurobiological systems involved in parental care in rodents, with a purposeful eye on providing information known or could be gleaned about parenting in various less-traditional members of Rodentia. We conclude from this analysis that the few commonly studied rodents are not necessarily even representative of the highly diverse members of Myomorpha, let alone other rodent suborders, and that additional laboratory and field studies of members of this order more broadly would surely provide invaluable information toward revealing a more representative picture of the rich diversity in rodent parenting.
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Affiliation(s)
- Mariana Pereira
- Department of Psychological and Brain Sciences, University of Massachusetts, Amherst, MA, USA
| | - Kristina O Smiley
- Centre for Neuroendocrinology & Department of Anatomy, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Joseph S Lonstein
- Department of Psychology & Neuroscience Program, Michigan State University, East Lansing, MI, USA.
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17
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Abellán-Álvaro M, Stork O, Agustín-Pavón C, Santos M. MeCP2 haplodeficiency and early-life stress interaction on anxiety-like behavior in adolescent female mice. J Neurodev Disord 2021; 13:59. [PMID: 34895132 PMCID: PMC8903671 DOI: 10.1186/s11689-021-09409-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/30/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Early-life stress can leave persistent epigenetic marks that may modulate vulnerability to psychiatric conditions later in life, including anxiety, depression and stress-related disorders. These are complex disorders with both environmental and genetic influences contributing to their etiology. Methyl-CpG Binding Protein 2 (MeCP2) has been attributed a key role in the control of neuronal activity-dependent gene expression and is a master regulator of experience-dependent epigenetic programming. Moreover, mutations in the MECP2 gene are the primary cause of Rett syndrome and, to a lesser extent, of a range of other major neurodevelopmental disorders. Here, we aim to study the interaction of MeCP2 with early-life stress in variables known to be affected by this environmental manipulation, namely anxiety-like behavior and activity of the underlying neural circuits. METHODS Using Mecp2 heterozygous and wild-type female mice we investigated the effects of the interaction of Mecp2 haplodeficiency with maternal separation later in life, by assessing anxiety-related behaviors and measuring concomitant c-FOS expression in stress- and anxiety-related brain regions of adolescent females. Moreover, arginine vasopressin and corticotropin-releasing hormone neurons of the paraventricular hypothalamic nucleus were analyzed for neuronal activation. RESULTS In wild-type mice, maternal separation caused a reduction in anxiety-like behavior and in the activation of the hypothalamic paraventricular nucleus, specifically in corticotropin-releasing hormone-positive cells, after the elevated plus maze. This effect of maternal separation was not observed in Mecp2 heterozygous females that per se show decreased anxiety-like behavior and concomitant decreased paraventricular nuclei activation. CONCLUSIONS Our data supports that MeCP2 is an essential component of HPA axis reprogramming and underlies the differential response to anxiogenic situations later in life.
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Affiliation(s)
- María Abellán-Álvaro
- Unitat Mixta d'Investigació en Neuroanatomia Funcional, Departamento de Biologia Cel·lular, Biologia Funcional i Antropologia Física, Universitat de València, 46100 Burjassot, València, Spain
| | - Oliver Stork
- Department of Genetics and Molecular Neurobiology, Institute of Biology, Otto-von-Guericke University, 39120, Magdeburg, Germany
| | - Carmen Agustín-Pavón
- Unitat Mixta d'Investigació en Neuroanatomia Funcional, Departamento de Biologia Cel·lular, Biologia Funcional i Antropologia Física, Universitat de València, 46100 Burjassot, València, Spain
| | - Mónica Santos
- CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.
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18
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Grieb ZA, Ford EG, Yagan M, Lau BYB, Manfredsson FP, Krishnan K, Lonstein JS. Oxytocin receptors in the midbrain dorsal raphe are essential for postpartum maternal social and affective behaviors. Psychoneuroendocrinology 2021; 131:105332. [PMID: 34182251 PMCID: PMC8405581 DOI: 10.1016/j.psyneuen.2021.105332] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/07/2021] [Accepted: 06/15/2021] [Indexed: 01/23/2023]
Abstract
Oxytocin receptors (OTRs) in the midbrain dorsal raphe (DR; the source of most forebrain serotonin) have recently been identified as a potential pharmacological target for treating numerous psychiatric disorders. However, almost all research on this topic has been conducted on males and the role of DR OTRs in female social and affective behaviors is mostly unknown. This may be particularly relevant during early motherhood, which is a time of high endogenous oxytocin signaling, but also a time of elevated risk for psychiatric dysfunction. To investigate whether OTRs in the DR are necessary for postpartum female social and affective behaviors, we constructed and then injected into the DR an adeno-associated virus permanently expressing an shRNA targeting OTR mRNA. We then observed a suite of social and affective behaviors postpartum. OTR knockdown in the maternal DR led to pup loss after parturition, decreased nursing, increased aggression, and increased behavioral despair. These effects of OTR knockdown in the DR may be due to disrupted neuroplasticity in the primary somatosensory cortex (S1), which mediates maternal sensitivity to the tactile cues from young, as we found significantly more plasticity-restricting perineuronal nets (PNNs) in the S1 rostral barrel field and fewer PNNs in the caudal barrel field of OTR-knockdown mothers. These results demonstrate that OTRs in the midbrain DR are essential for postpartum maternal social and affective behaviors, are involved in postpartum cortical plasticity, and suggest that pharmacotherapies targeting OTRs in the DR could be effective treatments for some peripartum affective disorders.
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Affiliation(s)
- Zachary A Grieb
- Neuroscience Program, Michigan State University, 108 Giltner Hall, East Lansing, MI 48824, USA.
| | - Emma G Ford
- Neuroscience Program, Michigan State University, 108 Giltner Hall, East Lansing, MI 48824, USA
| | - Mahircan Yagan
- Deparment of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA
| | - Billy Y B Lau
- Deparment of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA
| | - Fredric P Manfredsson
- Department of Translational Neuroscience, College of Human Medicine, Michigan State University, 400 Monroe Ave NW, Grand Rapids, MI 49503, USA
| | - Keerthi Krishnan
- Deparment of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA
| | - Joseph S Lonstein
- Neuroscience Program, Michigan State University, 108 Giltner Hall, East Lansing, MI 48824, USA
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19
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Stevenson P, Casenhiser DM, Lau BY, Krishnan K. Systematic analysis of goal-related movement sequences during maternal behaviour in a female mouse model for Rett syndrome. Eur J Neurosci 2021; 54:4528-4549. [PMID: 34043854 PMCID: PMC8450021 DOI: 10.1111/ejn.15327] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 05/17/2021] [Accepted: 05/23/2021] [Indexed: 11/28/2022]
Abstract
Rodent dams seek and gather scattered pups back to the nest (pup retrieval), an essential aspect of maternal care. Systematic analysis of the dynamic sequences of goal-related movements that comprise the entire behavioural sequence, which would be ultimately essential for understanding the underlying neurobiology, is not well-characterized. Here, we present such analysis across 3 days in alloparental female mice (Surrogates or Sur) of two genotypes; Mecp2Heterozygotes (Het), a female mouse model for Rett syndrome and their wild type (WT) siblings. We analysed CBA/CaJ and C57BL/6J WT surrogates for within-strain comparisons. Frame-by-frame analysis over different phases was performed manually using DataVyu software. We previously showed that surrogate Het are inefficient at pup retrieval, by end-point analysis such as latency index and errors. Here, the sequence of searching, pup-approach and successful retrieval streamlines over days for WT, while Het exhibits variations in this pattern. Goal-related movements between Het and WT are similar in other phases, suggesting context-driven atypical patterns in Het during the pup retrieval phase. We identified proximal pup approach and pup grooming as atypical tactile interactions between pups and Het. Day-by-day analysis showed dynamic changes in goal-related movements in individual animals across genotypes and strains. Overall, our approach (1) highlights natural variation in individual mice on different days, (2) establishes a "gold-standard" manually curated dataset to help build behavioural repertoires using machine learning approaches, and (3) suggests atypical tactile sensory processing and possible regression in a female mouse model for Rett syndrome.
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Affiliation(s)
- Parker Stevenson
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996
| | - Devin M. Casenhiser
- Audiology and Speech Pathology Department, University of Tennessee Health Sciences Center, Knoxville, TN 37996
| | - Billy Y.B. Lau
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996
| | - Keerthi Krishnan
- Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996
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20
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Longo F, Klann E. Reciprocal control of translation and transcription in autism spectrum disorder. EMBO Rep 2021; 22:e52110. [PMID: 33977633 PMCID: PMC8183409 DOI: 10.15252/embr.202052110] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/20/2021] [Accepted: 04/19/2021] [Indexed: 12/11/2022] Open
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social communication and the presence of restricted patterns of interest and repetitive behaviors. ASD is genetically heterogeneous and is believed to be caused by both inheritable and de novo gene variations. Studies have revealed an extremely complex genetic landscape of ASD, favoring the idea that mutations in different clusters of genes interfere with interconnected downstream signaling pathways and circuitry, resulting in aberrant behavior. In this review, we describe a select group of candidate genes that represent both syndromic and non-syndromic forms of ASD and encode proteins that are important in transcriptional and translational regulation. We focus on the interplay between dysregulated translation and transcription in ASD with the hypothesis that dysregulation of each synthetic process triggers a feedback loop to act on the other, which ultimately exacerbates ASD pathophysiology. Finally, we summarize findings from interdisciplinary studies that pave the way for the investigation of the cooperative impact of different genes and pathways underlying the development of ASD.
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Affiliation(s)
| | - Eric Klann
- Center for Neural ScienceNew York UniversityNew YorkNYUSA
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21
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Presymptomatic training mitigates functional deficits in a mouse model of Rett syndrome. Nature 2021; 592:596-600. [PMID: 33762729 DOI: 10.1038/s41586-021-03369-7] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 02/17/2021] [Indexed: 01/26/2023]
Abstract
Mutations in the X-linked gene MECP2 cause Rett syndrome, a progressive neurological disorder in which children develop normally for the first one or two years of life before experiencing profound motor and cognitive decline1-3. At present there are no effective treatments for Rett syndrome, but we hypothesized that using the period of normal development to strengthen motor and memory skills might confer some benefit. Here we find, using a mouse model of Rett syndrome, that intensive training beginning in the presymptomatic period dramatically improves the performance of specific motor and memory tasks, and significantly delays the onset of symptoms. These benefits are not observed when the training begins after symptom onset. Markers of neuronal activity and chemogenetic manipulation reveal that task-specific neurons that are repeatedly activated during training develop more dendritic arbors and have better neurophysiological responses than those in untrained animals, thereby enhancing their functionality and delaying symptom onset. These results provide a rationale for genetic screening of newborns for Rett syndrome, as presymptomatic intervention might mitigate symptoms or delay their onset. Similar strategies should be studied for other childhood neurological disorders.
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22
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D'Mello SR. MECP2 and the Biology of MECP2 Duplication Syndrome. J Neurochem 2021; 159:29-60. [PMID: 33638179 DOI: 10.1111/jnc.15331] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/21/2021] [Accepted: 02/18/2021] [Indexed: 11/27/2022]
Abstract
MECP2 duplication syndrome (MDS), a rare X-linked genomic disorder affecting predominantly males, is caused by duplication of the chromosomal region containing the methyl CpG binding protein-2 (MECP2) gene, which encodes methyl-CpG-binding protein 2 (MECP2), a multi-functional protein required for proper brain development and maintenance of brain function during adulthood. Disease symptoms include severe motor and cognitive impairment, delayed or absent speech development, autistic features, seizures, ataxia, recurrent respiratory infections and shortened lifespan. The cellular and molecular mechanisms by which a relatively modest increase in MECP2 protein causes such severe disease symptoms are poorly understood and consequently there are no treatments available for this fatal disorder. This review summarizes what is known to date about the structure and complex regulation of MECP2 and its many functions in the developing and adult brain. Additionally, recent experimental findings on the cellular and molecular underpinnings of MDS based on cell culture and mouse models of the disorder are reviewed. The emerging picture from these studies is that MDS is a neurodegenerative disorder in which neurons die in specific parts of the central nervous system, including the cortex, hippocampus, cerebellum and spinal cord. Neuronal death likely results from astrocytic dysfunction, including a breakdown of glutamate homeostatic mechanisms. The role of elevations in the expression of glial acidic fibrillary protein (GFAP) in astrocytes and the microtubule-associated protein, Tau, in neurons to the pathogenesis of MDS is discussed. Lastly, potential therapeutic strategies to potentially treat MDS are discussed.
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23
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Negwer M, Piera K, Hesen R, Lütje L, Aarts L, Schubert D, Nadif Kasri N. EHMT1 regulates Parvalbumin-positive interneuron development and GABAergic input in sensory cortical areas. Brain Struct Funct 2020; 225:2701-2716. [PMID: 32975655 PMCID: PMC7674571 DOI: 10.1007/s00429-020-02149-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 09/10/2020] [Indexed: 02/08/2023]
Abstract
Mutations in the Euchromatic Histone Methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a rare form of intellectual disability (ID) with strong autistic traits and sensory processing deficits. Proper development of inhibitory interneurons is crucial for sensory function. Here we report a timeline of Parvalbumin-positive (PV+) interneuron development in the three most important sensory cortical areas in the Ehmt1+/- mouse. We find a hitherto unreported delay of PV+ neuron maturation early in sensory development, with layer- and region-specific variability later in development. The delayed PV+ maturation is also reflected in a delayed maturation of GABAergic transmission in Ehmt1+/- auditory cortex, where we find a reduced GABA release probability specifically in putative PV+ synapses. Together with earlier reports of excitatory impairments in Ehmt1+/- neurons, we propose a shift in excitatory-inhibitory balance towards overexcitability in Ehmt1+/- sensory cortices as a consequence of early deficits in inhibitory maturation.
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Affiliation(s)
- Moritz Negwer
- Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB, Nijmegen, The Netherlands
| | - Karol Piera
- Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB, Nijmegen, The Netherlands
| | - Rick Hesen
- Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB, Nijmegen, The Netherlands
| | - Lukas Lütje
- Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB, Nijmegen, The Netherlands
| | - Lynn Aarts
- Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB, Nijmegen, The Netherlands
| | - Dirk Schubert
- Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6500 HB, Nijmegen, The Netherlands
| | - Nael Nadif Kasri
- Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition, and Behaviour, 6500 HB, Nijmegen, The Netherlands.
- Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6500 HB, Nijmegen, The Netherlands.
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24
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Ramirez JM, Karlen-Amarante M, Wang JDJ, Bush NE, Carroll MS, Weese-Mayer DE, Huff A. The Pathophysiology of Rett Syndrome With a Focus on Breathing Dysfunctions. Physiology (Bethesda) 2020; 35:375-390. [PMID: 33052774 PMCID: PMC7864239 DOI: 10.1152/physiol.00008.2020] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/21/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023] Open
Abstract
Rett syndrome (RTT), an X-chromosome-linked neurological disorder, is characterized by serious pathophysiology, including breathing and feeding dysfunctions, and alteration of cardiorespiratory coupling, a consequence of multiple interrelated disturbances in the genetic and homeostatic regulation of central and peripheral neuronal networks, redox state, and control of inflammation. Characteristic breath-holds, obstructive sleep apnea, and aerophagia result in intermittent hypoxia, which, combined with mitochondrial dysfunction, causes oxidative stress-an important driver of the clinical presentation of RTT.
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Affiliation(s)
- Jan-Marino Ramirez
- Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, Washington
- Departments of Neurological Surgery and Pediatrics, University of Washington School of Medicine, Seattle, Washington
| | - Marlusa Karlen-Amarante
- Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, Washington
- Department of Physiology and Pathology, School of Dentistry of Araraquara, São Paulo State University (UNESP), Araraquara, Brazil
| | - Jia-Der Ju Wang
- Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, Washington
| | - Nicholas E Bush
- Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, Washington
| | - Michael S Carroll
- Data Analytics and Reporting, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Division of Autonomic Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Debra E Weese-Mayer
- Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois
- Division of Autonomic Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Alyssa Huff
- Center for Integrative Brain Research, Seattle Children's Research Institute, University of Washington School of Medicine, Seattle, Washington
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25
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Sandweiss AJ, Brandt VL, Zoghbi HY. Advances in understanding of Rett syndrome and MECP2 duplication syndrome: prospects for future therapies. Lancet Neurol 2020; 19:689-698. [PMID: 32702338 DOI: 10.1016/s1474-4422(20)30217-9] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2019] [Revised: 05/07/2020] [Accepted: 05/12/2020] [Indexed: 01/07/2023]
Abstract
The X-linked gene encoding MECP2 is involved in two severe and complex neurodevelopmental disorders. Loss of function of the MeCP2 protein underlies Rett syndrome, whereas duplications of the MECP2 locus cause MECP2 duplication syndrome. Research on the mechanisms by which MeCP2 exerts effects on gene expression in neurons, studies of animal models bearing different disease-causing mutations, and more in-depth observations of clinical presentations have clarified some issues even as they have raised further questions. Yet there is enough evidence so far to suggest possible approaches to therapy for these two diseases that could go beyond attempting to address specific signs and symptoms (of which there are many) and instead target the pathophysiology underlying MECP2 disorders. Further work could bring antisense oligonucleotides, deep brain stimulation, and gene therapy into the clinic within the next decade or so.
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Affiliation(s)
- Alexander J Sandweiss
- Department of Pediatrics, Section of Neurology and Developmental Neurosciences, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA
| | - Vicky L Brandt
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA
| | - Huda Y Zoghbi
- Department of Pediatrics, Section of Neurology and Developmental Neurosciences, Baylor College of Medicine, Houston, TX, USA; Howard Hughes Medical Institute, and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA.
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26
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Adcock KS, Chandler C, Buell EP, Solorzano BR, Loerwald KW, Borland MS, Engineer CT. Vagus nerve stimulation paired with tones restores auditory processing in a rat model of Rett syndrome. Brain Stimul 2020; 13:1494-1503. [PMID: 32800964 DOI: 10.1016/j.brs.2020.08.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 07/26/2020] [Accepted: 08/07/2020] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Rett syndrome is a rare neurological disorder associated with a mutation in the X-linked gene MECP2. This disorder mainly affects females, who typically have seemingly normal early development followed by a regression of acquired skills. The rodent Mecp2 model exhibits many of the classic neural abnormalities and behavioral deficits observed in individuals with Rett syndrome. Similar to individuals with Rett syndrome, both auditory discrimination ability and auditory cortical responses are impaired in heterozygous Mecp2 rats. The development of therapies that can enhance plasticity in auditory networks and improve auditory processing has the potential to impact the lives of individuals with Rett syndrome. Evidence suggests that precisely timed vagus nerve stimulation (VNS) paired with sound presentation can drive robust neuroplasticity in auditory networks and enhance the benefits of auditory therapy. OBJECTIVE The aim of this study was to investigate the ability of VNS paired with tones to restore auditory processing in Mecp2 transgenic rats. METHODS Seventeen female heterozygous Mecp2 rats and 8 female wild-type (WT) littermates were used in this study. The rats were exposed to multiple tone frequencies paired with VNS 300 times per day for 20 days. Auditory cortex responses were then examined following VNS-tone pairing therapy or no therapy. RESULTS Our results indicate that Mecp2 mutation alters auditory cortex responses to sounds compared to WT controls. VNS-tone pairing in Mecp2 rats improves the cortical response strength to both tones and speech sounds compared to untreated Mecp2 rats. Additionally, VNS-tone pairing increased the information contained in the neural response that can be used to discriminate between different consonant sounds. CONCLUSION These results demonstrate that VNS-sound pairing may represent a strategy to enhance auditory function in individuals with Rett syndrome.
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Affiliation(s)
- Katherine S Adcock
- The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA; The University of Texas at Dallas, School of Behavioral and Brain Sciences, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA
| | - Collin Chandler
- The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA; The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA
| | - Elizabeth P Buell
- The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA; The University of Texas at Dallas, School of Behavioral and Brain Sciences, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA
| | - Bleyda R Solorzano
- The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA
| | - Kristofer W Loerwald
- The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA
| | - Michael S Borland
- The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA; The University of Texas at Dallas, School of Behavioral and Brain Sciences, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA
| | - Crystal T Engineer
- The University of Texas at Dallas, Texas Biomedical Device Center, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA; The University of Texas at Dallas, School of Behavioral and Brain Sciences, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA; The University of Texas at Dallas, Erik Jonsson School of Engineering and Computer Science, 800 West Campbell Road BSB11, Richardson, TX, 75080, USA.
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Lateralized Expression of Cortical Perineuronal Nets during Maternal Experience is Dependent on MECP2. eNeuro 2020; 7:ENEURO.0500-19.2020. [PMID: 32332080 PMCID: PMC7294466 DOI: 10.1523/eneuro.0500-19.2020] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 04/10/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023] Open
Abstract
Cortical neuronal circuits along the sensorimotor pathways are shaped by experience during critical periods of heightened plasticity in early postnatal development. After closure of critical periods, measured histologically by the formation and maintenance of extracellular matrix structures called perineuronal nets (PNNs), the adult mouse brain exhibits restricted plasticity and maturity. Mature PNNs are typically considered to be stable structures that restrict synaptic plasticity on cortical parvalbumin+ (PV+) GABAergic neurons. Changes in environment (i.e., novel behavioral training) or social contexts (i.e., motherhood) are known to elicit synaptic plasticity in relevant neural circuitry. However, little is known about concomitant changes in the PNNs surrounding the cortical PV+ GABAergic neurons. Here, we show novel changes in PNN density in the primary somatosensory cortex (SS1) of adult female mice after maternal experience [called surrogate (Sur)], using systematic microscopy analysis of a whole brain region. On average, PNNs were increased in the right barrel field and decreased in the left forelimb regions. Individual mice had left hemisphere dominance in PNN density. Using adult female mice deficient in methyl-CpG-binding protein 2 (MECP2), an epigenetic regulator involved in regulating experience-dependent plasticity, we found that MECP2 is critical for this precise and dynamic expression of PNN. Adult naive Mecp2-heterozygous (Het) females had increased PNN density in specific subregions in both hemispheres before maternal experience, compared with wild-type (WT) littermate controls. The laterality in PNN expression seen in naive Het (NH) was lost after maternal experience in Sur Het (SH) mice, suggesting possible intact mechanisms for plasticity. Together, our results identify subregion and hemisphere-specific alterations in PNN expression in adult females, suggesting extracellular matrix plasticity as a possible neurobiological mechanism for adult behaviors in rodents.
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Fagiolini M, Patrizi A, LeBlanc J, Jin LW, Maezawa I, Sinnett S, Gray SJ, Molholm S, Foxe JJ, Johnston MV, Naidu S, Blue M, Hossain A, Kadam S, Zhao X, Chang Q, Zhou Z, Zoghbi H. Intellectual and Developmental Disabilities Research Centers: A Multidisciplinary Approach to Understand the Pathogenesis of Methyl-CpG Binding Protein 2-related Disorders. Neuroscience 2020; 445:190-206. [PMID: 32360592 DOI: 10.1016/j.neuroscience.2020.04.037] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 12/20/2022]
Abstract
Disruptions in the gene encoding methyl-CpG binding protein 2 (MECP2) underlie complex neurodevelopmental disorders including Rett Syndrome (RTT), MECP2 duplication disorder, intellectual disabilities, and autism. Significant progress has been made on the molecular and cellular basis of MECP2-related disorders providing a new framework for understanding how altered epigenetic landscape can derail the formation and refinement of neuronal circuits in early postnatal life and proper neurological function. This review will summarize selected major findings from the past years and particularly highlight the integrated and multidisciplinary work done at eight NIH-funded Intellectual and Developmental Disabilities Research Centers (IDDRC) across the US. Finally, we will outline a path forward with identification of reliable biomarkers and outcome measures, longitudinal preclinical and clinical studies, reproducibility of results across centers as a synergistic effort to decode and treat the pathogenesis of the complex MeCP2 disorders.
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Affiliation(s)
- Michela Fagiolini
- Children's Hospital Intellectual and Developmental Disabilities Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
| | - Annarita Patrizi
- Children's Hospital Intellectual and Developmental Disabilities Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jocelyn LeBlanc
- Children's Hospital Intellectual and Developmental Disabilities Research Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Lee-Way Jin
- UC Davis MIND Institute, University of California, Sacramento, CA, USA
| | - Izumi Maezawa
- UC Davis MIND Institute, University of California, Sacramento, CA, USA
| | - Sarah Sinnett
- UNC Intellectual and Developmental Disabilities Research Center, University of North Carolina, Gene Therapy Center and Dept. of Ophthalmology, Chapel Hill, NC, USA; Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Steven J Gray
- UNC Intellectual and Developmental Disabilities Research Center, University of North Carolina, Gene Therapy Center and Dept. of Ophthalmology, Chapel Hill, NC, USA; Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Sophie Molholm
- The Cognitive Neurophysiology Laboratory, Departments of Pediatrics, Neuroscience, and Psychiatry and Behavioral Sciences, Albert Einstein College of Medicine, Bronx, NY, USA
| | - John J Foxe
- The Cognitive Neurophysiology Laboratory, Ernest J. Del Monte Institute for Neuroscience, Department of Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Michael V Johnston
- Kennedy Krieger Institute Intellectual and Developmental Disabilities Research Center/Hugo Moser Research Institute at Kennedy Krieger and Johns Hopkins School of Medicine, USA
| | - Sakkubai Naidu
- Kennedy Krieger Institute Intellectual and Developmental Disabilities Research Center/Hugo Moser Research Institute at Kennedy Krieger and Johns Hopkins School of Medicine, USA
| | - Mary Blue
- Kennedy Krieger Institute Intellectual and Developmental Disabilities Research Center/Hugo Moser Research Institute at Kennedy Krieger and Johns Hopkins School of Medicine, USA
| | - Ahamed Hossain
- Kennedy Krieger Institute Intellectual and Developmental Disabilities Research Center/Hugo Moser Research Institute at Kennedy Krieger and Johns Hopkins School of Medicine, USA
| | - Shilpa Kadam
- Kennedy Krieger Institute Intellectual and Developmental Disabilities Research Center/Hugo Moser Research Institute at Kennedy Krieger and Johns Hopkins School of Medicine, USA
| | - Xinyu Zhao
- Waisman Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Quiang Chang
- Waisman Center, University of Wisconsin-Madison, Madison, WI, USA
| | - Zhaolan Zhou
- Department of Genetic, Epigenetic Institute, University of Pennsylvania Perelman School of Medicine, Intellectual and Developmental Disabilities Research Center, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA
| | - Huda Zoghbi
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, USA
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