The prolonged and sex-dependent impact of maternal immune activation (MIA) during gestation on the molecular pathways of the amygdala, a brain region that influences social, emotional, and other behaviors, is only partially understood. To address this gap, we investigated the effects of viral-elicited MIA during gestation on the amygdala transcriptome of pigs, a species of high molecular and developmental homology to humans. Gene expression levels were measured using RNA-Seq on the amygdala for 3-week-old female and male offspring from MIA and control groups. Among the 403 genes that exhibited significant MIA effect, a prevalence of differentially expressed genes annotated to the neuroactive ligand-receptor pathway, glutamatergic functions, neuropeptide systems, and cilium morphogenesis were uncovered. Genes in these categories included corticotropin-releasing hormone receptor 2, glutamate metabotropic receptor 4, glycoprotein hormones, alpha polypeptide, parathyroid hormone 1 receptor, vasointestinal peptide receptor 2, neurotensin, proenkephalin, and gastrin-releasing peptide. These categories and genes have been associated with the MIA-related human neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Gene network reconstruction highlighted differential vulnerability to MIA effects between sexes. Our results advance the understanding necessary for the development of multifactorial therapies targeting immune modulation and neurochemical dysfunction that can ameliorate the effects of MIA on offspring behavior later in life.

Signalling by retinoid compounds is vital for embryonic development, with particular importance for neurogenesis in the human brain. Retinoids, metabolites of vitamin A, exert influence over the expression of thousands of transcripts genome wide, and thus, act as master regulators of many important biological processes. A significant body of evidence in the literature now supports dysregulation of the retinoid system as being involved in the aetiology of schizophrenia. This includes mechanistic insights from large-scale genomic, transcriptomic and, proteomic studies, which implicate disruption of disparate aspects of retinoid biology such as transport, metabolism, and signalling. As a result, retinoids may present a valuable clinical opportunity in schizophrenia via novel pharmacotherapies and dietary intervention. Further work, however, is required to expand on the largely observational data collected thus far and confirm causality. This review will highlight the fundamentals of retinoid biology and examine the evidence for retinoid dysregulation in schizophrenia.

An association between isotretinoin (13-cis-retinoic acid, sold under trade names including Accutane [Hoffmann-La Roche Inc, Basel, Switzerland]) and birth defects, depression, and suicide is well documented but controversial. A link to psychosis and exacerbation of bipolar symptoms is less extensively addressed in the literature.

Given recent conceptualization of psychotic disorders as neurodevelopmental, and current interest in possible shared etiology of different neurodevelopmental disorders such as psychosis, autism, and intellectual disability, this review concurrently examines the literature on developmental (primarily teratogenic) and psychiatric side effects of isotretinoin exposure. The goal of concurrent review is to identify shared mechanisms in the literature that may inform future efforts to clarify the neurocognitive and psychiatric effects of isotretinoin exposure at different developmental stages or given different genetic backgrounds.

Literature was obtained by PubMed search for the term isotretinoin in combination with each of the terms psychosis, psychiatric, and teratogenic. Resulting articles met inclusion criteria for review if they addressed psychiatric side effects of isotretinoin treatment or the neurobehavioral teratology of isotretinoin.

The association of isotretinoin exposure with prenatal developmental toxicity is well established. Although numerous reports also link isotretinoin treatment with psychiatric side effects, this association remains controversial.

The extent to which isotretinoin influences pediatric and adult development and cognition, and whether and why certain individuals may be susceptible to psychiatric side effects, remains to be clarified. Curr Ther Res Clin Exp. 2019; 80:XXX-XXX).

This review provides the rationale and reports on the progress to date regarding the targeting of retinoid receptors for the treatment of schizophrenia and schizoaffective disorder and the role of retinoic acid in functions of the normal brain, and in psychotic states. After a brief introduction, we describe the normal function of retinoic acid in the brain. We then examine the evidence regarding retinoid dysregulation in schizophrenia. Finally, findings from two add-on clinical trials with a retinoid (bexarotene) are discussed. The authors of this review suggest that targeting retinoid receptors may be a novel approach to treat schizophrenia and schizoaffective disorder. Further studies are warranted.

Moderate to severe dysregulation in retinoid signaling during early development is associated with a constellation of physical malformations and/or neural tube defects, including spina bifida. It is thought that more subtle dysregulation of this system, which might be achievable via dietary (i.e. hypervitaminosis A) or pharmacological (i.e. valproic acid) exposure in humans, will manifest on behavioral domains including sociability, without overt physical abnormalities.

During early life, zebrafish were exposed to low doses of two chemicals that disrupt retinoid signaling. From 0 to 5dpf, larvae were reared in aqueous solutions containing retinoic acid (0, 0.02, 0.2 or 2nM) or valproic acid (0, 0.5, 5.0 or 50μM). One cohort of zebrafish was assessed using a locomotor activity screen at 6-dpf; another was reared to adulthood and assessed using a neurobehavioral test battery (startle habituation, novel tank exploration, shoaling, and predator escape/avoidance).

There was no significant increase in the incidence of physical malformation among exposed fish compared to controls. Both retinoic acid and valproic acid exposures during development disrupted larval activity with persisting behavioral alterations later in life, primarily manifesting as decreased social affiliation.

Social behavior and some aspects of motor function were altered in exposed fish; the importance of examining emotional or psychological consequences of early life exposure to retinoid acting chemicals is discussed.

This review highlights morphological and functional anomalies found along the entire visual pathway in schizophrenia, from the retina to the cortex. Based on the evidence of widespread anatomical and functional visual abnormalities, we posited that a neurodevelopmental anomaly occurring early in life was likely to explain those. Incidentally, support to the neurodevelopmental theory of schizophrenia is strongly emerging from many neurobiological domains. In vertebrates, the first visual structures migrate toward the orbit position at the end of the fourth week of gestation. A neurodevelopmental defect around that time on these embryonic structures could account for the visual anomalies in schizophrenia. Retinol activity might be involved in the process. Future research in schizophrenia should focus on early visual testing, on trials combining multiple visual anomaly assessments and a closer look to retinol activity during the pregnancy.

The higher frequency of minor physical anomalies (MPAs) in schizophrenia provides morphological evidence for the neurodevelopmental theory. Abnormal gamma oscillations (>30 Hz) seen in the electroencephalogram (EEG) in schizophrenia have been hypothesized to result from developmental insults. This study investigated spontaneous gamma oscillations in schizophrenia patients having higher and lower number of MPAs. Forty drug naïve/free schizophrenia patients and 20 matched healthy controls were assessed for MPAs on the Extended Waldrop Scale (EWS). All participants underwent an awake, resting 192-channel EEG recording. Spontaneous gamma spectral power and coherence were estimated in the low- (30-50 Hz) and high-gamma (51-70 and 71-100 Hz) bands. Significantly higher power was observed in high-MPA than healthy control group in low-gamma band over right frontal, parietal and temporal regions. Spectral power in the high-gamma band (71-100 Hz) was also significantly higher in the high-MPA schizophrenia subgroup than in the healthy control group over left frontal, parietal and temporal regions. Additionally, regional intra-hemispheric and inter-hemispheric coherence in the low-gamma band was significantly higher in the high-MPA schizophrenia subgroup than on the healthy control group. This study is the first to provide evidence of increased spontaneous gamma power and synchrony in schizophrenia patients having higher MPAs, supporting the idea that it may represent a distinct subgroup of schizophrenia with a neurodevelopmental basis.

Prenatal micronutrient deficiency has been linked to later development of schizophrenia among offspring; however, no study has specifically investigated the association between vitamin A and this disorder. Vitamin A is an essential nutrient which is required by the early embryo and fetus for gene expression and regulation, cell differentiation, proliferation and migration. Previous work suggests that vitamin A deficiency in the second trimester may be particularly relevant to the etiopathogenesis of neurobehavioral phenotypes some of which are observed in schizophrenia.

We examined whether low maternal vitamin A levels in the second trimester are associated with the risk of schizophrenia and other schizophrenia spectrum disorders (SSD) in the Prenatal Determinants of Schizophrenia study; third trimester vitamin A levels were also examined in relation to SSD. The cases were derived from a population-based birth cohort; all cohort members belonged to a prepaid health plan. Archived maternal serum samples were assayed for vitamin A in cases (N=55) and up to 2 controls per case (N=106) matched on length of membership in the health plan, date of birth (±28 days), sex, and gestational timing and availability of archived maternal sera.

For the second trimester, low maternal vitamin A, defined as values in the lowest tertile of the distribution among controls, was associated with a greater than threefold increased risk of SSD, adjusting for maternal education and age (OR=3.04, 95% CI=1.06, 8.79, p=.039). No association between third trimester maternal vitamin A and SSD was observed.

Although further investigations are warranted, this is the first birth cohort study to our knowledge to report an association between low maternal vitamin A levels and SSD among offspring.

Schizophrenia is a complex disorder with involvement of multiple genes.

In this study, genome-wide screening for DNA copy-number variations (CNVs) was conducted for ten pairs, a total of 20 cases, of affected siblings using oligonucleotide array-based CGH.

We found negative symptoms were significantly more severe (p < 0.05) in the subgroup that harbored more genetic imbalance (n >== 13, n = number of CNV-disrupted genes) as compared with the subgroup with fewer CNVs (n <== 6), indicating that the degree of genetic imbalance may influence the severity of the negative symptoms of schizophrenia. Four central nervous system (CNS) related genes including CCAAT/enhancer binding protein, delta (CEBPD, 8q11.21), retinoid x receptor, alpha (RXRA, 9q34.2), LIM homeobox protein 5 (LHX5, 12q24.13) and serine/threonine kinase 11 (STK11, 19p13.3) are recurrently (incidence >== 16.7%) disrupted by CNVs. Two genes, PVR (poliovirus receptor) and BU678720, are concordantly deleted in one and two, respectively, pairs of co-affected siblings. However, we did not find a significant association of this BU678720 deletion and schizophrenia in a large case-control sample.

We conclude that the high genetic loading of CNVs may be the underlying cause of negative symptoms of schizophrenia, and the CNS-related genes revealed by this study warrant further investigation.

The well-documented excess of minor physical anomalies (MPAs) among individuals with schizophrenia generally supports the neurodevelopmental model, which posits that both genetic and environmental factors contribute to structural and functional brain changes in the intrauterine and perinatal periods that predispose one to developing schizophrenia. This review synthesizes select areas of research findings on MPAs to address the question, Are MPAs part of the syndrome of schizophrenia? Although MPAs are not specific to schizophrenia, their presence in some patients indicates that aberrations in the development of the nervous system contribute to risk for the disorder. The broadly defined, heterogeneous MPA construct may be of limited value in further elucidating the specific pathophysiology of schizophrenia, though particular anomalies, such as those pertaining to nasal volumes, palatal abnormalities, or craniofacial morphology, may be informative. Given the availability of more sophisticated microarray technologies, and in light of recent findings on spontaneous mutations in patients with schizophrenia, it is possible that MPAs will prove to be useful in identifying etiologic subtypes and/or the loci of genetic risk factors. It remains to be determined whether MPAs-which, of course, are fixed markers present throughout childhood and adolescence well before the onset of the prodrome and psychosis-may have utility in terms of risk stratification for future preventive efforts. Taken together, research findings on MPAs indicate that these minor anomalies are indeed part of some schizophrenia syndromes, representing a stable systemic or physical set of manifestations of the underlying neurodevelopmental processes that lead to the illness.

The complex molecular pathways that mediate the effects of vitamin A and its derivatives, are increasingly recognized as a component of the repair capacity that could be activated to induce protection and regeneration in the mature nervous tissue. Retinoid and retinoid-associated signaling plays an essential role in normal neurodevelopment and appears to remain active in the adult CNS. In this paper, we review evidence which supports the hypothesis of an activation of retinoid-associated signaling molecular pathways in the mature nervous tissue and its significance in the context of neurodegenerative, trauma-induced and psychiatric disorders, at spinal and supra-spinal levels. Finally, we summarize the potential therapeutic avenues based on the modulation of retinoid targets undergoing reactivation under conditions of acute injury and chronic degeneration in the central nervous system, and discuss some of the unresolved issues linked to this treatment strategy.

Phenotypic discordance for schizophrenia in monozygotic twins clearly indicates involvement of environmental factors as key determinants in disease development. Positive findings from genome scans, linkage and association studies apply in only a minority of those affected, while post-mortem brain investigations reveal altered expression of genes and proteins involved in numerous neurodevelopmental, metabolic and neurotransmitter pathways. Such altered expressions could result, on the one hand, from mutations in coding regions or polymorphisms in the promoter and regulatory regions in genes within those areas identified by gene searches or, on the other hand, from inadequate amounts of modulators, transporters and synthesizers of transcription factors necessary for regulation of the putative genes. Hormones and vitamins are such modulators. They could serve as bridges between genes and environment in schizophrenia. Multiple evidence supports the suggestion of retinoids and thyroid hormones as plausible actors in these roles. Both are not only essential for normal development of the central nervous system but also regulate the expression of many neurotransmitters, their synthesizing enzymes and receptors, and other genes in broader signaling transduction cascades affecting pathways that are altered in response to treatment. Functional and positional candidate genes include retinoic acid and thyroid hormone receptors, retinaldehyde dehydrogenases and deiodinases, which synthesize the powerful morphogens, retinoic acid and triiodothyronine, and the enzymes involved in their inactivation. This review highlights selective evidence supporting the retinoid and thyroid hormone hypotheses of schizophrenia.

Retinoid receptors (RARs and RXRs) regulate brain morphogenesis and function. Defects in these receptors may contribute to schizophrenia or other psychiatric diseases. To test the hypothesis that genetic variants of the retinoid receptor genes may predispose to schizophrenia and other psychiatric diseases, the six RAR and RXR genes and a heterodimer partner, the NURR1 gene, were scanned in 100 schizophrenia patients, along with pilot studies in 20-24 patients with bipolar disorder (BPD), attention-deficit hyperactivity disorder (ADHD), autism, or alcoholism. A total of 5.4 megabases of genomic sequence was scanned. No variants affecting protein structure or expression (VAPSEs) were found in four of the genes. One uncommon missense variant was found in each of the RARbeta, RARgamma, and RXRgamma genes. We conclude that structural variants in the RAR/RXR and NURR1 genes do not play a major role in the etiology of schizophrenia.

Mounting evidence suggests that schizophrenia is a neurodevelopmental disease resulting in dysfunctional connectivity between various brain regions. Retinoid pathway dysregulation has been proposed as a potentially important factor in the etiology of schizophrenia. Retinoid signaling plays a central role in many aspects of development, ranging from neurogenesis to activity-dependent plasticity, and regulates the expression of many candidate genes for schizophrenia. The retinoid pathway acts through two families of nuclear receptors highly expressed in the hippocampus, the retinoic acid (RAR) and retinoid X (RXR) receptors, both existing in three different subtypes (alpha, beta and gamma) and several isoforms. The present study examines the expression of the retinoid receptors in the dentate gyrus of schizophrenia and nonpsychiatric controls. The proportion of granule cells of the dentate gyrus expressing RAR(alpha) is increased by twofold in schizophrenia, while the proportion of cells expressing RAR(gamma)1 and 2, as well as RXR(beta) and gamma, is unchanged. These results demonstrate a dysregulation in the expression of at least one member of the RAR family of retinoid receptors in schizophrenia. Understanding the basis for this and how it affects downstream molecular pathways associated with hippocampal plasticity may provide insight into the dysfunctional connectivity of schizophrenia.

Covalent modifications of DNA and its surrounding chromatin constitute an essential and powerful regulatory mechanism for gene transcription. Epigenetics is the study of this regulatory system. There is now strong albeit indirect evidence that epigenetic mechanisms contribute to the pathophysiology of schizophrenia. Furthermore, the discovery that valproic acid, a widely used psychotropic, has powerful epigenetic effects in clinically relevant concentrations suggests new therapeutic possibilities, i.e., drugs that act on chromatin structure. Fortunately, many proteins engaged in these processes, particularly chromatin remodeling, are accessible to pharmacological agents that have a high likelihood of crossing the blood brain barrier. This review will first summarize the essentials of the epigenetic regulatory system, then address the molecular evidence for altered epigenetic mechanisms in schizophrenia, and finally focus on the retinoic acid family of ligand-activated nuclear transcription factors as a likely system for new drug development in the management of schizophrenia-related symptoms.

Disturbances in the central nervous system originating during foetal life may increase the risk of schizophrenia.

To illuminate the hypothesis that prenatal exposure to analgesics may affect foetal neurodevelopment, leading to increased risk of schizophrenia in adulthood.

Using data from the Copenhagen Perinatal Cohort and from the Danish Psychiatric Central Register, we studied the relationship between prenatal exposure to analgesics and the risk of schizophrenia. The effect of prenatal exposure was adjusted for parental history of schizophrenia, second-trimester viral infections, concomitant drug treatment during pregnancy, an index of pregnancy complications, parental social status and parental age.

In a risk set of 7999 individuals, 116 cases of schizophrenia were found (1.5%). Prenatal exposure to analgesics in the second trimester was associated with an elevated risk (adjusted odds ratio 4.75, 95% CI1.9-12.0). Independent of the covariates, the effect remained statistically significant.

Independent of a wide range of possible confounders, a significant association between second-trimester exposure to analgesics and increased risk of schizophrenia was observed.

Vitamin A is a very intriguing natural compound. The molecule not only has a complex array of physiological functions, but also represents the precursor of promising and powerful new pharmacological agents. Although several aspects of human retinol metabolism, including absorption and tissue delivery, have been clarified, the type and amounts of vitamin A derivatives that are intracellularly produced remain quite elusive. In addition, their precise function and targets still need to be identified. Retinoic acids, undoubtedly, play a major role in explaining activities of retinol, but, recently, a large number of physiological functions have been attributed to different retinoids and to vitamin A itself. One of the primary roles this vitamin plays is in embryogenesis. Almost all steps in organogenesis are controlled by retinoic acids, thus suggesting that retinol is necessary for proper development of embryonic tissues. These considerations point to the dramatic importance of a sufficient intake of vitamin A and explain the consequences if intake of retinol is deficient. However, hypervitaminosis A also has a number of remarkable negative consequences, which, in same cases, could be fatal. Thus, the use of large doses of retinol in the treatment of some human diseases and the use of megavitamin therapy for certain chronic disorders as well as the growing tendency toward vitamin faddism should alert physicians to the possibility of vitamin overdose.

Present antipsychotic drugs, whose clinical activity correlates with direct binding to dopamine D2 or other receptors, alleviate some of the symptoms of schizophrenia, but not all and not completely in many patients. In continuation of our overview of potential novel antipsychotic pharmacotherapy that would be based upon indirect modulation of dopamine or other neurotransmitter functioning, we focus in this article on the postulated use of retinoid analogs as novel antipsychotic agents. Several lines of evidence can be viewed as implicating retinoid dysregulation in schizophrenia, either as a causative or contributory factor. It has been proposed that using retinoid analogs to alter the downstream expression of dopamine D2 receptors might represent a novel approach to the treatment of the disease or amelioration of symptoms when used either as monotherapy or as adjunct pharmacotherapy to dopamine D2 receptor antagonists.

Because retinoid cascades are involved in the regulation and development of the central nervous system, including dopaminergic neurons, retinoic acid signaling defects may contribute to schizophrenia and substances dependence. Retinoid X receptors (RXRs) form heterodimer complexes with nuclear-related receptor 1 (NURR1) or with peroxisome proliferator-activated receptors (PPARs). We examined 48 Japanese patients with schizophrenia and 32 patients with alcohol dependence to detect mutations in the retinoid X receptor beta gene (RXRB) on chromosome 6p21.3, the NURR1 gene (NR4A2) on chromosome 2q22-q23, and the PPAR alpha gene (PPARA) on chromosome 22q12.2-13.1. A Val95Ala polymorphism of the RXRB gene, a Val227Ala polymorphism in the PPARA gene, and two synonymous single-nucleotide and CA repeat polymorphisms in the 5' region and 3' untranslated region of the NR4A2 gene were identified. Extended case control samples did not suggest an association between the diseases and the RXRB or PPARA polymorphisms. However, they revealed a significant association between the NR4A2 gene haplotype and alcohol dependence, indicating that 2q22-q23 including the NR4A2 gene locus is a possible genomic region contributing to genetic susceptibility to alcohol dependence.

The authors review environmental and neurodevelopmental risk factors for schizophrenic disorders, with emphasis on minor physical anomalies, particularly craniofacial anomalies and dermatoglyphic variations. The high prevalence of these anomalies among schizophrenic subjects supports the neurodevelopmental theory of the etiology of schizophrenia, since they suggest either genetically or epigenetically controlled faulty embryonic development of structures of ectodermal origin like brain and skin. This may disturb neurodevelopment that in turn may cause these subjects to be at increased risk for the development of schizophrenia and related disorders. The precise confirmation of this theory, at least in some cases, will provide further understanding of these illnesses, allowing easy and inexpensive identification of subjects at risk and providing guidelines for the development of new pharmacological interventions for early treatment and even for primary prevention of the illness.

A meeting on the molecular and neurobiological basis of schizophrenia was held April 11-14, 1999 at the Banbury Center of The Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. This report is a summary of the predominant views of the participants, as perceived by the organizers. The purpose of this meeting was integrative-to bring together in a relaxed environment three dozen outstanding scientists in disparate underlying disciplines: psychiatry, psychology, genetics, neurobiology, biochemistry, molecular biology, and pharmacology. Brief talks emphasized concepts and questions rather than presentation of data. Exchanges of information and concepts provided an emerging synthesis of current and novel, even highly speculative, ideas. The reader is cautioned that the ideas, data supporting them, and data interpretations are not critiqued in this report. Nor is there much distinction made between speculations and findings that have more experimental support. The main questions and conclusions that emerged are presented in this report, which covers the following: 1) macrobiology (what schizophrenia is in terms of definition and improved diagnostics, genetics and environment, brain structure, development, and mind), 2) cell and molecular biology (defects of the expressed disease at both the membrane and nuclear levels, molecular defects of development, neuroreceptor genes and transcriptional control, and ligands), 3) therapies (current approaches, possible targets, and animal models), and 4) newer approaches (gene expression, early treatment and prevention strategies, and other problems). Two references per participant and abstracts (available from the organizers) served as a common basis.

This paper reports evidence for a possible "chromosome 13 syndrome," which includes panic disorder, kidney or bladder problems, serious headaches, thyroid problems (usually hypothyroid), and/or mitral valve prolapse (MVP). In the course of a genetic linkage study of panic disorder, we noted these medical conditions in individual family members. (We were blind to family relationships and marker data.) We hypothesized that there may exist a subgroup of panic families with these medical conditions, which for simplicity we called it the "syndrome." Subsequently we reclassified the families as with or without the "syndrome" and extended the phenotype for analysis to include the above medical conditions. All these classifications were also done before the analysis and blind to marker data. We then examined our linkage results, looking for significant differences between families with and without the "syndrome" (using several definitions of the "syndrome")-i.e., testing for genetic heterogeneity. When the families with and without bladder/kidney problems were separated from each other, one marker-D13S779 (ATA26D07)-yielded a lod score of over 3 in the families with bladder/kidney problems. This lod score went up to 4.2 in these families when we diagnosed any individual with any one of the "syndrome" conditions as affected. These results were statistically significant even after applying an extremely overconservative Bonferroni correction for multiple tests. We present these results in order to alert other investigators working on panic disorder, for replication. If replicated, one may hypothesize that a candidate gene for the syndrome should be expressed in CNS, kidney, gut, thyroid, etc. We also noted that two independent studies report recent linkage findings between schizophrenia and the same region on chromosome 13. No connection between schizophrenia and panic disorder has ever been reported. Finally, we suggest that genetic studies of psychiatric disorders might prove more fruitful if phenotypes were expanded to include possible manifestations of the disorder in medical (non-mental) symptoms. Am. J. Med. Genet.(Neuropsychiatr. Genet.) 96:24-35, 2000.

Schizophrenia is thought to be a disease of early development that ultimately affects forebrain neurons and circuits. There may be a relationship between disrupted forebrain development; malformations of the limb, face, and heart; and signaling via the steroid-like hormone retinoic acid (RA) in some schizophrenic patients. The limbs, face, heart, and forebrain all develop from sites where neural crest-derived, RA-producing mesenchyme contributes to induction and differentiation of adjacent epithelia. Induction between neural crest-derived, RA-producing mesenchyme, the anterior neural tube, and the anterior surface epithelium of the embryo guides regional differentiation and pathway formation during forebrain development. Furthermore, there are at least two mouse mutations--in the Pax-6 and Gli-3 genes--that cause peripheral malformations and specifically disrupt neural crest mediated, RA-dependent induction and differentiation in the forebrain. These observations suggest that induction might provide a common target for genes that alter morphogenesis of peripheral structures, disrupt RA-signaling, and compromise forebrain development. In the forebrain, some of these disruptions might influence the numbers or cellular properties of neurons and circuits. Such changes might be reflected in the aberrant forebrain function that characterizes schizophrenia.

Retinoid dysregulation may be an important factor in the etiology of schizophrenia. This hypothesis is supported by three independent lines of evidence that triangulate on retinoid involvement in schizophrenia: (i) congenital anomalies similar to those caused by retinoid dysfunction are found in schizophrenics and their relatives; (ii) those loci that have been suggestively linked to schizophrenia are also the loci of the genes of the retinoid cascade (convergent loci); and (iii) the transcriptional activation of the dopamine D2 receptor and numerous schizophrenia candidate genes is regulated by retinoic acid. These findings suggest a close causal relationship between retinoids and the underlying pathophysiological defects in schizophrenia. This leads to specific strategies for linkage analyses in schizophrenia. In view of the heterodimeric nature of the retinoid nuclear receptor transcription factors, e.g., retinoid X receptor beta at chromosome 6p21.3 and retinoic acid receptor beta at 3p24.3, two-locus linkage models incorporating genes of the retinoid cascade and their heterodimeric partners, e.g., peroxisome proliferator-activated receptor alpha at chromosome 22q12-q13 or nuclear-related receptor 1 at chromosome 2q22-q23, are proposed. New treatment modalities using retinoid analogs to alter the downstream expression of the dopamine receptors and other genes that are targets of retinoid regulation, and that are thought to be involved in schizophrenia, are suggested.