Preliminary evidence for association between schizophrenia and polymorphisms in the regulatory Regions of the ADRA2A,DRD3 and SNAP-25 Genes

The results of linkage and candidate gene association studies have led to a range of hypotheses about the pathogenesis of schizophrenia. We limited our study to polymorphisms in candidate genes involved in dopaminergic and noradrenergic systems, and in the 25 KDa synaptosomal-associated protein (SNAP-25) gene that is related to neurotransmitter exocytosis. Eight single nucleotide polymorphisms (SNPs) in regulating or coding regions of genes for the alpha-2A adrenergic receptor (ADRA2A), dopamine receptors D1 and D3 (DRD1 and DRD3), dopamine β-hydroxylase (DBH) and SNAP-25 were genotyped in male patients with schizophrenia (n=192) and in healthy controls (n=213). These polymorphisms were previously associated with schizophrenia. The allelic association between schizophrenia and ADRA2A rs1800544 polymorphism, SNAP-25 rs1503112 polymorphism, and DRD3 rs6280 polymorphism was found in our study. However, only observations for rs1503112 survived correction for multiple testing. Association was also evaluated by considering the polymorphisms as interactions; in this case, a likelihood ratio test (LRT) revealed evidence for association with schizophrenia in four polymorphism combinations: two DRD3*SNAP-25 combinations (rs6280*rs3746544 and rs6280*rs3746544, P=0.02), one ADRA2A*SNAP25 combination (rs1800544*rs3746544) and one ADRA2A*DBH combination (rs1800544*rs2519152). Our results are in agreement with the previously proposed role of DNA polymorphisms involved in dopaminergic, noradrenergic and synaptic functions in the pathogenesis of schizophrenia. Further relevant studies including larger sample size and more markers are needed to confirm our results.     

Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia

Deficits in central, subcortical dopamine (DA) signaling may underlie negative symptom severity, particularly anhedonia, in healthy individuals and in schizophrenia. To investigate these relationships, we assessed negative symptoms with the Schedule for the Assessment of Negative Symptoms and the Brief Negative Symptom Scale (BNSS) and self-reported anhedonia with the Scales for Physical and Social Anhedonia (SPSA), Temporal Experience of Pleasure Scale, and Snaith-Hamilton Pleasure Scale in 36 healthy controls (HC), 27 siblings (SIB) of individuals with schizophrenia, and 66 individuals with schizophrenia or schizoaffective disorder (SCZ). A subset of participants (N = 124) were genotyped for DA-related polymorphisms in genes for DRD4, DRD2/ANKK1, DAT1, and COMT, which were used to construct biologically-informed multi-locus genetic profile (MGP) scores reflective of subcortical dopaminergic signaling. DA receptor type 2 (D2R) binding was assessed among a second subset of participants (N = 23) using PET scans with the D2R-selective, non-displaceable radioligand (N-[¹¹C]methyl)benperidol. Higher MGP scores, reflecting elevated subcortical dopaminergic signaling capacity, were associated with less negative symptom severity, as measured by the BNSS, across all participants. In addition, higher striatal D2R binding was associated with less physical and social anhedonia, as measured by the SPSA, across HC, SIB, and SCZ. The current preliminary findings support the hypothesis that subcortical DA function may contribute to negative symptom severity and self-reported anhedonia, independent of diagnostic status.     

Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder

L. Zhan, J. R. Kerr, M.‐J. Lafuente, A. Maclean, M. V. Chibalina, B. Liu, B. Burke, S. Bevan and J. Nasir (2011) Neuropathology and Applied Neurobiology 37, 206–219
Altered expression and coregulation of dopamine signalling genes in schizophrenia and bipolar disorder Introduction: Signalling through dopamine receptors is of critical importance in the brain and is implicated in schizophrenia and bipolar disorder, but its underlying molecular mechanisms remain poorly understood. Materials and methods: Using a yeast two‐hybrid approach, we previously identified 11 novel dopamine receptor‐interacting proteins. Here we compare gene expression levels for 17 genes [including all 11 dopamine receptor interacting proteins, all 5 dopamine receptors (DRD1–DRD5) and DARPP‐32] by real‐time polymerase chain reaction, using prefrontal cortex post mortem brain samples from 33 schizophrenic, 32 bipolar disorder and 34 control subjects. Results: The expression of C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP‐32 genes was altered in schizophrenia and/or bipolar disorder samples relative to controls (P < 0.05). Hierarchical clustering analysis revealed the expression of these five genes (C14ORF28, GNB2L1, MLLT3, DARPP‐32, DRD2) is closely correlated in patients. However, in controls, DRD2 expression in relation to the other genes appears to be very different, suggesting abnormal DRD2 activity is an important trigger in the pathophysiology of schizophrenia and bipolar disorder. Conclusions: Our data suggest: (i) C14ORF28, GNB2L1, MLLT3, DRD2 and DARPP‐32 are important in the pathogenesis of schizophrenia and bipolar disorder; (ii) these two disorders share common disease‐related mechanisms linked to dopamine signalling; (iii) the expression of these genes is closely correlated; and (iv) DRD2 provides the initial trigger in the pathogenesis of these disorders.     

Genetics of impulse control disorders in Parkinson’s disease

Impulse control disorders (ICD) have been recognised in Parkinson’s disease (PD) as adverse effects of dopamine replacement therapy, particularly with dopamine agonists. Although virtually all PD patients are treated with dopaminergic drugs, only a minority will develop hyperdopaminergic states, suggesting predisposing and/or protecting factors. The age at onset, the sex and the dose or type of dopaminergic drugs have been identified as clinical predictive factors. Recent genetic studies have investigated associations between ICD and polymorphisms of genes involved in the dopamine metabolism pathway (COMT, DAT), dopamine receptors (DRD1, DRD2, DRD3, DRD4), serotonin receptors and its transporter (HTR2A, 5HTT), and glutamate receptors (GRIN2B). Although validation in larger and independent cohorts is needed, the results from these studies give us some insights into the pathophysiology of hyperdopaminergic states and may be useful, at term, in personalising antiparkinsonian treatment in clinical practice.     

Role of genetic polymorphisms of the dopaminergic system in Parkinson's disease patients with impulse control disorders

BackgroundThe mechanisms underlying the development of impulse control disorders (ICDs) like compulsive gambling, buying, sexual, and eating behaviors in Parkinson’s disease (PD) are debated. We assessed whether allelic variants of dopamine D2 receptors (DRD2), catechol-O-methyltransferase (COMT) and dopamine transporter (DAT) were associated with the development of ICDs in PD.MethodWe enrolled 89 idiopathic PD patients (48 without ICDs and 41 with ICDs). All patients were screened with the Minnesota Impulsive Disorders Interview (MIDI) and fulfilled DSM-IV criteria for the ICD positive cohort. Differences in the frequency of the genotypes between ICDs and non-ICDs groups were assessed using the χ² test.ResultsGenotyping was performed for variants of the DRD2 Taq1A (rs1800497), COMT Val¹⁵⁸Met (rs4680), DAT1 (3′ UTR 40 bp VNTR). Variants of DRD2 Taq1A, COMT and DAT1 were not associated with the risk of developing ICDs.ConclusionIn our study, there were no differences in the frequency of variant of DRD2 Taq1A, COMT and DAT1 between the two groups. Polymorphisms of dopaminergic genes do not play a relevant role in the development of ICD in PD suggesting that ICD originate from inability to filter inappropriate behaviors triggered by dopaminergic therapy.     

The role of atypical semantic activation and stress in odd speech: Implications for individuals with psychometrically defined schizotypy

BackgroundOdd speech is a cardinal symptom of schizophrenia; however, little is known about the mechanisms that lead to this construct in schizophrenia or schizotypy, the estimated 10% of the population who exhibit traits presumed to reflect genetic liability to schizophrenia. The lack of research concerning specific mechanisms of odd speech represents an important knowledge gap. Here, our primary aim was to examine how atypical semantic activation (ASA) and stress are related to odd speech in individuals with psychometrically-defined schizotypy.MethodsWe employed highly sensitive laboratory procedures to test whether significant differences in ASA exist between psychometric schizotypy (n = 45) and non-psychometric schizotypy (n = 26) groups. We also examined odd speech across four conditions that varied according to valence (pleasant, unpleasant) and arousal (high, low) and analyzed whether ASA mediates odd speech in schizotypy.ResultsThe psychometric schizotypy group demonstrated significantly increased ASA, in the large effect size range. They also demonstrated a significant increase in one odd speech condition and a trend level group by arousal interaction was observed. Our hypothesis that ASA mediates odd speech in schizotypy was not supported.ConclusionsIndividuals with psychometric schizotypy exhibit semantic activation that is similar to patients with schizophrenia, albeit in a milder form. This study also provides evidence that ASA is a potential endophenotype of schizophrenia. Future studies should further explore properties of odd speech and ASA. Suggested avenues include cognitive deficits, particularly working memory, exploring underlying mechanisms, and examining how these constructs affect individuals across the schizophrenia-spectrum.     

ARVCF single marker and haplotypic association with schizophrenia

We present a schizophrenia association study using an extensive linkage disequilibrium (LD) mapping approach in seven candidate genes with a well established link to dopamine, including receptors (DRD2, DRD3) and genes involved in its metabolism and transport (ACE, COMT, DAT, MAO-A, MAO-B). The sample included 242 subjects diagnosed with schizophrenia and related disorders and 373 hospital-based controls. 84 tag SNPs in candidate genes were genotyped. After extensive data cleaning 70 SNPs were analyzed for association of single markers and haplotypes. One block of four SNPs (rs165849, rs2518823, rs887199 and rs2239395) in the 3′ downstream region of the COMT gene which included a non-dopaminergic candidate gene, the ARVCF (Armadillo like VeloCardio Facial) gene, was associated with the risk of schizophrenia. The genetic region including the ARVCF gene in the 22q11.21 chromosome is associated with schizophrenia in a Spanish series. Our results will assist in the interpretation of the controversy generated by genetic associations of COMT and schizophrenia, which could be the result of different LD patterns between COMT markers and the 3′ region of the ARVCF gene.     

Family association study between DRD2 and DRD3 gene polymorphisms and schizophrenia in a Portuguese population

Schizophrenia is a highly heritable condition, as demonstrated in family, twin and adoption studies. Candidate genes from the dopaminergic system have long been hypothesized to be involved in the etiology of this disorder. In the present study, we investigated the genetic association between polymorphisms in the D2 and D3 dopamine receptor (DRD2, DRD3) genes and schizophrenia. We examined 90 trios from Portugal, and negative results were obtained from association studies with both Haplotype Relative Risk (HRR) and Transmission Disequilibrium Test (TDT), as well as TRANSMIT. Therefore, we conclude that neither the DRD2 nor the DRD3 gene polymorphisms investigated are associated with schizophrenia in our sample.     

Genetic association of the GDNF alpha-receptor genes with schizophrenia and clozapine response

GDNF (glial-cell-line derived neurotrophic factor) is a potent neurotrophic factor for dopaminergic neurons. Neuropsychiatric diseases and their treatments are associated with alterations in the levels of both GDNF and its receptor family (GDNF family receptor alpha or GFRA). GFRA1, GFRA2 and GFRA3 are located in chromosomal regions with suggestive linkage to schizophrenia. In this study we analyzed polymorphisms located in all four known GFRA genes and examined association with schizophrenia and clozapine response. We examined SNPs across the genes GFRA1-4 in 219 matched case-control subjects, 85 small nuclear families and 140 schizophrenia patients taking clozapine for 6 months. We observed that GFRA3 rs11242417 and GFRA1 rs11197557 variants were significantly associated with schizophrenia after combining results from both schizophrenia samples. Furthermore, we found an overtransmission of the G-C GFRA1 rs7920934-rs730357 haplotype to subjects with schizophrenia and association of A-T-G-G GFRA3 rs10036665-rs10952-rs11242417-rs7726580 with schizophrenia in the case-control sample. On the other hand, GFRA2 variants were not associated with schizophrenia diagnosis but subjects carrying T-G-G rs1128397-rs13250096-rs4567028 haplotype were more likely to respond to clozapine treatment. The statistical significance of results survived permutation testing but not Bonferroni correction. We also found nominally-significant evidence for interactions between GFRA1, 2 and 3 associated with schizophrenia and clozapine response, consistent with the locations of these three genes within linkage regions for schizophrenia.     

Dopaminergic system genes in childhood aggression: Possible role for DRD2

Abstract

Excessive or deficient levels of extracellular dopamine have been hypothesized to contribute to a broad spectrum of mood, motor, and thought abnormalities, and dopaminergic system genes have been implicated in aggressive behaviour from animal and human studies. Objective. We examined selected members of the dopaminergic system genes for association with child aggression. Method. We analyzed polymorphisms in the dopamine transporter DAT1/SLC6A3, dopamine receptor DRD2, and DRD4 genes in our sample of pervasive childhood aggression consisting of 144 cases paired with 144 healthy controls, matched for sex and ethnicity. Results. Aggressive children were significantly more likely to have the at least one copy of the G allele for the DRD2 A-241G polymorphism (genotypic P=0.02; allelic P=0.01). The DRD2 rs1079598 CC genotype was overrepresented in aggressive children compared to controls (genotype P=0.04). The DRD2 TaqIA T allele (P=0.01) and the TT genotype (P=0.01) were also significantly overrepresented in aggressive children. Conclusions. Our preliminary results suggest that three polymorphisms in DRD2 are associated with childhood aggression. Future studies are required to replicate the current results and to further explore the relationship between the dopamine system and aggressive behaviour in children.     

Convergent functional genomics of anxiety disorders: translational identification of genes,biomarkers, pathways and mechanisms

Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug—yohimbine, and an anti-anxiety drug—diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain–blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders—notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain.     

Affecting coping: Does neurocognition predict approach and avoidant coping strategies within schizophrenia spectrum disorders?

According to various diathesis-stress models of schizophrenia, life stress plays a defining role in the onset and course of schizophrenia-spectrum disorders. In this regard, individual differences in coping strategies and affective traits, variables related to the management and experience of stress, may play a large role in susceptibility to the disorder and symptom exacerbation. Furthermore, it has been posited that cognitive deficits may limit an individuals' ability to effectively respond to stressful situations. We investigated the relationships between attention, immediate memory, trait negative affect (NA), trait positive affect (PA) and specific coping strategies within three groups: chronic schizophrenia patients (n=27), psychometrically-defined schizotypy (n=89), and schizotypy demographically-matched controls (n=26). As hypothesized affective traits displayed predictable relationships with specific coping strategies, such that NA was associated with the greater use of avoidant coping strategies within the schizophrenia and schizotypy group, while PA was associated with greater use of approach coping styles within all groups. The schizotypy group reported significantly higher levels of NA and also greater use of avoidant coping strategies than both the control and schizophrenia group. As expected group differences were found in trait affect, coping strategies, and cognitive functioning. Importantly, these group differences remained significant even when demographic variables were entered as covariates. Contrary to our expectations, cognitive functioning displayed only a few tenuous relationships with coping strategies within the schizophrenia and schizotypy groups. Overall, results support the notion that affective traits and not cognitive functioning is the best predictor of approach and avoidant coping strategies.     

Genetic susceptibility to Parkinson’s disease among South and North Indians: I. Role of polymorphisms in dopamine receptor and transporter genes and association of DRD4 120-bp duplication marker

The depletion of dopamine levels in the brain due to degeneration of dopaminergic neurons of substantia nigra pars compacta is a hallmark of Parkinson’s disease (PD). The cumulative contribution of genetic variations in genes from the dopaminergic pathway has been widely implicated to confer susceptibility to idiopathic PD. We present in this paper an extensive association analysis of a total of 20 markers including single nucleotide polymorphism/short tandem repeat/variable number tandem repeat/duplication markers from five candidate genes (namely, dopamine receptors DRD1, DRD2, DRD3, and DRD4, and dopamine transporter) with PD among two independent sample sets. The allelic, genotypic, and haplotypic association of these markers with PD was tested in South Indian (SI) samples (147 cases, 130 controls) and replicated in a larger North Indian (NI) sample set (340 cases, 344 controls). Of the several markers analyzed, 120 bp duplication marker of DRD4 gene showed promising results with PD in both of the sample sets. A significant allelic association in SI [odds ratio, OR (95% confidence interval, CI)=0.67 (0.47–0.97) for 120 bp dup; 1.48 (1.03–2.13) for 120 bp WT] and genotypic association in SI [OR (95% CI)= 0.56 (0.35–0.91) for 120 bp dup/dup; 1.62 (0.99–2.64) for 120 bp dup/120 bp WT] and in NI [OR (95% CI)= 1.41 (1.03–1.93) for 120 bp dup/ 120 bp WT] was observed. This is the first report on the association of dopaminergic gene polymorphisms with PD from the Indian sub-continent. Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users. An erratum to this article can be found at     

Additional support for the cognitive model of schizophrenia: evidence of elevated defeatist beliefs in schizotypy

ObjectivesThe cognitive model of poor functioning in schizophrenia posits that defeatist performance beliefs—overgeneralized negative beliefs about one's ability to perform tasks—develop prior to the onset of psychosis and contribute to the development and maintenance of negative symptoms and poor functioning. Although several studies with schizophrenia samples have provided support for the model, there is a paucity of research investigating these beliefs in individuals with schizotypy—those exhibiting traits reflecting a putative genetic liability for schizophrenia. This study had two aims: to examine whether defeatist performance beliefs (1) are elevated in schizotypy compared to controls and (2) are associated with decreased quality of life and working memory and increased negative but not positive schizotypy traits in the schizotypy group.MethodsSchizotypy (n = 48) and control (n = 53) groups completed measures of schizotypy traits, defeatist performance beliefs, quality of life, and working memory.ResultsAnalyses revealed that the schizotypy group reported significantly more defeatist performance beliefs than the control group. Within the schizotypy group, increased defeatist performance beliefs were significantly associated with greater negative schizotypy traits and lower quality of life. No significant associations were observed between defeatist performance beliefs and positive schizotypy traits and working memory.ConclusionsResults generally support the theoretical validity of the cognitive model of poor functioning in schizophrenia and suggest that elevated defeatist performance beliefs may contribute to the manifestation of subclinical negative symptom traits and reduced quality of life among those with a latent vulnerability for schizophrenia.     

Are dopa-responsive dystonia and Parkinson’s disease related disorders? A case report

Objectivel-Dopa-responsive dystonia (DRD) is a hereditary dystonia characterized by an excellent response to low dosages of levodopa. DRD patients may also develop Parkinsonism which resembles idiopathic Parkinson’s disease. In classical DRD no changes in the dopaminergic uptake have been observed.MethodsA 65-year old woman presented with clinically remarkably slowly progressing Parkinson’s disease (PD) without any dystonic signs and excellent response to dopaminergic medications. We obtained a [¹²³I] FP-CIT-SPECT (DaTSCAN?) in order to elucidate a striatal dopaminergic deficit.ResultsWe found a reduced uptake in the [¹²³I] FP-CIT-SPECT (DaTSCAN?) contralateral to the more affected body side. Additionally, the patient showed a heterozygous deletion of the GHC1 gene.ConclusionsPatients with mild parkinsonian symptoms, excellent response to low dosages of dopaminergic drugs and a reduced dopamine-transporter uptake in [¹²³I] FP-CIT-SPECT might more commonly be GCH1 mutation carriers than has previously been supposed. PD patients with a positive family history of DRD and combination of these clinical symptoms should be offered genetic counselling and testing for GCH1.     

The dopamine D3 receptor (DRD3) gene and risk of schizophrenia: Case–control studies and an updated meta-analysis

The dopamine D3 receptor (DRD3) has been suggested to be involved in the pathophysiology of schizophrenia. DRD3 has been tested for an association with schizophrenia, but with conflicting results. A recent meta-analysis suggested that the haplotype T–T–T–G for the SNPs rs7631540–rs1486012–rs2134655–rs963468 may confer protection against schizophrenia. However, almost all previous studies of the association between DRD3 and schizophrenia have been performed using a relatively small sample size and a limited number of markers. To assess whether DRD3 is implicated in vulnerability to schizophrenia, we conducted case–control association studies and performed an updated meta-analysis. In the first population (595 patients and 598 controls), we examined 16 genotyped single nucleotide polymorphisms (SNPs), including tagging SNPs selected from the HapMap database and SNPs detected through resequencing, as well as 58 imputed SNPs that are not directly genotyped. To confirm the results obtained, we genotyped the SNPs rs7631540–rs1486012–rs2134655–rs963468 in a second, independent population (2126 patients and 2228 controls). We also performed an updated meta-analysis of the haplotype, combining the results obtained in five populations, with a total sample size of 7551. No supportive evidence was obtained for an association between DRD3 and schizophrenia in our Japanese subjects. Our updated meta-analysis also failed to confirm the existence of a protective haplotype. To draw a definitive conclusion, further studies using larger samples and sufficient markers should be carried out in various ethnic populations.     

Working memory brain activity and capacity link MAOA polymorphism to aggressive behavior during development

A developmental increase in working memory capacity is an important part of cognitive development, and low working memory (WM) capacity is a risk factor for developing psychopathology. Brain activity represents a promising endophenotype for linking genes to behavior and for improving our understanding of the neurobiology of WM development. We investigated gene–brain–behavior relationships by focusing on 18 single-nucleotide polymorphisms (SNPs) located in six dopaminergic candidate genes (COMT, SLC6A3/DAT1, DBH, DRD4, DRD5, MAOA). Visuospatial WM (VSWM) brain activity, measured with functional magnetic resonance imaging, and VSWM capacity were assessed in a longitudinal study of typically developing children and adolescents. Behavioral problems were evaluated using the Child Behavior Checklist (CBCL). One SNP (rs6609257), located ∼6.6 kb downstream of the monoamine oxidase A gene (MAOA) on human chromosome X, significantly affected brain activity in a network of frontal, parietal and occipital regions. Increased activity in this network, but not in caudate nucleus or anterior prefrontal regions, was correlated with VSWM capacity, which in turn predicted externalizing (aggressive/oppositional) symptoms, with higher WM capacity associated with fewer externalizing symptoms. There were no direct significant correlations between rs6609257 and behavioral symptoms. These results suggest a mediating role of WM brain activity and capacity in linking the MAOA gene to aggressive behavior during development.     

Investigation of the expression of genes affecting cytomatrix active zone function in the amygdala in schizophrenia: effects of antipsychotic drugs

The cytomatrix active zone (CAZ) is a specialized cellular structure regulating release of vesicles. We reported previously increased expression of three CAZ genes, piccolo, RIMS2 and RIMS3 in the amygdala in schizophrenia. This study determined the levels of gene and protein expression for components of the active zone including two additional CAZ genes in the amygdala from subjects with schizophrenia and non-psychiatric controls, as well as the effects of antipsychotic drugs. Whilst relative real-time PCR analysis did not identify significant change in the expression of six additional active zone genes, Western blot analysis showed increased piccolo and RIMS2 protein expression in the amygdala in schizophrenia. In vitro analysis suggests antipsychotic drug treatment was unlikely to have caused the changes in RIMS2, RIMS3 and piccolo expression observed in the amygdala in schizophrenia. Therefore, this study provides further evidence suggesting that piccolo, RIMS2, RIMS3, but not the entire components of the active zone are involved in the neurobiology of schizophrenia.