Altered gene expression in the amygdala in schizophrenia: Up-regulation of genes located in the cytomatrix active zone

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Abstract

The amygdala is implicated in the pathophysiology of schizophrenia through its function in the processing of emotions. However, the genes involved in the dysfunction of the amygdala in schizophrenia are yet to be identified. This study examined gene expression in the amygdala in postmortem tissue from seven matched pairs of schizophrenia and non-psychiatric control subjects, using oligonucleotide-microarrays representing 19,000 gene transcripts and real-time PCR confirmation of gene expression changes in eleven matched pairs. Genes involved in presynaptic function, myelination and cellular signalling were identified as being consistently dysregulated in this cohort of subjects with schizophrenia. In particular, the expression of three genes involved in the cytomatrix active zone, Regulating membrane exocytosis 2, Regulating membrane exocytosis 3 and Piccolo, was up-regulated. These results implicate for the first time the dysfunction of the cytomatrix active zone of synapses in the amygdala in the pathophysiology of schizophrenia.

Introduction

A number of studies have successfully used microarrays to examine gene expression differences in several brain regions in schizophrenia including the prefrontal cortex (PFC) (Hakak et al., 2001, Middleton et al., 2002, Mimmack et al., 2002, Mirnics et al., 2000, Mirnics et al., 2001, Tkachev et al., 2003, Vawter et al., 2001, Vawter et al., 2002), entorhinal cortex (Hemby et al., 2002), cerebellum (Vawter et al., 2001) and middle temporal gyrus (Aston et al., 2004, Vawter et al., 2001). In these studies, few individual gene expression changes have been replicated. This may be due to a number of reasons including the heterogeneity within the symptoms of schizophrenia, as well as the different microarray platforms used and the lack of consistency of genes represented on the microarrays. However, most studies have found alterations in different genes of the same functional or family group, including genes involved in synaptic plasticity, presynaptic function, myelination, neuronal development, neurotransmission, metabolism and proteolytic function (Aston et al., 2004, Middleton et al., 2002, Mimmack et al., 2002, Mirnics et al., 2000, Mirnics et al., 2001, Tkachev et al., 2003, Vawter et al., 2001, Vawter et al., 2002).

The amygdala is involved in emotion and memory processing. Dysfunction of emotion processing is a major symptom of schizophrenia, and alterations in the neural circuits of emotion, particularly in the amygdala, have been identified in schizophrenia (Takahashi et al., 2004). In addition, functional (Kosaka et al., 2002) and structural (Hulshoff Pol et al., 2001, Wright et al., 1999) magnetic resonance imaging and immunohistochemical analysis (Yang et al., 1998) in schizophrenia have implicated the amygdala in the pathophysiology of this disorder.

To date, there have been few attempts to identify alterations in gene expression in the amygdala that may contribute to the development of schizophrenia. This study used oligonucleotide-microarrays to identify genes with altered expression in the amygdala in schizophrenia compared to non-psychiatric controls. The function of these differentially expressed genes may lead to a greater understanding of the pathogenesis of schizophrenia.

Section snippets

Microarrays

Of the 19,000 gene transcripts analysed on the microarrays, an average of 5394 ± 2220 genes were expressed on each microarray comparison, although only 4311 were expressed in at least four of the seven pairs. In comparison to previously published microarray studies of postmortem brains in schizophrenia (e.g. Mirnics et al., 2000), this level of gene expression is low. Indeed, this appears to be specific to the amygdala since a similar study underway in the superior temporal gyrus using the same

Discussion

Utilising a matched pair paradigm and 19,000 gene oligonucleotide-microarrays, this study identified 132 genes with altered expression in the amygdala in schizophrenia. Many of these genes are located within known schizophrenia linkage sites and are members of functional groups relevant to the pathophysiology of schizophrenia (Table 2, Table 3). Consistent with most schizophrenia gene expression studies (Hemby et al., 2002, Middleton et al., 2002, Mimmack et al., 2002, Tkachev et al., 2003,

Case characteristics

Ethical approval (number H-244-0202) for this study was granted by the University of Newcastle Human Research Ethics Committee. Blocks of coronally sectioned postmortem amygdala tissue (1 cm thick) were sourced from the NSW Tissue Resource Centre (The University of Sydney). Consent was obtained from the next of kin, and a diagnosis of schizophrenia according to the DSM-IV criteria was confirmed by medical file review using the Item Group Checklist of the Schedules for Clinical Assessment in

Acknowledgments

This work was supported by: NISAD, utilising infrastructure funding from NSW Health and Ms. Margarete Ainsworth.

The Hunter Medical Research Institute, utilising infrastructure funding from NSW Health.

HMRI Adamstown Lions Club Young Investigator Award.

School of Biomedical Sciences RIBG and the University of Newcastle Strategic Reserve.

The Clive and Vera Ramaciotti Functional Genomics Centre, University of New South Wales.

The Adelaide Microarray Facility, supported by the Australian Cancer

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