Biomedical Sciences ETDs

Publication Date

5-1-2010

Abstract

One of the most consistent findings in schizophrenia is the dysfunction of specific subsets of GABAergic interneurons in distributed brain regions including the prefrontal cortex and cerebellum. Analyses of post-mortem tissue from cerebellar hemispheres from 13 schizophrenic patients and 13 matched controls by quantitative real-time PCR (qRT-PCR) revealed that the mRNA levels of both the 67 kDa and 65 kDa isoforms of glutamic acid decarboxylase (GAD67 and GAD65) are decreased. Additionally, the presynaptic GABA transporter GAT-1 and the Golgi cell specific neuromodulator metabotropic glutamate receptor 2 (mGluR2) were decreased in the schizophrenic group. Postsynaptic upregulation of GABAA-alpha6 and delta along with downregulation of neuronal nitric oxide synthase (nNOS), a negative modulator of GABA release, were also seen, suggesting a compensatory mechanism to counteract deficits in GABAergic transmission. In addition to GABAergic alterations in schizophrenia, N-methyl-D-aspartate (NMDA) receptor dysfunction has been proposed. To investigate this possibility, we measured NMDA receptor subunit mRNAs in the same samples and found that the NR2B subunit showed a near-significant decrease (p=0.0681) in the patients. In contrast, the kainic acid receptor subunits GluR6 and KA2 were upregulated in the granule cell layer. In an effort to understand the mechanisms for these gene expression changes, we examined adult rats chronically exposed to NMDA receptor antagonist phencyclidine (PCP, 2.58 mg/kg/day, i.p.), which elicits schizophrenia-like symptoms in both humans and animal models. Analyses of PCP-treated rat cerebellar hemispheres demonstrated similar decreases in all GABAergic marker mRNAs as seen in patients, as well as a decrease in Golgi cell GAD67 as shown by quantitative in situ hybridization (qISH). Additionally, decreases in both NR2B and NR2D transcripts, which are present in Golgi cells and colocalize extra-synaptically, were seen. Since low doses of PCP preferentially block NMDA receptors in GABAergic interneurons, chronic PCP administration could preferentially affect Golgi cells in the cerebellum. Deficits in these GABAergic interneurons may lead to disinhibited firing of cerebellar granule cells, as suggested by our previous studies of increased activity-dependent gene expression in these neurons. In conclusion, our results support the notion that GABA deficits are key elements in the pathophysiology of schizophrenia.

Keywords

Schizophrenia, PCP, Phencyclidine, GABA, NMDA, Cerebellum, Real-time PCR, In situ

Sponsors

The MIND Institute

Document Type

Dissertation

Language

English

Degree Name

Biomedical Sciences

Level of Degree

Doctoral

Department Name

Biomedical Sciences Graduate Program

First Committee Member (Chair)

Bustillo, Juan

Second Committee Member

Ness, Scott

Third Committee Member

Wilson, Michael

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