Altered Expression of GABAA Delta and Alpha 4 Receptor Subunits in Schizophrenia

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DESCRIPTION (provided by applicant): Deficits in inhibitory neurotransmission appear to play a prominent role in the dysfunction of the prefrontal cortex (PFC) in schizophrenia. Although the density of some GABAA receptors is upregulated, apparently compensating for decreased GABAergic neurotransmission, our preliminary data suggest that the mRNA expression levels of the GABAA subunits sigma and alpha4 are decreased in schizophrenia. GABAA receptors containing sigma and alpha4 subunits mediate "tonic inhibition", which increases a cell's input conductance, making it less likely that an action potential is generated. Thus, decreased GABAergic signaling mediated by these receptors could contribute to altered inhibitory regulation of PFC circuitry. In addition, the pathogenetic mechanisms that cause deficits in the expression of sigma and alpha4 subunits are unknown. Studies suggest that deficits in GABA-related markers in schizophrenia are associated with reduced neurotransmission through NMDA receptors. However, it is unknown whether decreased NMDA receptor signaling results in decreased levels of sigma and alpha4 subunits. Aim 1. To determine whether the mRNA levels of sigma and alpha4 subunits are decreased in the PFC in schizophrenia. We will assess the anatomical localization and expression pattern of these transcripts across the PFC of matched pairs of schizophrenia and control subjects, using in situ hybridization and grain counting techniques. Aim 2. To determine whether changes in the expression of sigma and alpha4 subunits are influenced by treatment with antipsychotic medications. The clinical relevance of reduced levels of sigma and alpha4 subunits in schizophrenia depends on whether these changes are specific to the disease process or are a consequence of exposure to antipsychotic medication. Therefore, we will use in situ hybridization to assess the mRNA levels of sigma and alpha4 subunits in the PFC of non-human primates chronically exposed to haloperidol, olanzapine or placebo. Aim 3. To determine whether the expression levels of sigma and alpha4 subunits are decreased in the PFC of NR1 hypomorphic mice. Decreased expression of sigma and alpha4 subunits in schizophrenia may represent a deficit in signaling through NMDA receptors. We will utilize in situ hybridization and grain counting techniques to assess the mRNA levels of sigma and alpha4 subunits in the prefrontal cortex (PFC) of mice genetically engineered to express reduced levels of the NMDA NR1 subunit. In addition, using immunocytochemistry, we will determine if the protein levels of sigma and alpha4 subunits are reduced in the PFC of NR1 hypomorphic mice. Together, these studies will provide an understanding of the pathological entities that contribute to deficits in inhibitory neurotransmission in schizophrenia and the mechanisms that may give rise to them.