Alterations in Metabotropic Glutamate Receptor 1α and Regulator of G Protein Signaling 4 in the Prefrontal Cortex in Schizophrenia

Objective: Certain cognitive deficits in individuals with schizophrenia have been linked to disturbed gamma-aminobutyric acid (GABA) and glutamate neurotransmission in the prefrontal cortex. Thus, it is important to understand how the mechanisms that regulate GABA and glutamate neurotransmission are altered in schizophrenia. For example, group I metabotropic glutamate receptors (mGluR1 alpha, mGluR5) modulate both GABA and glutamate systems. In addition, regulator of G protein signaling 4 (RGS4) reduces intracellular signaling through several different G protein-coupled receptors, including group I mGluRs. Finally, the endocannabinoid system plays an important role in regulating GABA and glutamate neurotransmission. The status of endocannabinoid ligands, such as 2-arachidonoylglycerol, can be inferred in part through measures of diacylglycerol lipase and monoglyceride lipase, which synthesize and degrade 2-arachidonoylglycerol, respectively. Method: Quantitative polymerase chain reaction was used to measure mRNA levels for group I mGluRs, RGS4, and markers of the endocannabinoid system in the prefrontal cortex Brodmann's area 9 of 42 schizophrenia subjects and matched normal comparison subjects. Similar analyses in monkeys chronically exposed to haloperidol, olanzapine, or placebo were also conducted. Results: Schizophrenia subjects had higher mRNA levels for mGluR1 alpha and lower mRNA levels for RGS4, and these differences did not appear to be attributable to antipsychotic medications or other potential confounds. In contrast, no differences between subject groups were found in mRNA levels for endocannabinoid synthesizing and metabolizing enzymes. Conclusions: Together, higher mGluR1 alpha and lower RGS4 mRNA levels may represent a disturbed molecular hub in schizophrenia that may disrupt the function of prefrontal cortical networks, including both GABA and glutamate systems.