|Certain cognitive deficits in individuals with schizophrenia have been linked to disturbed GABA and glutamate neurotransmission in the prefrontal cortex (PFC). 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 (mGluR1α and 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 mGluR. Finally, the endocannabinoid system plays an important role in regulating GABA and glutamate neurotransmission; the status of endocannabinoid ligands, such as 2-arachidonoylglycerol (2-AG), can be inferred, in part, through measures of diacylglycerol lipase and monoglyceride lipase, which synthesize and degrade 2-AG, respectively. We used quantitative PCR to measure mRNA levels for group I mGluR, RGS4, and markers of the endocannabinoid system in PFC area 9 from 42 schizophrenia subjects and matched normal comparison subjects. Schizophrenia subjects had higher mRNA levels for mGluR1α 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. Together, higher mGluR1α and lower RGS4 mRNA levels may represent a disturbed “molecular hub” in schizophrenia that may disrupt the function of PFC cortical networks. For example, as shown in the figure, under normal conditions, activation of mGluR1α results in long-term potentiation of NMDA and AMPA receptors and activation of DAGL which leads to synthesis of 2-AG and suppression of GABA release from nearby inhibitory axon terminals that contain the CB1 receptor. In addition, RGS4 reduces signaling through several different G protein-coupled receptors, including group I mGluR, opioid, serotonin, and dopamine receptors. In schizophrenia, higher mGluR1α and lower RGS4 mRNA levels suggest the presence of enhanced signaling through mGluR1α. Higher mGluR1α signaling may have diverse effects on multiple components of neural transmission in schizophrenia (red font), including greater long-term potentiation of NMDA and AMPA receptors, enhanced 2-AG synthesis, and greater suppression of GABA release from inhibitory axon terminals that contain the CB1 receptor. In addition, lower RGS4 levels may result in less inhibition of several classes of G protein-coupled receptors (yellow font).