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 neurotrans-mission 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 metabo-tropic glutamate receptors (mGluR1α, mGluR5) modulate both GABA and gluta-mate systems. In addition, regulator of G protein signaling 4 (RGS4) reduces intra-cellular 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 neurotrans-mission. 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.


METHODS
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 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.


CONCLUSIONS
Together, higher mGluR1α 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.
Volk
David W
DW
Department of Psychiatry, University of Pittsburgh, PA 15213, USA. volkdw@upmc.edu
Eggan
Stephen M
SM
Lewis
David A
DA
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008071:Lipoprotein Lipase / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008875:Middle Aged; D008994:Monoacylglycerol Lipases / Q000378:metabolism; D000077152:Olanzapine; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D020710:RGS Proteins / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*
D014150:Antipsychotic Agents; C578935:GRM5 protein, human; D020710:RGS Proteins; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; D001569:Benzodiazepines; C098799:RGS4 protein; D008994:Monoacylglycerol Lipases; D008071:Lipoprotein Lipase; D006220:Haloperidol; D000077152:Olanzapine