Cell and receptor type-specific alterations in markers of GABA neurotransmission in the prefrontal cortex of subjects with schizophrenia.
Impairments in cognitive control, such as those involved in working memory, are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC) in individuals with schizophrenia. This dysfunction appears to result, at least in part, from abnormalities in GABA-mediated neurotransmission. In this paper, we review recent findings indicating that the altered DLPFC circuitry in subjects with schizophrenia reflects changes in the expression of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission. Specifically, using a combination of methods, we found that subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding presynaptic regulators of GABA neurotransmission, neuropeptide markers of specific subpopulations of GABA neurons, and certain subunits of the GABA(A) receptor. In particular, alterations in the expression of the neuropeptide somatostatin suggested that GABA neurotransmission is impaired in the Martinotti subset of GABA neurons that target the dendrites of pyramidal cells. In contrast, none of the GABA-related transcripts assessed to date were altered in the DLPFC of monkeys chronically exposed to antipsychotic medications, suggesting that the effects observed in the human studies reflect the disease process and not its treatment. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia may be attributable to altered GABA neurotransmission in specific DLPFC microcircuits.
Lewis
David A
DA
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15213, USA. lewisda@upmc.edu
Hashimoto
Takanori
T
Morris
Harvey M
HM
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008568:Memory / Q000502:physiology*; D009434:Neural Pathways; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D017397:Prefrontal Cortex / Q000378:metabolism / Q000503:physiopathology*; D017729:Presynaptic Terminals / Q000502:physiology; D017966:Pyramidal Cells / Q000378:metabolism / Q000503:physiopathology; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D015415:Biomarkers; D017981:Receptors, Neurotransmitter; D005680:gamma-Aminobutyric Acid