Implications for altered glutamate and GABA metabolism in the dorsolateral prefrontal cortex of aged schizophrenic patients.
OBJECTIVE
Pharmacological, clinical, and postmortem studies suggest altered gamma-aminobutyric acid (GABA)-ergic and glutamatergic function in patients with schizophrenia. The dorsolateral prefrontal cortex is one key locus of abnormality. The precise neurochemical mechanisms underlying neurotransmitter alterations, such as hypoglutamatergia or GABA dysfunction, are not well understood. This study investigated key biochemical elements of GABA and glutamate metabolism in brain specimens from schizophrenic patients. The activities of nine principal GABA and glutamate-associated metabolic enzymes were measured concurrently in the dorsolateral prefrontal cortex of antemortem-assessed and neuropathologically characterized schizophrenic and comparison subjects.


METHODS
Postmortem dorsolateral prefrontal cortex specimens from schizophrenia, Alzheimer's disease, and normal nonpsychiatric comparison subjects were assayed to determine activities of the principal glutamate and GABA-metabolizing enzymes glutamine synthetase, glutamate dehydrogenase, alpha-ketoglutarate dehydrogenase, phosphate-activated glutaminase, alanine aminotransferase, aspartate aminotransferase, glutamic acid decarboxylase, GABA-transaminase, and succinic semialdehyde dehydrogenase.


RESULTS
Glutamic acid decarboxylase activities were twofold greater and phosphate-activated glutaminase activities were fourfold greater in the schizophrenic group than in the comparison group. Differences in postmortem interval, tissue pH, inhibition of phosphate-activated glutaminase, and medication effects could not account for the differences. Differences in phosphate-activated glutaminase and glutamic acid decarboxylase activities in equivalent specimens from Alzheimer's patients were not observed. The activities of the remaining enzymes were unchanged.


CONCLUSIONS
Greater phosphate-activated glutaminase and glutamic acid decarboxylase activities, specific to schizophrenia patients, provide additional biochemical evidence that dorsolateral prefrontal cortex glutamate and GABA metabolism is altered in schizophrenic subjects. These greater activities are consistent with models of a dysregulated glutamatergic/GABA-ergic state in schizophrenia.
Gluck
Martin R
MR
Departmnent of Neurology, Medical Research Building, Bronx Veterans Medical Center, 130 West Kingsbridge Road, Bronx, NY 10468, USA. gluck.martin@bronx.va.gov
Thomas
Rohan G
RG
Davis
Kenneth L
KL
Haroutunian
Vahram
V
D000367:Age Factors; D000368:Aged; D002950:Citrate (si)-Synthase / Q000032:analysis / Q000502:physiology; D005260:Female; D007839:Functional Laterality / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000032:analysis / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism* / Q000502:physiology; D005972:Glutaminase / Q000032:analysis / Q000502:physiology; D006801:Humans; D008297:Male; D011180:Postmortem Changes; D017397:Prefrontal Cortex / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D012559:Schizophrenia / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000502:physiology
D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D002950:Citrate (si)-Synthase; D005972:Glutaminase; D005968:Glutamate Decarboxylase