UP-REGULATION OF GABA A RECEPTOR BINDING ON NEURONS OF THE PREFRONTAL CORTEX IN SCHIZOPHRENIC SUBJECTS F. M. BENES,*²‡ S. L. VINCENT,* A. MARIE* and Y. KHAN* *Laboratory for Structural Neuroscience, McLean Hospital, 115 Mill Street, Belmont, MA 02178, U.S.A. ²Department of Psychiatry and the Program in Neuroscience, Har vard Medical School, Boston, Massachusetts, U.S.A. Abstract––Recent investigations have reported a reduced density of interneurons and an increase of GABA A receptor binding occurring preferentially in layer II of the anterior cingulate cortex of schizophrenic subjects [Benes F. M. et al. (1992) J. Neurosci. 12, 924–929]. Since a reduction in the density of interneurons has also been found in layer II of the prefrontal cortex, this study has sought to determine whether an up-regulation of the GABA A receptor binding activity might also be found in this region of schizophrenics. A high-resolution autoradiographic analysis of bicuculline-sensitive [ 3 H]muscimol (GABA A ) receptor binding on individual neuron cell bodies in layers II, III, IV and VI has been applied to Brodmann area 10 from normal controls (n = 16) and schizophrenic (n = 7) subjects. A computer- assisted technique has been used under strictly blind conditions to determine whether differences in binding occur in the schizophrenic group. A significant increase of GABA A receptor binding activity has been observed in layers II, III, V and VI in the schizophrenic group. When the binding is expressed as a density with respect to neuronal cell size, there is a gradient of binding across layers II, III, V and VI, with neuronal cell bodies in layer II having the greatest density of grains. When different subpopulations of neurons distinguished according to size criteria are examined separately, large (pyramidal) neurons show significantly higher binding, particularly in layer II, where it was increased by 90% in schizophrenics. Small (non-pyramidal) cells do not show significant differences in binding in schizophrenics, except in layer VI, where there was a 135% increase. Potential confounding effects from age and post mortem interval do not explain the differences between the two groups, because both young and old schizophren- ics, as well as schizophrenics with long and short post mortem intervals, showed increased GABA A receptor binding activity when compared to control cases distinguished in a corresponding fashion. These data suggest that there may be a preferential reduction of inhibitory GABAergic inputs to pyramidal neurons, particularly in layer II of the prefrontal cortex, in schizophrenia. This change could potentially result in an increased excitatory outflow from the prefrontal area to other cortical regions of the schizophrenic brain. Overall, these results are consistent with the idea that reduced amounts of GABAergic activity in the prefrontal cortex could be related to a perinatal disturbance and could be a potentially important component of the pathophysiology of psychosis. Copyright  1996 IBRO. Published by Elsevier Science Ltd. Key words: Pyramidal cells, non-pyramidal neurons, layer II, Brodmann area 10. In recent years, a renewed interest in the question of whether there are histopathological changes in the brains of schizophrenic patients has been generated by reports of volume loss, 13,14 decreased numbers of neurons 4,6,12,18,24 and other subtle cytoarchitectural variations 3,5,7,23,27 in corticolimbic brain regions of individuals with schizophrenia. One study reported a reduction in the density of non-pyramidal neurons, particularly in layer II, of the anterior cingulate cortex and suggested that the missing cells might be GABAergic interneurons. 6 To test the hypothesis that this latter change might result in a compensatory up-regulation of the postsynaptic receptor, a high- resolution receptor binding technique for GABA A receptor binding activity 48 was modified for human post mortem cortex. 10 Using this approach, a marked increase of receptor binding was found in the neuropil of layer I and on neuronal cell bodies of layers II and III in the anterior cingulate cortex of schizophrenics; 10 there was no increase of binding in the deeper laminae of this region. These results were interpreted as being consistent with a loss of inhibi- tory interneurons having occurred during the perina- tal period, a time when basket cells in superficial laminae are actively differentiating. 30,31 Although cortical areas differ considerably with regard to their anatomical and functional specializa- tions, one study has suggested that diverse regions of ‡To whom correspondence should be addressed. A bbreviations: ANOVA, analysis of variance; PMI, post mortem interval. Pergamon N euroscience Vol. 75, No. 4, pp. 1021–1031, 1996 Copyright  1996 IBRO. Published by Elsevier Science Ltd Printed in Great Britain 0306–4522/96 $15.00+ 0.00 PII: S0306-4522(96)00328-4 1021