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Cerebral Cortex, Vol. 12, No. 10, 1063-1070, October 2002
© 2002 Oxford University Press

Reciprocal Alterations in Pre- and Postsynaptic Inhibitory Markers at Chandelier Cell Inputs to Pyramidal Neurons in Schizophrenia

David W. Volk1, Joseph N. Pierri2, Jean-Marc Fritschy4, Sungyoung Auh3, Allan R. Sampson3 and David A. Lewis1,2

1 Departments of Neuroscience, , 2 Psychiatry and , 3 Statistics, University of Pittsburgh, PA 15260, USA and , 4 Institute of Pharmacology, University of Zurich, CH-8057 Zurich, Switzerland

David A. Lewis, University of Pittsburgh, 3811 O’Hara Street, W1650 BST, Pittsburgh, PA 15213, USA. Email: lewisda{at}msx.upmc.edu.

In the prefrontal cortex of subjects with schizophrenia, markers of the synthesis and re-uptake of GABA appear to be selectively altered in a subset of interneurons that includes chandelier cells. Determining the effect of these disturbances in presynaptic GABA markers on inhibitory signaling requires knowledge of the status of GABAA receptors at the postsynaptic targets of chandelier cells, the axon initial segments (AIS) of pyramidal neurons. Because the {alpha}2 subunit of the GABAA receptor is preferentially localized at pyramidal neuron AIS, we quantified {alpha}2 subunit immunoreactive AIS in tissue sections containing prefrontal cortex area 46 from 14 matched triads of subjects with schizophrenia, subjects with major depression and control subjects. Systematic, random sampling revealed that the mean number of {alpha}2-labeled AIS per mm2 in subjects with schizophrenia was significantly (P = 0.007) increased by 113% compared to control subjects and non-significantly increased compared to subjects with major depression. Furthermore, within subjects with schizophrenia, the density of {alpha}2-labeled AIS was negatively correlated (r = –0.49, P = 0.038) with the density of chandelier axon terminals immunoreactive for the GABA membrane transporter. These data suggest that GABAA receptors are up-regulated at pyramidal neuron AIS in response to deficient GABA neuro-transmission at chandelier axon terminals in schizophrenia. Thus, disturbances in inhibition at the chandelier neuron–pyramidal neuron synapse may be a critical component of prefrontal cortical dysfunction in schizophrenia.


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