A SUBCLASS OF PREFRONTAL GAMMA-AMINOBUTYRIC-ACID AXON TERMINALS ARE SELECTIVELY ALTERED IN SCHIZOPHRENIA

In the primate cerebral cortex, morphologically and functionally diver se classes of local circuit neurons containing the inhibitory neurotra nsmitter gamma-aminobutyric acid (GABA) differentially regulate the ac tivity of pyramidal cells, the principal type of excitatory output neu rons. In schizophrenia, GABA neurotransmission in the prefrontal corte x (PFC) appears to be disturbed but whether specific populations of GA BA neurons are affected is not known, The chandelier class of GABA neu rons are of particular interest because their axon terminals, which fo rm distinctive arrays termed ''cartridges,'' provide inhibitory input exclusively to the axon initial segment of pyramidal cells. Thus, chan delier cells are positioned to powerfully regulate the excitatory outp ut of pyramidal neurons and, consequently, to substantially affect the patterns of neuronal activity within the PFC, In this study, an antib ody directed against the GABA membrane transporter GAT-1 was used to l abel GABA axon terminals in postmortem human brains, The relative dens ity of GAT-1-immunoreactive axon cartridges furnished by chandelier ne urons was decreased by 40% in the PFC of schizophrenic subjects compar ed with matched groups of normal control and nonschizophrenic psychiat ric subjects. In contrast, markers of the axon terminals of other popu lations of GABA neurons were not altered in the schizophrenic subjects , Furthermore, the density of GAT-1-immunoreactive axon cartridges was not altered in psychiatric subjects who had been treated with antipsy chotic medications. The changes in GAT-1-immunoreactive axon cartridge s of chandelier neurons in schizophrenia are likely to reflect altered information processing within the PFC and in its output connections t o other brain regions and could contribute to the cognitive impairment s seen in this disorder.