Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia

Dysfunction of the dorsolateral prefrontal cortex appears to be a central f eature of the pathophysiology of schizophrenia, and this dysfunction may be related to alterations in gamma aminobutyric acid (GABA) neurotransmission . Determining the causes and consequences of altered GABA neurotransmission in schizophrenia, and the relationship of these changes to other abnormali ties in prefrontal cortical circuitry, requires an understanding of which o f the multiple subpopulations of cortical GABA neurons are affected The cha ndelier class of GABA neurons, especially those located in the middle layer s of the prefrontal cortex (PFC), have been hypothesized to be preferential ly involved in schizophrenia because they 1) receive direct synaptic input from dopamine axons, 2) exert powerful inhibitory control over the excitato ry output of layer 3 pyramidal neurons, and 3) undergo substantial developm ental changes during late adolescence, the typical age of onset of schizoph renia. Consistent with this hypothesis, the axon terminals of chandelier ne urons, as revealed by immunoreactivity for the GABA membrane transporter, a re reduced substantially in the middle layers of the PFC in schizophrenic s ubjects. This alteration appears to be selective for the chandelier class o f GABA neurons and for the disease process of schizophrenia. These findings provide insight into the pathophysiologic mechanisms underlying prefrontal cortical dysfunction in schizophrenia, and they reveal new targets for the rapeutic intervention in this illness. Biol Psychiatry 1999;46:616-626 (C) 1999 Society of Biological Psychiatry.