GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia.
The pathophysiology of schizophrenia involves dysfunction of the dorsolateral prefrontal cortex, and this dysfunction may be related to alterations in GABA neurotransmission. Determining the causes and consequences of altered GABA neurotransmission in schizophrenia requires knowledge of which subpopulations of cortical GABA neurons are affected. The chandelier class of GABA neurons are of interest in this regard because their axon terminals form distinctive vertical arrays (termed 'cartridges') which synapse exclusively with the axon initial segments of pyramidal neurons, the principal class of cortical excitatory neurons. We evaluated the integrity of chandelier neuron cell bodies and axon cartridges in PFC areas 9 and 46 of schizophrenic subjects using immunocytochemical techniques and antibodies against parvalbumin and the GABA membrane transporter GAT-1. Schizophrenic subjects did not differ from matched control subjects in the relative density, laminar distribution or size of parvalbumin-containing neurons. In contrast, the density of GAT-1-immunoreactive chandelier neuron axon cartridges was decreased by 40% in schizophrenic subjects compared to both normal controls and subjects with other psychiatric disorders. The axon terminals of other subclasses of GABA neurons did not appear to be similarly affected. These findings suggest that disturbed GABA neurotransmission in the PFC of schizophrenic subjects may be due to a selective alteration of GAT-1 protein in the axon terminals of chandelier neurons.
Lewis
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University of Pittsburgh, Departments of Psychiatry and Neuroscience, W1650 BST, 3811 O'Hara Street, Pittsburgh, PA, USA. lewis@cortex.psychiatry.pitt.edu
D006801:Humans; D009434:Neural Pathways / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D017397:Prefrontal Cortex / Q000473:pathology*; D012559:Schizophrenia / Q000473:pathology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D005680:gamma-Aminobutyric Acid