Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects

Objective: Abnormalities in prefrontal cortical gamma-aminobutyric acid (GA BA) neurotransmission may contribute to cognitive dysfunction in schizophre nia. The density of chandelier neuron axon terminals (cartridges) immunorea ctive for the GABA membrane transporter (GAT-1) has been reported to be red uced in the dorsolateral prefrontal cortex of schizophrenic subjects. Becau se cartridges regulate the output of pyramidal cells, this study analyzed t he laminar distribution of GAT-1-immunoreactive cartridges to determine whe ther certain subpopulations of pyramidal cells are preferentially affected. Method: Measurements were made of the density of GAT-1-immunoreactive cart ridges in layers 2-3a, 3b-4, and 6 of dorsolateral prefrontal cortex area 4 6 in 30 subjects with schizophrenia, each of whom was matched to one normal and one psychiatric comparison subject. GAT-l-immunoreactive cartridge den sity was also examined in monkeys chronically treated with haloperidol. Res ults: Relative to both comparison groups, the schizophrenic subjects had si gnificantly lower GAT-1-immunoreactive cartridge density in layers 2-3a and 3b-4. The decrease was most common and most marked in layers 3b-4, where 8 0% of the schizophrenic subjects exhibited an average 50.1% decrease in car tridge density in comparison with the matched normal subjects. In contrast, GAT-l-immunoreactive cartridge density was unchanged in the haloperidol-tr eated monkeys. Conclusions: These findings demonstrate that the density of GAT-1-immunoreactive cartridges is reduced in the majority of schizophrenic subjects and that this alteration may most prominently affect the function of pyramidal cells located in the middle cortical layers. This abnormality may reflect a number of underlying deficits, including a primary defect in dorsolateral prefrontal cortex circuitry or a secondary response to altere d thalamic input to this region.