Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia

Deficient excitatory drive to parvalbumin-containing cortical interneurons is proposed as a key neural substrate for altered gamma oscillations and cognitive dysfunction in schizophrenia. However, a pathological entity producing such a deficit has not been identified. The authors tested the hypothesis that cortical parvalbumin interneurons receive fewer excitatory synaptic inputs in individuals with schizophrenia.

Fluorescent immunohistochemistry, confocal microscopy, and post-image processing techniques were used to quantify the number of putative excitatory synapses (i.e., the overlap of vesicular glutamate transporter 1-positive [VGlut1+] puncta and postsynaptic density protein 95-positive [PSD95+] puncta) per surface area of parvalbumin-positive (PV+) or calretinin-positive (CR+) neurons in the dorsolateral prefrontal cortex from schizophrenia subjects and matched unaffected comparison subjects.

Mean density of VGlut1+/PSD95+ puncta on PV+ neurons was 18% lower in schizophrenia, a significant difference. This deficit was not influenced by methodological confounds or schizophrenia-associated comorbid factors, not present in monkeys chronically exposed to antipsychotic medications, and not present in CR+ neurons. Mean density of VGlut1+/PSD95+ puncta on PV+ neurons predicted the activity-dependent expression levels of parvalbumin and glutamic acid decarboxylase 67 (GAD67) in schizophrenia subjects but not comparison subjects.

To the authors' knowledge, this is the first demonstration that excitatory synapse density is lower selectively on parvalbumin interneurons in schizophrenia and predicts the activity-dependent down-regulation of parvalbumin and GAD67. Because the activity of parvalbumin interneurons is required for generation of cortical gamma oscillations and working memory function, these findings reveal a novel pathological substrate for cortical dysfunction and cognitive deficits in schizophrenia.