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

• Published in: The American journal of psychiatry Vol. 173; no. 11; pp. 1131 - 1139
• Main Authors: Chung, Daniel W, Fish, Kenneth N, Lewis, David A
• Format: Journal Article
• Language: English
• Published: United States American Psychiatric Association 01.11.2016
• Subjects: Adult; Animals; Antipsychotic Agents - pharmacology; Calbindin 2 - metabolism; Case-Control Studies; Disks Large Homolog 4 Protein; Female; Fluorescence; Glutamate Decarboxylase - biosynthesis; Humans; Immunohistochemistry; Interneurons - drug effects; Interneurons - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Macaca fascicularis; Male; Membrane Proteins - metabolism; Middle Aged; Neurons; Parvalbumins - drug effects; Parvalbumins - metabolism; Pathology; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Schizophrenia; Schizophrenia - metabolism; Schizophrenia - pathology; Vesicular Glutamate Transport Protein 1 - metabolism
• ISSN: 0002-953X; 1535-7228
• DOI: 10.1176/appi.ajp.2016.16010025

Objective: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.Method: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.Results: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.Conclusions: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.