The mitochondrial matrix protein cyclophilin D contributes to deficits in parvalbumin interneurons in schizophrenia

Author:

O’Brien John T.,Jalilvand Sophia P.,Suji Neha A.,Phensy Aarron,Jupelly Rohan K.,Mwirigi Juliet M.,Elahi Hajira,Price Theodore J.ORCID,Kroener SvenORCID

Abstract

AbstractBACKGROUNDCognitive deficits in schizophrenia are linked to dysfunctions of the dorsolateral prefrontal cortex (DLPFC), including alterations in parvalbumin (PV)-expressing interneurons (PVIs). Redox dysregulation and oxidative stress may represent convergence points in the pathology of schizophrenia, causing dysfunction of GABAergic interneurons and loss of PV. Here, we show that the mitochondrial matrix protein cyclophilin-D (CypD), a critical initiator of the mitochondrial permeability transition pore (mPTP) and modulator of the intracellular redox state, is altered in PVIs in schizophrenia.METHODSWestern blotting was used to measure CypD protein levels in postmortem DLPFC specimens of schizophrenic (n=27) and matched comparison subjects with no known history of psychiatric or neurological disorders (n=26). In a subset of this cohort, multilabel immunofluorescent confocal microscopy with unbiased stereological sampling methods were used to quantify 1) numbers of PVI across the cortical mantle (20 control, 15 schizophrenia) and 2) PV and CypD protein levels from PVIs in the cortical layers 2-4 (23 control, 19 schizophrenia).RESULTSIn schizophrenic subjects, the overall number of PVIs in the DLPFC was not significantly altered, but in individual PVIs of layers 2-4 PV protein levels decreased along a superficial-to-deep gradient when compared to unaffected comparison subjects. These laminar-specific PVI alterations were reciprocally linked to significant CypD elevations both in PVIs and within total DLPFC gray matter.CONCLUSIONSOur findings support previously reported PVI anomalies in schizophrenia and suggest that CypD-mediated mPTP formation could be a potential contributor to PVI dysfunction in schizophrenia.

Publisher

Cold Spring Harbor Laboratory

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