Elevations in the Mitochondrial Matrix Protein Cyclophilin D Correlate With Reduced Parvalbumin Expression in the Prefrontal Cortex of Patients With Schizophrenia

John T O'Brien; Sophia P Jalilvand; Neha A Suji; Rohan K Jupelly; Aarron Phensy; Juliet M Mwirigi; Hajira Elahi; Theodore J Price; Sven Kroener

doi:10.1093/schbul/sbae016

Elevations in the Mitochondrial Matrix Protein Cyclophilin D Correlate With Reduced Parvalbumin Expression in the Prefrontal Cortex of Patients With Schizophrenia

Schizophr Bull. 2024 Feb 27:sbae016. doi: 10.1093/schbul/sbae016. Online ahead of print.

Authors

John T O'Brien¹, Sophia P Jalilvand¹, Neha A Suji¹, Rohan K Jupelly¹, Aarron Phensy¹, Juliet M Mwirigi¹, Hajira Elahi¹, Theodore J Price¹, Sven Kroener¹

Affiliation

¹ School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX, USA.

PMID: 38412332
DOI: 10.1093/schbul/sbae016

Abstract

Background and hypothesis: Cognitive 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.

Study design: Western blotting was used to measure CypD protein levels in postmortem DLPFC specimens of schizophrenic patients (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 unaffected comparison, 14 schizophrenia) and (2) PV and CypD protein levels from PVIs in the cortical layers 2-4 (23 unaffected comparison, 18 schizophrenia).

Study results: In schizophrenic patients, 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 total DLPFC gray matter.

Conclusions: Our 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.

Keywords: CypD; mitochondria; oxidative stress; parvalbumin; schizophrenia.