Deletion of the mitochondrial matrix protein cyclophilin-D prevents parvalbumin interneuron dysfunction and cognitive deficits in a mouse model of NMDA hypofunction

Redox dysregulation and oxidative stress are final common pathways in the pathophysiology of a variety of psychiatric disorders, including schizophrenia. Oxidative stress causes dysfunction of GABAergic parvalbumin-positive interneurons (PVI), which are crucial for the coordination of neuronal synchrony during sensory- and cognitive-processing. Mitochondria are the main source of reactive oxygen species (ROS) in neurons and they control synaptic activity through their roles in energy production and intracellular calcium homeostasis. We have previously shown that in male mice transient blockade of NMDA receptors during development (subcutaneous injections of 30 mg/kg ketamine (KET) on postnatal days 7, 9, and 11) results in long-lasting alterations in synaptic transmission and reduced parvalbumin expression in the adult prefrontal cortex (PFC), contributing to a behavioral phenotype that mimics multiple symptoms associated with schizophrenia. These changes correlate with oxidative stress and impaired mitochondrial function in both PVI and pyramidal cells. Here, we show that genetic deletion (Ppif-/-) of the mitochondrial matrix protein cyclophilin D (CypD) prevents perinatal KET-induced increases in ROS and the resulting deficits in PVI function, and changes in excitatory and inhibitory synaptic transmission in the PFC. Deletion of CypD also prevented KET-induced behavioral deficits in cognitive flexibility, social interaction, and novel object recognition. Taken together, these data highlight how mitochondrial activity may play an integral role in modulating PVI-mediated cognitive processes. Significance StatementMitochondria are important modulators of oxidative stress and cell function, yet how mitochondrial dysfunction affects cell activity and synaptic transmission in psychiatric illnesses is not well understood. NMDA receptor blockade with ketamine during development causes oxidative stress, dysfunction of parvalbumin-positive interneurons (PVI), and long-lasting physiological and behavioral changes. Here we show that mice deficient for the mitochondrial matrix protein cyclophilin D show robust protection from PVI dysfunction following perinatal NMDAR-blockade. Mitochondria serve as an essential node for a number of stress-induced signaling pathways and our experiments suggest that failure of mitochondrial redox regulation can contribute to PVI dysfunction.