Schizophrenia is a neurodevelopmental brain disorder in which genetic predispositions and environmental stressors converge. Accumulating evidence suggests that the diverse causes of schizophrenia converge on two interdependent factors: brain redox imbalance and NMDA receptor (NMDAR) hypofunction. A functional loss of NMDARs (caused by oxidative stress), specifically on parvalbumin-positive interneurons (PVI), may disrupt the cortical excitation-inhibition balance, leading to secondary overstimulation of downstream neurotransmitter systems. Mitochondria play a major role in redox regulation and mitochondrial dysfunction has also been highlighted in the etiology of schizophrenia. Activation of the mitochondrial matrix protein cyclophilin-D (CypD) is a critical step in loss of mitochondrial redox regulation. We propose here that CypD-mediated oxidative stress underlies NMDAR dysfunction in PVI in schizophrenia and that genetic removal of CypD will prevent the development of cognitive and negative deficits in an animal model of schizophrenia. The overarching goals of this application are 1) to study the contribution of mitochondrial redox regulation to behavioral and synaptic changes that occur in a developmental NMDAR hypofunction model of schizophrenia, and 2) to determine if manipulations of the mitochondrial matrix protein CypD can diminish oxidative stress and prevent the pathological changes caused by perinatal NMDAR blockade. This application will utilize a combination of electrophysiological, molecular and behavioral approaches to answer these questions.
In Aim 1 we will test adult CypD-KO and WT mice on a battery of behavioral tasks that assess rodent equivalents of cognitive, negative, and positive symptoms of schizophrenia. We will also study if CypD knock-out protects against the loss of PVI that result from developmental oxidative stress and which contribute to the behavioral deficits. Experiments in Aim 2 will correlate changes in network activation during a cognitive task (measured as c-Fos activation in brain areas that project to the PFC) with changes in glutamatergic synaptic transmission in local or long-range connections that may drive NMDAR dysfunction in PVI and pyramidal neurons of the PFC. Whole-cell recordings in WT and CypD-KO mice will measure input-specific changes in NMDAR:AMPAR ratios and release-probability induced by oxidative stress. Experiments in Aim 3 will test the hypothesis that CypD-mediated mitochondrial dysfunction contributes to NMDAR dysfunction in PVI. We will study the consequences of CypD ablation on mitochondrial function and intracellular redox balance, as well as NMDAR-trafficking and -insertion in PVI from ketamine-treated mice. The information provided by this grant has implications for our understanding of the aberrant connectivity and changes in E/I balance that contribute to neurodevelopmental psychiatric disorders such as schizophrenia. In addition, our studies into PVI-specific changes in mitochondrial function may suggest novel targets for antioxidant treatment in the disease.
While current available antipsychotic regimens are crucial to prevent psychotic episodes in schizophrenia, they have proven ineffective in treating the severely debilitating cognitive and social deficits associated with the disease. These deficits may be a consequence of dysfunction in mitochondria resulting in a loss of inhibitory control in the prefrontal cortex which is responsible for executive and cognitive function. Here we investigate a novel mechanism in which activation of the mitochondrial-regulating protein, CypD, drives loss of cortical inhibition and manifestation of cognitive and social deficits observed in a developmental animal model of schizophrenia.
