In vivo assessment of the mitochondrial complex I in subjects with schizophrenia

New York University School Of Medicine, New York NY

Investigators

Abstract

Project Summary/Abstract In schizophrenia (SCH), impairment in cognitive function, a core element of this illness, is observed prior to the onset of psychosis and has been tied to long-term outcomes. One suggested pathophysiologic mechanism for the cognitive deficits in SCH is disturbances in the ability of neurons to engage in synchronous oscillatory activity, a phenomenon thought to be essential for normal cognitive function. Increased cognitive load normally results in gamma range (30 – 100 Hz) oscillatory activity in the dorsolateral prefrontal cortex (DLPFC) but the generation of gamma activity is impaired in subjects with SCH. Gamma oscillatory activity is dependent on networks of fast- spiking, parvalbumin positive (PV+), GABA interneurons (IN) which synchronize pyramidal cell firing. Fast- spiking PV IN are highly energy dependent and, in turn, highly dependent on mitochondrial function. Given the energy requirements of the PV IN, abnormalities in brain energetics and/or mitochondrial function may play significant role in the cognitive symptoms of SCH. Given that the generation of gamma oscillatory activity relies on cellular energy production it is highly sensitive to disruptions in mitochondrial function. Mitochondria generate the majority of energy in the brain producing 95% of cellular adenosine triphosphate (ATP) through oxidative phosphorylation (OxPhos) via the electron transport chain (ETC). An impairment in mitochondrial function will result in reduced energy generation and a shift from OxPhos to the pathway of aerobic glycolysis (AG; lactate production in the presence of O2), with a resulting increase of lactate and reduction in pH. The first enzyme in the ETC, mitochondrial complex I (MC-I), is the rate limiting step in neuronal oxygen utilization. Dysfunction of MC-I in SCH is observed in post mortem studies as well as in peripheral blood cells. In vivo measures of brain OxPhos using phosphorus magnetic resonance spectroscopy (31P-MRS) provide direct measures of ATP, phosphocreatine (PCr) and inorganic phosphorus (Pi) and suggest a deficit of OxPhos in SCH, although no clear pattern has emerged. The current application seeks to examine in vivo brain energetics in SCH by utilizing [18F]BCPP-EF positron emission tomography (PET) to establish MC-I distribution and 31P-MRS to measure more detailed brain energetics (ATP, PCr, Pi). 10 medication-free individuals with SCH and 10 age and sex matched HC will participate in this study. [18F]BCPP-EF standardized uptake value ratio (SUVR-1) will be measured in both groups in the DLPFC. We will test whether lower DLPFC SUVR-1 in SCH will predict impairment on the Brief Assessment of Cognitive Function in Schizophrenia. In the same subjects, at the same time, PCr/ATP and Pi/ATP will be measured with 31P-MRS and correlated with [18F]BCPP-EF SUVR-1. The data from this application will provide a more comprehensive understanding of MC-I in SCH and its relationship to the shift in brain energetics to AG. These results will lay the groundwork for understanding whether mitochondrial OxPhos is impaired in SCH and exacerbates the cognitive impairments observed in this illness. The ultimate goal is that a deeper understanding of brain energetics in SCH will lead to the development of improved therapeutics.