Vulnerability of inhibitory basket cells to oxidative stress during maturation and its impact on schizophrenia and epilepsy

• Applicant: Dr. Richard Kovács
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; Developmental Neurobiology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 235802993

Schizophrenia is a major psychiatric disorder affecting ~ 1 % of the world population. Disturbances of brain oscillatory activity in the gamma band are a hallmark of schizophrenia suggesting that altered network activity underlies behavioural and cognitive deficits. Perisomatic inhibition provided by parvalbumin (PV) containing fast spiking basket cells plays a crucial role in gamma band synchronisation. Indeed, basket cell dysfunction was described in patients suffering from schizophrenia and in animal models of the disease. Oxidative stress during maturation of basket cells is has been suggested to induce alterations in their function and phenotype with a concomitant reduction of gamma oscillations. Decreased glutathione (GSH) levels and disturbance of thiol redox potential are common findings in schizophrenia patients. Despite the facts that i, the main source of reactive oxygen species are the mitochondria, ii, basket cells present with an elaborate network of mitochondria and they are dependent on intensive oxidative metabolism iii, structural and functional alterations of the mitochondrial network are described in schizophrenia patients, less is known on the involvement of mitochondrial free radical formation in the development of this disease. We hypothesize that PV containing fast spiking basket cells, due to their intensive oxidative energy metabolism, are particularly susceptible to disturbance of the antioxidant defence system during development. Moderate oxidative stress alters PV expression and electrophysiological properties of basket cells thereby leading to impaired synchronisation of network activity. As a consequence, the power of hippocampal gamma oscillations decreases whereas the susceptibility of the network to generate epileptiform discharges increase. Here we seek to develop and characterise a novel in vitro model of schizophrenia based on induction of oxidative stress in hippocampal slice cultures from rat or PV-Cre mice. Moderate oxidative stress during in vitro maturation of PV containing basket cells will be induced by: i, inhibition of GSH synthesis, ii, inhibition of thioredoxin-2 reductase and iii, exposure to NMDA antagonist. Fast spiking basket cells will be identified by fluorescent and electrophysiological means and the effects of oxidative stress on energy metabolism and mitochondrial free radical formation will be compared between the different treatment groups. The effects of oxidative stress mediated basket cell dysfunction on network activity will be investigated on carbachol-induced gamma oscillations and on the susceptibility of the cultures to develop epileptiform activity. The results obtained in the in vitro model will be compared with animal experiments using the same type of perinatal oxidative stress in cooperation with Dr. Otáhal´s lab within the framework of the present bilateral project.

• DFG Programme: Research Grants
• International Connection: Czech Republic
• Partner Organisation: Czech Science Foundation
• Participating Persons: Privatdozent Dr. Zoltán Gerevich; Dr. Jakub Otáhal