GABAergic interneurons in a Disc1-Mouse model for depression - Influence on neuronal network activity in the prefrontal cortex and behaviour

• Applicant: Professorin Dr. Marlene Bartos
• Subject Area: Cognitive, Systems and Behavioural Neurobiology ; Human Cognitive and Systems Neuroscience
• Term: from 2012 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 218641338

Depression affect life quality of the effected individuals. It is characterized by various symptoms including hopelessness, reduced motivation and anhedonia. Abnormal brain rhythms are considered as potential pathophysiological mechanisms causing mental disease. Indeed, individuals with depression show disturbed fast gamma (30-100 Hz) activity patterns. The underlying network defects remained, however, largely unknown. In our recently published work we addressed this question in the medial prefrontal cortex (mPFC) of the recently engineered transgenic mouse model, in which a truncated Disc1 (Disrupted-in-Schizophrenia-1; Disc1) gene was expressed, thereby reproducing one of the best supported candidate gene mutations underlying depression. Disc1 mice exhibit marked depression-related behavioural deficits such as enhanced freezing in the tail-suspension (TST) and forced swim test. By using a systems-biological approach we recently showed that gamma synchrony in the mPFC of Disc1 mice is markedly reduced in the prefrontal cortex. This reduction was correlated with a diminished number of parvalbumin (PV)-expressing GABAergic inhibitory cells (PVIs), a ~60% reduced synaptic transmission at their output synapses, reduced excitatory drive onto PVIs and a threefold increase in their connectivity in the mPFC. In spite of these impressive changes, a causal relationship between altered PVI function in the mPFC and depression-related behaviour was only assumed but not shown. Moreover, it remained unclear how changes in PVI input and output function may influence neuronal population activity. In the proposed study we aim to address this fundamental question by combining in vivo electrophysiological and optophysiological investigations with viral tools and behavioural analysis. (1) We aim to understand the temporal activity patterns of individual PVIs and principal cells (PCs) during fast network oscillations in behaving mice using single unit recordings. (2) We aim to perform in vivo whole-cell recordings in head-fixed mice to identify the timing and strength of synaptic excitatory and inhibitory inputs in mPFC cells. (3) We will examine whether optophysiological manipulation of PVI activity may rescue gamma power in the mPFC and behaviour. (4) We aim to examine whether Disc1 expression in PVIs is sufficient to reduce gamma power and to induce depression-related behaviour. With this multidisciplinary approach we believe to provide new information on the role of PVIs in the emergence of depression-related behaviour and thereby may reveal new targets for therapeutic treatments to support improvement of the life situation of individuals suffering from this illness.

• DFG Programme: Research Grants