Optogenetic and chemogenetic dissection of the causal role of ventral hippocampal hyperactivity for schizophrenia-related deficits

• Applicant: Professor Dr. Dennis Kätzel
• Subject Area: Biological Psychiatry
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 388492565

The development of drug therapies for cognitive and negative symptoms of schizophrenia has stalled since 4 decades, likely because the underlying circuit pathologies causing such deficits remain unknown. Using genetically targeted remote control of neural activity by light (optogenetics) in behaving mice, we wish to directly test, if specific neuronal pathological changes observed in patients are indeed causal for deficits related to the disorder. During the last two years we have successfully re-created a pathological hyperactivity of the output of the rodent ventral hippocampus by optogenetics, and found a direct causal link to the deficit of aberrant salience (failing short-term habituation of attention), that was predicted earlier from studies in patients. With the current proposal we wish to build on this work to: (1) determine which deficits across all three symptom domains of schizophrenia are actually caused by such an hyperactivity, using two complementary approaches,(2) identify the physiological underpinnings of deficits caused by the hyperactivity of the connection from ventral hippocampus to medial prefrontal cortex (and its potential subsequent depression), and(3) assess the therapeutic potential of a chemogenetic moderation of the hyperactivity of the ventral hippocampus, as an intervention that could stop the progression of the disease from the prodromal to the psychotic state.Combining state-of-the art circuit neuroscience methods including optogenetics, chemogenetics, in vivo electrophysiology, fMRI, behavioral testing and pharmacology, we hope to derive causal links between a validated circuit abnormality in schizophrenia and its actual symptoms, and translate this knowledge into a therapeutic approach.

• DFG Programme: Research Grants