HIPPOCAMPAL HYPERACTIVITY AS A TRANSLATIONAL TARGET IN SCHIZOPHRENIA AND EPILEPSY

Hippocampal hyperactivity is a feature of many neuropsychiatric disorders, including schizophrenia and epilepsy. This hyperactivity may underscore neuropsychiatric-associated behavioural phenotypes, and therefore may be an important target for therapeutic intervention. In this study, we quantified hippocampal dorsal CA1 pyramidal neuron activity using calcium imaging and a dual-colour Miniscope across the induction of the chronic ketamine schizophrenia model and during acute PTZ-induced seizures in mice. We also examined whether an activity-suppressing gene therapy was sufficient to reduce ketamine-induced hyperlocomotion. We found that psychotomimetic doses (30mg/kg) of ketamine induced stereotypical rotational behaviour and hyperlocomotion in an open field, which were associated with hyperactivity of excitatory hippocampal neurons, and this was modulated by the activity-dependent gene therapy. More extreme neural hyperactivity was observed during induction of seizures, including distinct waves of epileptiform activity and spreading depolarisation. We also find that epileptiform activity during severe seizures creates challenges for standard imaging-based cell detection pipelines as it can exceed standard activity limits and saturate typical ROIs used in CNMFe and other cell detection algorithms. Our findings highlight the continuum of neural hyperactivity across different neuropsychiatric disorders and provide a basis for exploring the phenotypic overlaps between psychotic disorders and epilepsy. Our work also provides preliminary support for the application of neural activity-modulating gene therapies for neuropsychiatric disorders.