Acute optogenetic induction of the prodromal endophenotype of CA1 hyperactivity causes schizophrenia-related deficits in cognition and salience attribution.

Abstract

Hyperactivity of the human anterior hippocampus has been reported to spread from its CA1 subfield to the subiculum around the onset of first-episode psychosis and could be a cellular target for early therapeutic intervention in the schizophrenia prodrome. However, to what extent CA1 hyperactivity actually causes schizophrenia-related symptoms remains unknown. Here, we mimic this endophenotype by direct optogenetic activation of excitatory cells in the homologous mouse region, ventral CA1 (vCA1) and assess its consequence in multiple schizophrenia-related behavioural tests. We find that hyperactivity of vCA1 causes hyperlocomotion and impairments of spatial and object-related short-term habituation (spatial novelty-preference and novel-object recognition memory) and spatial working memory, whereas social interaction, spatial exploration, and anxiety remain unaltered. Stimulation of the ventral subiculum, in contrast, only increased locomotion and exploration. In conclusion, CA1 hyperactivity may be a direct driver of prodromal cognitive symptoms and of aberrant salience assignment leading to psychosis.