Disorganized Inhibitory Dynamics and Functional Connectivity in Hippocampal area CA1 of 22q11.2 Deletion Mutant Mice

Abstract

Individuals with the 22q11.2 deletion syndrome, one of the strongest genetic risk factors for schizophrenia, demonstrate cognitive impairments such as episodic memory dysfunction. Place cell dynamics in the hippocampus supporting episodic memory are also impaired in a mouse model for the 22q11.2 deletion (Df(16)A+/-). While hippocampal neural dynamics are under strong inhibitory control, there is no available information about functional alterations of molecularly identified inhibitory circuits in mouse models for the 22q11.2 deletion. Here, we examined interneuron subtype-specific activity dynamics in hippocampal area CA1 ofDf(16)A+/-mice performing random foraging and goal-oriented reward learning tasks. We found thatDf(16)A+/-inhibitory interneurons carry markedly reduced spatial information during random foraging. Mutant mice perseverate at rewarded locations during reward learning, and multiple interneuron types exhibit aberrant responses to reward locations. We observe task-dependent changes in functional correlation structure among multiple GABAergic subtypes, suggesting a broadly disorganized microcircuit functional connectivity in mutant mice. Overall, we identify widespread and heterogeneous subtype-specific alterations in interneuron dynamics during learning, depicting inhibitory microcircuits with impaired flexibility. Our study provides novel biological insights into how schizophrenia-risk mutations affect local-circuit interactions among diverse cell types in the mouse hippocampus during learning.