Modular, circuit-based interventions rescue hippocampal-dependent social and spatial memory in a 22q11.2 deletion syndrome mouse model.

Abstract Background 22q11.2 deletion syndrome (22qDS) presents with myriad symptoms, including multiple neuropsychiatric disorders. Complications associated with the polygenic haploinsufficiency makes symptoms particularly difficult to manage via traditional therapeutic approaches. However, the varying mechanistic consequences often culminate to generate inappropriate regulation of neuronal circuit activity. We explored if managing this aberrant activity in adults could be a therapeutically beneficial strategy. Methods To assess and dissect hippocampal circuit function, we performed functional imaging in acute slices and targeted eloquent circuits (specific sub-circuits tied to specific behavioral tasks) to provide relevant behavioral outputs. For example, the ventral and dorsal CA1 regions critically support social and spatial discrimination, respectively. We focally introduced chemogenetic constructs in 34 control and 24 22qDS model mice via adeno-associated viral vectors, driven by excitatory neuron-specific promoter elements, to manipulate circuit recruitment in an on-demand fashion. Results 22qDS model mice exhibited CA1 excitatory ensemble hyperexcitability and concomitant behavioral deficits in both social and spatial memory. Remarkably, acute chemogenetic inhibition of pyramidal cells successfully corrected the memory deficits, and did so in a regionally-specific manner: ventrally targeted constructs only rescued social behavior, while those expressed dorsally selectively affected spatial memory. Additionally, manipulating activity in control mice could recapitulate the memory deficits in a regionally-specific manner. Conclusions These data suggest that retuning activity dysregulation can rescue function in disease-altered circuits, even in the face of a polygenetic haploinsufficiency with a strong developmental component. Targeting circuit excitability in a focal, modular manner may prove an effective therapeutic for treatment-resistant symptoms of mental illness.