Selective targeting of hippocampal fast-spiking basket cell interneurons via noninvasive enhancer-AAV delivery

Abstract

Accurate targeting of specific brain regions through non-invasive methods has long been a major goal of basic and translational neuroscience. Systemic delivery of AAVs expressing highly region- and cell-type-specific regulatory elements (enhancer-AAVs) continues to emerge as a tractable solution. Here we performed an independent characterization of a novel enhancer element with apparent robust transgene expression in fast-spiking basket cell interneurons in mouse hippocampus. Surprisingly, this vector did not induce expression in other brain regions harboring the same neuron class. Following intravenous administration in mice, robust labeling of FS-BCs across all hippocampal subfields was observed. We validated the FS-BC specificity in hippocampus using immunofluorescence and electrophysiological recordings. Viral labeling was confined to parvalbumin-positive cells exhibiting basket cell morphology and fast-spiking responses. This approach represents a promising avenue for both mechanistic investigation of hippocampal circuit function and potential therapeutic interventions targeting hippocampal pathophysiologies such as epilepsy, schizophrenia, and other neurological disorders in mice and potentially other species.