Parvalbumin Neuron-Targeted Loss of Alzheimer's Disease Risk GeneIs Insufficient to Drive Cognitive or Network Excitability Changes.

Abstract

() is one of the strongest genetic risk factors for Alzheimer's disease (AD), yet its function in the brain and role in AD remain unclear. Neuronalisoform levels are decreased in AD, and recent data show an important role ofin inhibitory neurons. Inhibitory neurons are key regulators of cognition and network excitability, with parvalbumin-expressing (PV) neurons as the most abundant subtype. We tested the hypothesis that loss of BIN1 from PV neurons contributes to AD-related cognitive dysfunction and network hyperexcitability. We generated a cell type-specific conditional knock-out mouse line,pvKO, and examined mice of both sexes. These mice showed few behavioral differences when assessed with traditional or machine learning-based behavioral tests, with only a slight reduction in exploratory behavior in aged cohorts.pvKO mice showed no significant differences in network excitability on measures of induced seizure susceptibility and spiking on cortical electroencephalographic recordings. Finally,pvKO mice exhibited no major differences in power spectral analysis of cortical electroencephalographic recordings, with only a modest reduction in delta power at high activity levels. These findings suggest that BIN1 loss in PV neurons alone is insufficient to drive the cognitive and network dysfunction observed in AD models. While these results do not exclude a role of BIN1 in PV neurons in AD models, if combined with a "second hit" or alterations in other cell types, they indicate that BIN1 loss in PV neurons alone does not recapitulate key AD-related phenotypes.