Inhibitory neurons marked by the connectivity molecule Kirrel3 regulate memory precision

The homophilic adhesion molecule Kirrel3 drives synapse formation between dentate granule (DG) neurons and GABA neurons, and Kirrel3 gene variants are associated with neurodevelopmental disorders in humans. However, the circuit function and behavioral relevance of Kirrel3-expressing neurons are unknown. Using intersectional genetics, we identified a population of Kirrel3-expressing GABA neurons that regulate memory discrimination in male and female mice. Using chemogenetics with in vivo electrophysiology and behavioral assays, we discovered that activating Kirrel3-expressing GABA neurons, but not parvalbumin neurons, potently inhibits CA3 neuron activity and impairs contextual memory discrimination during recall, revealing a critical role for these neurons in the retrieval of precise memories. Light and electron microscopy of Kirrel3-expressing GABA neurons suggests that they receive direct excitation from DG neurons and project onto CA3 dendrites. Together, this multi-scale approach demonstrates how cell type-specific expression of adhesion molecules mark subsets of neurons that control key features guiding memory and behavior. SIGNIFICANCE STATEMENTHere, we identified a never-before studied group of inhibitory neurons defined by expression of the gene Kirrel3, which is a synaptic cell adhesion molecule and risk gene for neurodevelopmental disorders. We show that Kirrel3 inhibitory neuron activity exerts exceptionally strong control over CA3 neuron activity and impairs the ability of mice to distinguish between different contexts during memory retrieval. Thus, Kirrel3 inhibitory neurons regulate memory precision in mice, and our study employs a powerful framework linking molecular identity and synaptic specificity to behavioral function in the adult brain.