Inhibitory neurons defined by a synaptogenic molecule impair memory discrimination.

Abstract

The CA3 region is central to hippocampal function during learning and memory because of its unique connectivity. CA3 pyramidal neurons are the targets of huge, excitatory mossy fiber synapses from DG axons and have an unusually high degree of excitatory recurrent connectivity. Thus, inhibition likely plays an outsized importance in constraining runaway excitation and shaping CA3 ensembles during learning and memory. Here, we investigate the function of a group of dendrite-targeting, hippocampal GABAergic neurons defined by expression of the synaptogenic adhesion molecule, Kirrel3. We discovered that activating Kirrel3-expressing GABAergic neurons impairs memory discrimination by inhibiting CA3 pyramidal neurons in novel contexts. Kirrel3 is required for DG-to-GABA synapse formation and variants in Kirrel3 are strong risk factors for neurodevelopmental disorders. Thus, our work suggests that Kirrel3-GABA neurons are a critical source of feed-forward inhibition from DG to CA3 during contextual memory whose activity may be specifically disrupted in some brain disorders.