A clinically identified Kirrel3 variant disrupts trans-synaptic circuit assembly

Trans-synaptic adhesion molecules guide selective connections between neurons to establish circuit specificity. Yet, there are gaps in the understanding of how many synaptic adhesion molecules function in vivo and if clinically identified variants perturb their function. Using cell-type-specific deletion in the mouse hippocampus, we show that Kirrel3 is required in both pre-synaptic DG neurons and post-synaptic GABA neurons to form DG-to-GABA excitatory synapses that drive a feed-forward inhibitory connection to CA3. These data provide in vivo, genetic evidence for a homophilic trans-synaptic Kirrel3 interaction driving synapse formation. Moderately increasing or decreasing wildtype Kirrel3 expression did not detectably alter synapse formation or CA3 neuron activity. In contrast, expression of a Kirrel3 missense variant identified in an individual with autism dominantly disrupts synapse formation and CA3 activity in vivo, providing a mechanism by which a single missense allele could disrupt circuit assembly and contribute to disease.