Regulation of synaptic development and function by synaptic cell adhesion molecule, Neph2

Abstract

Synaptic adhesion molecules regulate diverse aspects of neuronal synapse development, including synapse specificity, formation, and maturation. Neph2, also known as Kirrel3, is an immunoglobulin superfamily adhesion molecule implicated in intellectual disability, neurocognitive delay associated with Jacobsen syndrome, and autism spectrum disorders. We here report a negative regulation of excitatory synapses by Neph2. Neph2 directly interacts with PSD-95, an abundant excitatory postsynaptic scaffolding protein, and redistributes PSD-95 to discrete dendritic clusters. Neph2-mutant ($Neph2^{-/-}$) mice exhibit specific synaptic connectivity defects. They show significantly increased dendritic spine density and spontaneous excitatory synaptic events in the dentate gyrus at postnatal 3 weeks but not at 8 weeks. Behaviorally, $Neph2^{-/-}$ mice show increased self-grooming and normal locomotion at 3 weeks, but normal self-grooming, hyperactivity, and impaired object recognition memory at 8-16 weeks. These results suggest that synaptic adhesion molecules can inhibit synaptic connectivity and is important for normal behavior.