UC San Diego

Glutamatergic synapses are the main excitatory synapses in the mammalian central nervous system. The assembly and regulation of these highly organized and asymmetric junctions requires extensive molecular signaling mechanisms. Although thousands of components and interactions within the synapse have been identified, the signaling logic that governs their assembly has remained elusive. We show that a conserved cell polarity signaling protein, Lgl1, is localized in the postsynaptic density. Conditional knockout of Lgl1 in hippocampal pyramidal neurons at postnatal day 7

resulted in increased synapse numbers, altered synaptic ultrastructure, altered compositions of synaptic proteins, and reduced AMPA/NMDA ratio. Conditional Lgl1 deletion from adult mice also produces synaptic phenotypes similar to what is observed in the deletion at postnatal day 7. Lgl1 and atypical Protein Kinase C mutually inhibit each other in apical-basal polarity signaling. We found that a double conditional knockout of both isoforms of atypical PKCs in hippocampal neurons at postnatal day 7 lead to changes in synaptic ultrastructure at postnatal day 14, but not synapse number. Reduction of synapse number was observed in adulthood, suggesting a role for aPKC in the maintenance of synapses rather than their initial formation. Conditional deletions of Lgl1 or atypical PKCs lead to deficits in novel object recognition and social interaction. Triple cKO of Lgl1 and atyptical PKCs restores synapse number and some of the behavioral functions, such as open field and novel object recognition, but not social behavior. The phenotypes observed following conditional deletion of Lgl1 or aPKC are consistent with their opposing roles in apical-basal polarity and their influence on other pathways such as the planar cell polarity pathway and cellular adhesion. Lgl1 is one of the genes commonly deleted in a severe but poorly known behavioral disorder, Smith-Magenis Syndrome (SMS), which is often diagnosed with autism. Lgl1+/- animals show increased synapse numbers, deficits in social interaction, and stereotyped repetitive behavior. Furthermore, three previously characterized NMDA antagonists can rescue social interaction in Lgl1+/- animals. Therefore, deletion of Lgl1 may contribute to neuropsychiatric symptoms in SMS and provides insight into cellular pathways that may underlie the behavioral phenotypes that are observed in the syndrome.