The study of molecular mechanism for synapse formation in neuronal development and brain function

Abstract

Synaptogenesis is a critical process in the establishment of neuronal connectivity during brain development. The key step is to transduce external stimuli into the internal signaling cascades. Cell adhesion molecules and scaffold proteins facilitate the transduction to achieve optimal connectivity through PDZ domain mediated interaction. FRMPD2, a product of a human-specific multi-copy gene with three PDZ domains, has been shown to localize to the tight junctions in epithelial cells, suggesting a role in inter-cellular interaction. Although the correlation between neurodevelopmental disorders and gene dosage alteration of FRMPD2 has been observed, its role in the nervous system remains unknown. Therefore, I investigated the role of FRMPD2 in neurodevelopment. I found that FRMPD2 localizes at the excitatory synapses and promotes synaptogenesis in rat neurons. Mechanistically, FERM domain is required for synaptic localization of FRMPD2 through the interaction with F-actin in spines. More importantly, I found that FRMPD2 associates with cell adhesion molecule Neuroligin-1 through PDZ domain mediated interaction, resulting in an increase in Neuroligin-1 surface expression and up-regulation of synaptogenesis. Results from in utero electroporation showed that overexpression of FRMPD2 in mouse brains delayed neuronal migration and increased dendritic arborization and spine formation. Remarkably, viral overexpression of FRMPD2 in mouse brains improved memory retention. Abnormalities in synaptogenesis during neurodevelopment can cause neurodevelopmental disorders, such as Autism Spectrum Disorders (ASDs). Genomic studies from cohorts of ASD patients have revealed the prevalence of dysfunctional genes in the ubiquitin-proteasome pathway, especially the E3 ligases, suggesting the E3 ligase as a key component in ASD pathogenesis. Genomic duplication or deletion of PARK2 gene, a E3 ligase gene, has been identified in ASD patients. Therefore, I explored the autistic phenotypes of the Park2 knockout (KO) mice. Indeed, the KO mice demonstrated features of typical ASD behaviors. Further, Park2 KO mice showed a reduction in spine number, dendritic arborization, and levels of neuronal activity. The alterations in synaptic property in Park2 KO mice may serve as the etiological factor for ASD. These findings provide insights into the role of a novel synaptic organizer scaffold protein for synapse formation during brain development, and a novel ASD model.