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New synaptic organizing proteins and their roles in excitatory and inhibitory synapse development Pettem, Katherine Laura


The brain consists of billions of neurons. During development, these neurons must migrate to their proper position and form connections with neighboring neurons to form networks. The specificity and maturation of these connections, or synapses, are critical for proper brain function, including learning, memory and cognition. Many cell adhesion molecules (CAMs) are involved in the formation and maturation of synapses, including the well-characterized neuroligin-neurexin pair. In this study, two new synapse modifying proteins, calsyntenin and MDGA, are characterized using in vitro assays and primary hippocampal neuron cultures. Calsyntenin-3 was identified in an un-biased screen to search for new synaptogenic proteins. It is a post-synaptic transmembrane protein that induces the formation of excitatory and inhibitory presynaptic specializations in contacting axons via extracellular cadherin and LNS domains. Overexpression of calsyntenin-3 in neurons increases presynaptic protein clustering. Interestingly, calsyntenin-3 binds to α-neurexins with high affinity, suggesting presynaptic induction is mediated through trans-synaptic signaling with neurexins. MDGAs are a family of synaptic GPI-linked proteins that bind neuroligin-2 with high affinity. MDGA1 blocks the presynaptic induction activity of neuroligin-2, through blocking binding to neurexins, via extracellular immunoglobulin domains. Overexpression of MDGA1 in neurons specifically decreases inhibitory synapses, while knockdown increases inhibitory synapses. Interestingly, like other synaptic proteins including neurexin and neuroligin, MDGAs have recently been linked to autism spectrum disorders and schizophrenia. Thus, the characterization of the synapse-promoting calsyntenin-3 and the synapse-reducing MDGA1 shed new light on the mechanisms by which synaptogenesis is regulated. Investigating the complex interplay between molecular players during synaptogenesis is critical not only for understanding normal brain development, but also for providing insight into neurodevelopmental disorders.

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