Synapse Formation in the Brain

Abstract

Precise synaptic connections between nerve cells in the brain provide the basis of perception, learning, memory, and cognition. Synapse formation is the key step in the development of neuronal networks and requires the coordinate assembly of large numbers of protein complexes. Trans-synaptic cell adhesion molecules are thought to mediate target recognition and induction of pre- and postsynaptic specializations. Despite the wealth of information on the molecular mechanisms of glutamatergic synaptogenesis proposed by in vitro studies using neuronal cell culture models, evidence for their relevance to synaptogenesis in vivo has been lacking. Thus, fundamental questions about how glutamatergic synapses are formed in the mammalian brain have remained unanswered. On the other hand, there is clear in vivo evidence that GluRδ2, a member of the δ-type glutamate receptor (GluR), plays an essential role in cerebellar Purkinje cell (PC) synapse formation. We found that a significant number of PC spines lack synaptic contacts with parallel fiber (PF) terminals and some of residual PF-PC synapses show mismatching between pre- and postsynaptic specializations in conventional and conditional GluRδ2 knockout mice. Recently, we have shown that the trans-synaptic interaction of postsynaptic GluRδ2 and presynaptic neurexins (NRXNs) through Cbln1 mediates PF-PC synapse formation. The assembly stoichiometry of the synaptogenic GluRδ2-Cbln1-NRXN1β triad provides the molecular insight into the mechanism of PF-PC synapse formation in the cerebellum. IL1-receptor accessory protein-like 1 (IL1RAPL1) is responsible for nonsyndromic mental retardation and autism. We have found that postsynaptic IL1RAPL1 mediates excitatory synapse formation of cortical neurons through trans-synaptic interaction with specific variants of presynaptic protein tyrosine phosphatase-δ. These results imply the impaired synapse formation as a common pathogenic pathway shared by mental retardation and autism.