Three phases of excitatory glutamatergic synapse formation have been described for the mammalian central nervous system. First, there is a period with a slow rate of synapse formation, then a period with a rapid rate of synapse formation, and finally a maturation and pruning phase. Kayser et al. provide evidence in mice that the second phase of fast synapse formation involves EphB2, a receptor tyrosine kinase that is present on the nascent dendrites of the postsynaptic cell. In cortical neuron cultures or in slice preparations from triple-knockout (TKO) mice deficient for EphB1, EphB2, and EphB3, but not double knockouts (DKO) deficient for EphB1 and EphB3, the initial phase of synapse formation appears to proceed normally, but the rapid phase appears to be compromised. Further, the TKO cells exhibited decreased filopodial motility, despite having increased numbers of filopodia and decreased density of mature dendrites, a phenotype that was copied by RNA interference to reduce EphB2 in the postsynaptic cells. RNA interference experiments to decrease EphB2 or EphB2 rescue experiments at specific times during development of cultured neurons suggested that EphB2 may serve a key role in the rapid phase of synapse formation and contribute to maturation of the dendritic spine. In neurons in which EphB2 was knocked down, expression of a constitutively active form of the kinase PAK, which is downstream of EphB2 in the pathway that regulates the cytoskeleton and cell motility, restored filopodial motility but not synaptic density. In cells in which endogenous EphB2 was knocked down, expression of a kinase-defective mutant of EphB2 or a form that could not bind its ligand on the presynaptic neuron EphrinB did not restore synaptic density or filopodial motility. However, coexpression of the kinase-inactive form of EphB2 and PAK in the cells in which endogenous EphB2 was knocked down did restore both motility and synapse formation. Thus, forward signaling by EphB2 appears to control filopodial motility and the ability to find a presynaptic cell, whereas reverse signaling appears to allow a stable connection with the presynaptic cell, thereby promoting synapse formation.
M. S. Kayser, M. J. Nolt, M. B. Dalva, EphB receptors couple dendritic filopodia motility to synapse formation. Neuron 59, 56-69 (2008). [PubMed]