Synapse Formation and Maintenance
Glutamate is the major excitatory neurotransmitter
in the mammalian brain, and modulation of glutamatergic synapse formation and function is thought to form the
molecular basis of learning and memory. Thus, defining the mechanisms underlying glutamatergic synaptogenesis
has broad implications for understanding nervous system function. While many of the components of the mature
central nervous system (CNS) synapse have been characterized, the molecular events that initiate the process of
synapse formation and maturation have only begun to be elucidated.
At the neuromuscular junction (NMJ), the receptor tyrosine kinase MuSK is required for the initiation of synapse formation, acting to cluster acetylcholine receptors on the postsynaptic membrane. Thus, the observation that EphB receptor tyrosine kinases are localized at excitatory synapses led us to test whether Eph receptors might interact with glutamate receptors. We have found that EphBs cluster and associate with N-methyl-D-aspartate (NMDA)-type glutamate receptors thereby modulating NMDA receptor function. EphrinB2 activation of EphB in primary cortical neurons potentiates NMDA receptor-dependent influx of calcium. Treatment of cells with ephrinB2 led to NMDA receptor tyrosine phosphorylation through activation of the Src family of tyrosine kinases. These ephrinB2-dependent events result in enhanced NMDA receptor-dependent gene expression. Furthermore, perturbation of EphB tyrosine kinase activity affects the number of synaptic specializations that form in cultured neurons. Our findings indicate that ephrinB2 stimulation of EphB modulates the functional consequences of NMDA receptor activation and suggest a mechanism whereby activity-independent and activity-dependent signals converge to regulate the development and remodeling of synaptic connections.
In addition to a role in the induction of new gene expression, NMDA receptor signaling also contributes to brain function and plasticity by directly controlling the growth and morphology of dendritic arbors and spines. Our findings indicate that the effects of NMDA receptor signaling on dendritic morphology are mediated, at least in part, by the Rac1-GEF Tiam1. Tiam1 interacts with the NMDA receptor and is phosphorylated in a calcium-dependent manner in response to NMDA receptor stimulation. Moreover, blockade of Tiam1 function with RNA-mediated interference (RNAi) and dominant-interfering mutants of Tiam1 suggests that Tiam1 mediates the effects of the NMDA receptor on dendritic development by inducing Rac1-dependent actin remodeling and protein synthesis. Taken together, these findings define a molecular mechanism that links NMDA receptor activation to changes in dendritic morphology.
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Tolias KF, Bikoff, JB, Burette A, Paradis S, Harrar D, Tavazoie S, Weinberg RJ, Greenberg ME. The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines. Neuron 2005; in press
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Tolias KF, Bikoff JB, Burette A, Paradis S, Harrar D, Tavazoie S, Weinberg RJ, Greenberg ME. The Rac1-GEF Tiam1 couples the NMDA receptor to the activity-dependent development of dendritic arbors and spines. Neuron. 2005 Feb 17;45(4):525-38.
Other research areas:
Activity-Dependent Gene Transcription
Regulation of Translation in Neurons
Neuronal Cell Fate Determination
Neuronal Survival and Apoptosis
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