locations and trafficking of glutamate receptors

Neurotransmission occurs at the specialized structure termed the synapse, which consists of the pre-synapse, synaptic cleft, and the post-synapse. Within the presynaptic terminal, there are many synaptic vesicles filled with neurotransmitters. When an action potential reaches the presynaptic terminal, calcium influx via activated voltage-gated calcium channels leads to synaptic vesicle fusion with the presynaptic membrane. Released neurotransmitters diffuse across a synaptic cleft and bind to neurotransmitter receptors that reside on the postsynaptic membrane, resulting in activation of receptors and eventual signal transduction. To ensure efficient neurotransmission between neurons, the pre-and postsynaptic compartments must align structurally and coordinate functionally. In the mammalian central nervous system, ionotropic glutamate receptors, α-amino-3-hydroxy-5-methyl-4-isoxazoleproionic acid (AMPA) receptors and N-methyl-D-aspartate (NMDA) receptors are two major types of glutamate receptors. AMPA receptors mediate the majority of fast excitatory neurotransmission. The trans-synaptic alignment between neurotransmitter release sites and receptors is one of the important determinants in the activation of receptors and therefore the efficacy of neurotransmission. Our recent study indicates that release sites are segregated within an active zone, with synchronous release uniformly distributed and asynchronous release sites enriched near the center of an active zone. Moreover, synchronous and asynchronous release sites are aligned with AMPA receptor and NMDA receptor clusters, respectively. Computational simulations indicate that this trans-synaptic organization of release sites and AMPA receptors and NMDA receptors are likely to contribute to better activation of NMDA receptors. In addition to the trans-synaptic alignment, the number of AMPA receptors also plays an important role in determining the strength of neurotransmission. Currently, clathrin-mediated endocytosis at postsynaptic terminals is thought to be the major pathway in regulating the number of the glutamate receptors, especially AMPA receptors. Endocytosis typically occurs at a specific region termed the endocytic zone (EZ) adjacent to the postsynaptic density (PSD). However, in our present study, we identified a clathrin-independent endocytosis that occurs directly within the PSD on a millisecond time scale. To further understand this novel endocytic pathway, we have to investigate how this pathway is triggered, what cargos are internalized, and what proteins mediate this pathway in future