Mechanisms and machinery mediating AMPA receptor anchoring in synaptic plasticity

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The brain is made up of nerve cells termed 'neurons', which communicate via specific cell junctions, called synapses. Synapses are small inter-cellular junctions where information between neurons is transmitted and stored (i.e. laid down as memories). Information storage at synapses is believed to be be mediated by changes in synapse efficacy (synaptic plasticity), which involves dynamic changes of protein distribution at the post-synaptic site.Signaling across synapses is initiated by the release of neurotransmitter chemicals from an 'upstream' neuron at the pre-synaptic site, onto the post-synapse of a downstream recipient cell. A primary neurotransmitter in the mammalian brain is the amino acid glutamate, which activates recipient protein molecules on the post-synapse, called 'receptors'. The glutamate receptor central to the application is the AMPA-receptor (AMPA-R). AMPA-Rs depolarize the post-synaptic membrane in response to binding glutamate and thereby initiate neurotransmission. Depolarization results from a glutamate-triggered influx of positively charged particles (cations), through the AMPA-R, into the post-synaptic neuron resulting in an electrical signal (depolarization). Synaptic potentiation, the substrate for information storage, results from the recruitment of additional AMPA-Rs to the postsynapse resulting in increased cation-influx and more depolarization. Potentiated transmission also requires the concentration or clustering of AMPA-Rs at the synapse and their retention opposite glutamate-release sites.In this proposal we will investigate mechanisms underlying AMPA-R dynamics at synapses that underlie synaptic plasticity (and thus 'learning'). We will assay the clustering and retention of AMPA-Rs at synapses in response to potentiating stimuli using high-resolution imaging and functional approaches. These will provide a detailed-snapshot of the AMPA-Rs dynamics underlying synaptic plasticity. We have preliminary evidence suggesting that the distal portion of the AMPA-R, the N-terminal domain (or NTD) regulates receptor diffusion/retention and clustering at post-synaptic sites. Hence, the NTD appears to play a currently elusive role in AMPA-R-mediated synapse potentiation and therefore in synaptic learning. AMPA-R retention also stabilizes post-synaptic structures, and our data point to a role for the NTD in this process. Since synapse elimination is a hallmark of neurodegneration, NTD-mediated receptor retention would have the potential to oppose neurological disorders such as Alzheimer's disease and related dementias. These observations, together with our accumulating evidence for the NTD as novel drug target, highlight a key role for the AMPA-R NTD in synapse function. In summary, our proposed work will provide mechanistic information into the role of AMPARs in synaptic learning and synapse stabilization.