Synaptic role of the AMPA receptor N-terminal domain

大脑由神经细胞或神经元（人脑约有900亿个，老鼠约有7500万个）组成，它们通过称为突触的特定细胞连接进行交流。突触是神经元之间传递和存储信息的地方（即作为记忆储存）；突触的信息存储被认为需要突触功能和功效的可塑性改变。突触间的信号传递是由“上游”神经元释放神经递质化学物质开始的，形成突触前位点，传递到下游受体细胞的突触后位点。哺乳动物大脑中的主要神经递质是氨基酸谷氨酸，当它被突触前释放时，激活突触后的受体蛋白分子。这些神经递质受体被称为受体，是这个建议的核心。谷氨酸受体的中心应用是ampa受体（AMPA-R；基于其选择性药理学性质）。AMPA-Rs启动兴奋性神经传递，即它们在结合谷氨酸的反应中使突触后膜去极化。去极化是由谷氨酸触发的带正电粒子（阳离子）通过AMPA-R通道的狭窄开口进入突触后神经元而产生的。突触增强是信息存储的基础，是由于额外的AMPA-Rs被募集到突触后，这种募集导致净阳离子流入增加，并增加去极化水平。增强传递还需要AMPA-Rs在突触上聚集，并在谷氨酸释放位点对面保留。在这一建议中，我们将研究AMPA-R在突触响应增强刺激时聚集和保留的机制。我们有初步的证据表明，AMPA-R的远端部分，n端结构域（或NTD）调节受体的扩散/保留和突触后位点的聚集。因此，NTD似乎在ampa - r介导的突触增强和突触学习中发挥了目前难以捉摸的作用。AMPA-R保留也稳定突触后结构，我们的数据指出NTD在这一过程中的作用。由于突触消除是神经变性的标志，ntd介导的受体保留将有可能对抗神经系统疾病，如阿尔茨海默病和相关痴呆。这些观察结果，连同我们积累的NTD作为新型药物靶点的证据，突出了AMPA-R NTD在突触功能中的关键作用。总之，我们提出的工作将为ampar在突触学习和突触稳定中的作用提供机制信息。

The brain is made up of nerve cells or neurons (~90 billions in the human brain, ~ 75 million in the mouse), which communicate via specific cell junctions termed synapses. Synapses are the sites where information between neurons is transmitted and stored (i.e. laid down as memories); information storage at synapses is believed to require plastic changes in synapse function and efficacy. Signaling across synapses is initiated by the release of neurotransmitter chemicals from an 'upstream' neuron, forming 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, when released by the pre-synapse, activates recipient protein molecules on the post-synapse. These neurotransmitter recipients are termed receptors and lie at the heart of this proposal. The glutamate receptor central to the application is the AMPA-receptor (AMPA-R; based on its selective pharmacological properties). AMPA-Rs initiate excitatory neurotransmission, i.e. they depolarize the post-synaptic membrane in response to binding glutamate. Depolarization results from a glutamate-triggered flux of positively charged particles (cations), through a narrow opening in the AMPA-R channel, into the post-synaptic neuron. Synaptic potentiation, the substrate for information storage, results from the recruitment of additional AMPA-Rs to the post-synapse - this recruitment gives rise to increased net cation-influx and augments the level of depolarization. Potentiated transmission also requires the clustering of AMPA-Rs at the synapse and their retention opposite glutamate-release sites. In this proposal we will investigate mechanisms underlying AMPA-R clustering and retention at synapses in response to potentiating stimuli. 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.