剛好前一陣子，有一篇文章寫到記憶與NMDA受體的關係，所以我就節錄上來一些部分了
Fei Li, M.D., Ph.D., and Joe Z. Tsien, Ph.D.
The N-methyl-D-aspartate (NMDA) receptor (NMDAR) is the predominantmolecular device for controlling synaptic plasticity and memoryfunction.1 Thus, an understanding of the control and actionof the NMDAR at central synapses may provide clues to therapeuticstrategies for treating memory disorders. Episodic and spatialmemories, which are often compromised in persons with Alzheimer'sdisease, critically depend on the hippocampus — in particular,the CA1 area — in both humans and laboratory animals.Blocking the NMDAR in the mouse brain impairs synaptic plasticityand compromises learning and memory. Conversely, genetic enhancementof NMDAR function improves memory in adult mice.1,2
Activation of the NMDAR, a major excitatory ligand-gated ionchannel in the central nervous system, depends on a couple ofcoincidental events: the binding of its natural ligand (glutamate)and depolarization — which effects the removal of magnesiumions that otherwise block the ion-channel pore. The NMDAR constitutesthe principal cellular machinery responsible for initiatingmany forms of synaptic plasticity in different areas of thebrain. It is a heterotetramer consisting of two obligatory NR1subunits and two of four possible NR2 subunits: NR2A, NR2B,NR2C, and NR2D. The NR2 subunits in the adult hippocampus andcortex are usually NR2A and NR2B, and the ratio of NR2B to NR2Adecreases with age in diverse animal species (including humans),starting from or before the onset of sexual maturity. NR2 compositiongoverns the properties of NMDAR channels and the extent of synapticplasticity; a relative abundance of NR2B in the juvenile brainconfers on it a greater plasticity than the adult brain. Thecore tetramer associates with a multiprotein complex that includesmore than 70 associated proteins, many of which influence thetransport, stability, subunit composition, or function of NMDARs.
In a recent study, Ng et al.3 showed that Neto1, a synaptictransmembrane protein known to be associated with the NMDAR,interacts with the receptor bivalently.3 The intracellular domainof Neto1 binds a synaptic protein (called PSD-95) that bindsthe receptor, and the extracellular domain of Neto1 interactswith NR2A and NR2B
Figure 1. Neuron Showing Glutamate Receptors and Synaptic Plasticity.
Various experiments suggest that memory formation involves two types of glutamate receptors: the N-methyl-D-aspartate receptor (NMDAR) and the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR). These receptors sit on the surface of postsynaptic neurons. AMPARs allow sodium to flow into the postsynaptic cell, resulting in depolarization. NMDARs are permeable to both ionic sodium and calcium. The subsequent influx of ionic calcium into the postsynaptic terminals through the NMDAR activates biochemical cascades that trigger the up-regulation of AMPARs to the membrane while increasing the AMPAR's sensitivity to glutamate and thus strengthen the synapses. A recent study by Ng et al.3 showed that the deletion of Neto1, a postsynaptic protein associated with the NMDAR complex, leads to deficits in both synaptic plasticity and cognition. Neto1 binds to PSD-95, a protein that is almost exclusively located in the postsynaptic density of neurons, and is important in anchoring synaptic proteins. Neto1 also binds to NR2A and NR2B, two isoforms of NR2 subunits that are essential for NMDAR functions. The composition of NR2A and NR2B in the NMDAR substantially modulates its channel properties. Stimulation of the AMPAR can partially compensate for deficits caused by Neto1 deletion.
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