Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors.
Neural cell adhesion molecule-associated polysialic acid regulates synaptic plasticity and learning by restraining the signaling through GluN2B-containing NMDA receptors.
复制标题
DOI：
10.1523/jneurosci.5806-09.2010
复制
发表时间：
2010-03-17
期刊：
影响因子：
--
通讯作者：
Dityatev A
中科院分区：
文献类型：
--
作者：
Kochlamazashvili G;Senkov O;Grebenyuk S;Robinson C;Xiao MF;Stummeyer K;Gerardy-Schahn R;Engel AK;Feig L;Semyanov A;Suppiramaniam V;Schachner M;Dityatev A
神经细胞黏附分子是哺乳动物脑内α-2，8-聚唾液酸的主要载体。PSA和NCAM表达的异常与人类精神分裂症有关，并导致小鼠海马区突触可塑性和背景恐惧条件反射的缺陷。在这里，我们发现PSA抑制由GluN1/2B(NR1/NR2B)或GluN1/2A/2B(NR1/NR2A/NR2B)组成的重组NMDA受体的开放，但不抑制GluN1/2A(NR1/NR2A)亚单位的开放。NCAM/PSA的缺陷增加了GluN2B介导的海马区CA1区的传递和钙瞬变。随着GluN2B介导的传递的增加，NCAM/PSA缺陷小鼠的CA1区长时程增强缺陷和背景恐惧记忆可以通过应用GluN2B选择性拮抗剂来消除。此外，用谷氨酸清除剂谷丙转氨酶、阻断Ras-GRF1(GluN2B信号转导p38MAPK的中介体)或直接抑制高活性的p38MAPK可以恢复缺乏PSA/NCAM的脑片突触的可塑性。因此，NCAM携带的PSA通过抑制GluN2B-Ras-GRF1-p38MAPK信号通路来调节可塑性和学习。这些发现表明，黏附分子携带的碳水化合物参与调节大脑中的NMDA受体信号，并证明了与去除与精神分裂症相关的黏附分子相关的认知缺陷的可逆性。
The neural cell adhesion molecule (NCAM) is the predominant carrier of α2,8 polysialic acid (PSA) in the mammalian brain. Abnormalities in PSA and NCAM expression are associated with schizophrenia in humans and cause deficits in hippocampal synaptic plasticity and contextual fear conditioning in mice. Here, we show that PSA inhibits opening of recombinant NMDA receptors composed of GluN1/2B (NR1/NR2B) or GluN1/2A/2B (NR1/NR2A/NR2B) but not of GluN1/2A (NR1/NR2A) subunits. Deficits in NCAM/PSA increase GluN2B-mediated transmission and Ca2+ transients in the CA1 region of the hippocampus. In line with elevation of GluN2B-mediated transmission, defects in long-term potentiation in the CA1 region and contextual fear memory in NCAM/PSA-deficient mice are abrogated by application of a GluN2B-selective antagonist. Furthermore, treatment with the glutamate scavenger glutamic-pyruvic transaminase, ablation of Ras-GRF1 (a mediator of GluN2B signaling to p38 MAPK), or direct inhibition of hyperactive p38 MAPK can restore impaired synaptic plasticity in brain slices lacking PSA/NCAM. Thus, PSA carried by NCAM regulates plasticity and learning by inhibition of the GluN2B-Ras-GRF1-p38 MAPK signaling pathway. These findings implicate carbohydrates carried by adhesion molecules in modulating NMDA receptor signaling in the brain and demonstrate reversibility of cognitive deficits associated with ablation of a schizophrenia-related adhesion molecule.