Science Education Center and Graduate Institute of Science Education, National Taiwan Normal University, No. 88, Sec. 4, Ting-Chou Rd., Taipei, 11677, Taiwan, Republic of China.
Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
Mol Brain. 2021 Oct 4;14(1):152. doi: 10.1186/s13041-021-00858-8.
The glutamatergic signaling pathway is involved in molecular learning and human cognitive ability. Specific single variants (SNVs, formerly single-nucleotide polymorphisms) in the genes encoding N-methyl-D-aspartate receptor subunits have been associated with neuropsychiatric disorders by altering glutamate transmission. However, these variants associated with cognition and mental activity have rarely been explored in healthy adolescents. In this study, we screened for SNVs in the glutamatergic signaling pathway to identify genetic variants associated with cognitive ability. We found that SNVs in the subunits of ionotropic glutamate receptors, including GRIA1, GRIN1, GRIN2B, GRIN2C, GRIN3A, GRIN3B, and calcium/calmodulin-dependent protein kinase IIα (CaMK2A) are associated with cognitive function. Plasma CaMK2A level was correlated positively with the cognitive ability of Taiwanese senior high school students. We demonstrated that elevating CaMK2A increased its autophosphorylation at T286 and increased the expression of its downstream targets, including GluA1 and phosphor- GluA1 in vivo. Additionally, methyl-CpG binding protein 2 (MeCP2), a downstream target of CaMK2A, was found to activate the expression of CaMK2A, suggesting that MeCP2 and CaMK2A can form a positive feedback loop. In summary, two members of the glutamatergic signaling pathway, CaMK2A and MeCP2, are implicated in the cognitive ability of adolescents; thus, altering the expression of CaMK2A may affect cognitive ability in youth.
谷氨酸能信号通路参与分子学习和人类认知能力。通过改变谷氨酸传递，编码 N-甲基-D-天冬氨酸受体亚基的基因中的特定单变体（SNV，以前称为单核苷酸多态性）与神经精神障碍有关。然而，这些与认知和心理活动相关的变体在健康青少年中很少被探索。在这项研究中，我们筛选了谷氨酸能信号通路中的 SNV，以确定与认知能力相关的遗传变体。我们发现，离子型谷氨酸受体亚基中的 SNV，包括 GRIA1、GRIN1、GRIN2B、GRIN2C、GRIN3A、GRIN3B 和钙/钙调蛋白依赖性蛋白激酶 IIα（CaMK2A）与认知功能有关。血浆 CaMK2A 水平与台湾高中生的认知能力呈正相关。我们证明，升高 CaMK2A 会增加其在 T286 处的自身磷酸化，并增加其下游靶标，包括 GluA1 和体内的磷酸化-GluA1 的表达。此外，CaMK2A 的下游靶标甲基化-CpG 结合蛋白 2（MeCP2）被发现激活 CaMK2A 的表达，表明 MeCP2 和 CaMK2A 可以形成正反馈环。总之，谷氨酸能信号通路的两个成员，CaMK2A 和 MeCP2，与青少年的认知能力有关；因此，改变 CaMK2A 的表达可能会影响年轻人的认知能力。
