The Implications of CaMK2A And MeCP2 Signalings In The Cognitive Ability of Adolescents

The glutamatergic signaling pathway is involved in molecular learning and human cognitive ability. Specific single nucleotide polymorphisms (SNPs) in the genes encoding NMDA receptor subunits have been associated with neuropsychiatric disorders by altering glutamate transmission. But how these polymorphisms associated with cognition and brain psychological activities were rarely been explored in healthy adolescents. In this study, we screened SNPs of the glutamatergic signaling pathway to identify genetic variants associated with cognitive ability. We found that single nucleotide polymorphisms (SNPs) in subunits of ionotropic glutamate receptors, including GRIA1, GRINN1, GRIN2B, GRIN2C, GRIN3A, GRIN3B, and Calcium/ Calmodulin-dependent protein kinase II α (CaMK2A) associated with the cognitive function of students. Importantly, the plasma CaMK2A levels correlated positively with the cognitive ability of senior high school students in Taiwan. We demonstrated that the elevated CaMK2A increased its autophosphorylation at T286 and increased the expression of its downstream targets, including GRIA1 and phosphor GRIA1 in vivo. Additionally, the Methyl CpG binding protein 2 (MeCP2), a downstream target of CaMK2A, can activate the expression of CaMK2A, suggesting that MeCP2 and CaMK2A could form a positive feedback loop. In summary, we concluded that members of the glutamatergic signaling, CaMK2A, and MeCP2 were implicated in the cognitive ability of adolescents, and alternating in the CaMK2A expressing may have collective effects on the cognitive ability of youths.