TY - JOUR
T1 - Association of CaMK2A and MeCP2 signaling pathways with cognitive ability in adolescents
AU - Lee, Li Ching
AU - Su, Ming Tsan
AU - Huang, Hsing Ying
AU - Cho, Ying Chun
AU - Yeh, Ting Kuang
AU - Chang, Chun Yen
N1 - Funding Information:
The authors are grateful to all those who participated in the study. This manuscript was edited by Wallace Academic Editing.
Funding Information:
This work was supported by the National Science Council of Taiwan under the contracts MOST 107-2511-H-003-010-MY3, MOST 108-2511-H-003-059, and MOST 107-2634-F-008-003 and financially supported by the Institute for Research Excellence in Learning Sciences of National Taiwan Normal University from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education of Taiwan. This work was also supported partially by grants (MOST 109-2321-B038-001 and MOST 109-2320-B-003-009) to MT Su received from the Ministry of Science and Technology.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
KW - Calcium/calmodulin-dependent protein kinase IIα (CaMK2A)
KW - Cognitive function
KW - Glutamatergic signaling pathway
KW - Methyl-CpG binding protein 2 (MeCP2)
KW - Single-nucleotide variant (SNV)
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UR - http://www.scopus.com/inward/citedby.url?scp=85116387269&partnerID=8YFLogxK
U2 - 10.1186/s13041-021-00858-8
DO - 10.1186/s13041-021-00858-8
M3 - Article
C2 - 34607601
AN - SCOPUS:85116387269
SN - 1756-6606
VL - 14
JO - Molecular Brain
JF - Molecular Brain
IS - 1
M1 - 152
ER -
