title: Noonan syndrome-associated SHP2 mutation differentially modulates the expression of postsynaptic receptors according to developmental maturation.
abstract: Glutamate is the major excitatory neurotransmitter in the central nervous system, and related signaling involves both AMPA and NMDA subtype receptors. The expression of glutamate receptors is dynamically regulated during development. Recent studies showed that the dysregulation of glutamate receptor expression and function is associated with neurodevelopmental disorders including intellectual disability. Previously, a Noonan syndrome (NS)-associated SHP2 mutation (SHP2D61G) was shown to increase the synaptic delivery of AMPA receptor, subsequently impairing synaptic plasticity and learning in adult mice. However, how the mutant SHP2 affects glutamate receptor expression during development is not known. Here, we found that the SHP2D61Gdifferentially regulates the expression of AMPA and NMDA receptors depending on the stage of neuronal maturation. In cultured neurons (immature stage; DIV 6), overexpression of SHP2D61Gsignificantly increased the average size and the number of NMDA receptor-containing particles, but not those with AMPA receptors. In early matured neurons (DIV 12), SHP2D61Gsignificantly increased only the average size of AMPA receptor particles, and subsequently increased their number in matured neurons (DIV 18). Importantly, all the changes described above for SHP2D61Gneurons were reversed by inhibiting MAPK. These data demonstrate that the increased activation of MAPK signaling pathway by SHP2D61Gcould deregulate the surface expression of synaptic receptors during neuronal development, which likely contributes to cognitive impairments in NS patients.
authors.affiliation: Dept of Medicine and Microbiology, College of Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea.
authors.forename: Jun-Young
authors.initials: JY
authors.lastname: Oh
authors.affiliation: Dept of Life Science, College of Natural Science, Chung-Ang University, Seoul 06974, Republic of Korea.
authors.forename: Sangmyung
authors.initials: S
authors.lastname: Rhee
authors.affiliation: Integrative Center for Learning and Memory, Dept of Neurobiology, Dept of Psychiatry and Biobehavioral Sciences, Dept of Psychology and Brain Research Institute, University of California Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Alcino J
authors.initials: AJ
authors.lastname: Silva
authors.affiliation: Dept of Physiology, Dept of Biomedical Science, Seoul National University College of Medicine, Seoul 03080, Republic of Korea. Electronic address: yongseok7@snu.ac.kr.
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Dept of Medicine and Microbiology, College of Medicine, Chungbuk National University, Cheongju 28644, Republic of Korea. Electronic address: hkkim69@chungbuk.ac.kr.
authors.forename: Hyong Kyu
authors.initials: HK
authors.lastname: Kim
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D006624:Hippocampus / Q000254:growth & development* / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D009634:Noonan Syndrome / Q000235:genetics* / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics*; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516727:Ptpn11 protein, rat
keywords: AMPA receptor; Developmental disorder; MAPK; NMDA receptor