Excitatory neuron-specific SHP2-ERK signaling network regulates synaptic plasticity and memory

• Published in: Science signaling Vol. 12; no. 571
• Main Authors: Ryu, Hyun-Hee, Kim, TaeHyun, Kim, Jung-Woong, Kang, Minkyung, Park, Pojeong, Kim, Yong Gyu, Kim, Hyopil, Ha, Jiyeon, Choi, Ja Eun, Lee, Jisu, Lim, Chae-Seok, Kim, Chul-Hong, Kim, Sang Jeong, Silva, Alcino J, Kaang, Bong-Kiun, Lee, Yong-Seok
• Format: Journal Article
• Language: English
• Published: United States 05.03.2019
• Subjects: Animals; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - metabolism; Hippocampus - metabolism; Long-Term Potentiation; MAP Kinase Signaling System; Memory; Mice; Mice, Transgenic; Mutation; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - metabolism
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.aau5755

Mutations in RAS signaling pathway components cause diverse neurodevelopmental disorders, collectively called RASopathies. Previous studies have suggested that dysregulation in RAS-extracellular signal-regulated kinase (ERK) activation is restricted to distinct cell types in different RASopathies. Some cases of Noonan syndrome (NS) are associated with gain-of-function mutations in the phosphatase SHP2 (encoded by ); however, SHP2 is abundant in multiple cell types, so it is unclear which cell type(s) contribute to NS phenotypes. Here, we found that expressing the NS-associated mutant SHP2 in excitatory, but not inhibitory, hippocampal neurons increased ERK signaling and impaired both long-term potentiation (LTP) and spatial memory in mice, although endogenous SHP2 was expressed in both neuronal types. Transcriptomic analyses revealed that the genes encoding SHP2-interacting proteins that are critical for ERK activation, such as GAB1 and GRB2, were enriched in excitatory neurons. Accordingly, expressing a dominant-negative mutant of GAB1, which reduced its interaction with SHP2 , selectively in excitatory neurons, reversed SHP2 -mediated deficits. Moreover, ectopic expression of GAB1 and GRB2 together with SHP2 in inhibitory neurons resulted in ERK activation. These results demonstrate that RAS-ERK signaling networks are notably different between excitatory and inhibitory neurons, accounting for the cell type-specific pathophysiology of NS and perhaps other RASopathies.