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

Abstract

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 PTPN11); 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 SHP2D61G 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 SHP2D61G, selectively in excitatory neurons, reversed SHP2D61G-mediated deficits. Moreover, ectopic expression of GAB1 and GRB2 together with SHP2D61G 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.

The impact of RASopathy-associated mutations on CNS development in mice and humans

“…However, most of the key RAS-ERK components, such as NF1, SHP2, BRAF, and MEK1/2, begin to be expressed before either embryonic day 10 or 15, which are initiation time points of neurogenesis or astrogliogenesis, respectively [212]. Recently, it has been shown that the expression of RAS-ERK signaling molecules was remarkably different between excitatory and inhibitory neurons in mouse hippocampus [162]. Thus, it would be interesting to examine whether the expression levels of various signaling molecules are differentially regulated in NSCs over different developmental stages.…”

“…For example, Omrani and colleagues showed that inhibitory neuron-specific attenuation of hyperpolarization-activated cyclic nucleotide-gated (HCN) currents can be an underlying mechanism for the cognitive deficits in Nf1 +/mice when they used an HCN agonist to rescue cognitive deficits in Nf1 +/mice [217]. Recently, Ryu and colleagues showed that selectively reducing the interaction between mutant SHP2 and Gab1 in excitatory neurons reversed the physiological and behavioral deficits in a mouse model of NS [162]. Conditional mutant mice with higher spatial and temporal resolution will provide clues when, where, and which cell types are most suited for interventions.…”

“…Along with structural abnormalities in CNS, several lines of evidence suggest that the distribution of NF1 in single neuronal cell type may also contribute to cognitive deficits in NF1. Transcriptome analyses of mouse brain have unveiled the enriched NF1 expression in inhibitory neurons rather than the in excitatory neurons, and provided a clue as to how NF1 mainly carries out its role in inhibitory synaptic function [162]. Furthermore, based on the conserved expression pattern of NF1 in human brain, it is suggested that the enriched expression of NF1 in inhibitory neurons may underlie cell type-specific pathophysiology and cognitive deficits in NF1 [163].…”

Neuron type-specific expression of a mutant KRAS impairs hippocampal-dependent learning and memory

“…SHP2 D61G/+ mice showed increased level of ERK activation only in excitatory neurons and enhanced glutamatergic synaptic transmission but no changes in inhibitory synaptic functions 32 . Ectopic expression of SHP2 D61G selectively in the excitatory but not in inhibitory neurons increased ERK activation and impaired spatial learning and LTP 19 . One explanation for these cell type-specific effects of RAS signalling is that the expression profiles of RAS-ERK signalling genes are significantly different between hippocampal excitatory and inhibitory neurons 19 .…”

“…In adult mice, Kras is expressed not only in inhibitory neurons but also in excitatory neurons 19 . To investigate the effects of ectopic KRAS G12V expression in the excitatory neurons on learning and memory, we injected AAV-KRAS G12V -HA into the dorsal hippocampus of αCaMKII-Cre mice ( Fig.…”