Increased Src Family Kinase Activity Disrupts Excitatory Synaptic Transmission and Impairs Remote Fear Memory in Forebrain Shp2-Deficient Mice

Mol Neurobiol. 2017 Nov;54(9):7235-7250. doi: 10.1007/s12035-016-0222-7. Epub 2016 Oct 29.

Abstract

Src homolog domain-containing phosphatase 2 (Shp2) signals a variety of cellular and physiological functions including learning and memory. Dysregulation of ERK signaling is known to be responsible for the cognitive deficits associated with gain-of-function mutated Shp2 mimicking Noonan syndrome. However, here, we report that CaMKIIα-cre induced knockout (CaSKO) of Shp2 in hippocampal pyramidal neurons resulted in increased Src activity, upregulated phosphorylation of N-methyl-D-aspartate receptors (NMDARs) at Y1325 of GluN2A and at Y1472 of GluN2B, disrupted the balance of synaptic transmission, and impaired long-term potentiation and remote contextual fear memory. Administration of PP2, a specific Src family kinase inhibitor, reversed the tyrosine phosphorylation of NMDARs, restored basal synaptic transmission, and rescued the contextual fear memory deficit in CaSKO mice without altering the phospho-ERK level. Taken together, our results reveal a novel role of Shp2 in NMDAR-dependent synaptic function and fear memory via the Src signaling pathway rather than the ERK pathway, and suggest a complicated mechanism for Shp2-associated cognitive deficits.

Keywords: LTP; Memory; NMDAR; Shp2; Src.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / physiology*
  • Fear / drug effects
  • Fear / physiology*
  • Male
  • Memory / drug effects
  • Memory / physiology*
  • Memory Disorders / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Prosencephalon / drug effects
  • Prosencephalon / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / deficiency*
  • Pyrimidines / pharmacology
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*
  • src-Family Kinases

Substances

  • AG 1879
  • Pyrimidines
  • src-Family Kinases
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11
  • Ptpn11 protein, mouse