Conditional knockout of MET receptor tyrosine kinase in cortical excitatory neurons leads to enhanced learning and memory in young adult mice but early cognitive decline in older adult mice

Baomei Xia, Jing Wei, Xiaokuang Ma, Antoine Nehme, Katerina Liong, Yuehua Cui, Chang Chen, Amelia Gallitano, Deveroux Ferguson, Shenfeng Qiu

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Human genetic studies established MET gene as a risk factor for autism spectrum disorders. We have previously shown that signaling mediated by MET receptor tyrosine kinase, expressed in early postnatal developing forebrain circuits, controls glutamatergic neuron morphological development, synapse maturation, and cortical critical period plasticity. Here we investigated how MET signaling affects synaptic plasticity, learning and memory behavior, and whether these effects are age-dependent. We found that in young adult (postnatal 2–3 months) Met conditional knockout (Metfx/fx:emx1cre, cKO) mice, the hippocampus exhibits elevated plasticity, measured by increased magnitude of long-term potentiation (LTP) and depression (LTD) in hippocampal slices. Surprisingly, in older adult cKO mice (10–12 months), LTP and LTD magnitudes were diminished. We further conducted a battery of behavioral tests to assess learning and memory function in cKO mice and littermate controls. Consistent with age-dependent LTP/LTD findings, we observed enhanced spatial memory learning in 2–3 months old young adult mice, assessed by hippocampus-dependent Morris water maze test, but impaired spatial learning in 10–12 months mice. Contextual and cued learning were further assessed using a Pavlovian fear conditioning test, which also revealed enhanced associative fear acquisition and extinction in young adult mice, but impaired fear learning in older adult mice. Lastly, young cKO mice also exhibited enhanced motor learning. Our results suggest that a shift in the window of synaptic plasticity and an age-dependent early cognitive decline may be novel circuit pathophysiology for a well-established autism genetic risk factor.

Original languageEnglish (US)
Article number107397
JournalNeurobiology of Learning and Memory
Volume179
DOIs
StatePublished - Mar 2021

Keywords

  • Autism
  • Cortical circuits
  • Electrophysiology
  • Learning and memory
  • Neurodevelopmental disorders
  • Synaptic plasticity

ASJC Scopus subject areas

  • Experimental and Cognitive Psychology
  • Cognitive Neuroscience
  • Behavioral Neuroscience

Fingerprint

Dive into the research topics of 'Conditional knockout of MET receptor tyrosine kinase in cortical excitatory neurons leads to enhanced learning and memory in young adult mice but early cognitive decline in older adult mice'. Together they form a unique fingerprint.

Cite this