Disruption of MET Receptor Tyrosine Kinase, an Autism Risk Factor, Impairs Developmental Synaptic Plasticity in the Hippocampus

Xiaokuang Ma, Ke Chen, Zhongming Lu, Mariel Piechowicz, Qiang Liu, Jie Wu, Shenfeng Qiu

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

As more genes conferring risks to neurodevelopmental disorders are identified, translating these genetic risk factors into biological mechanisms that impact the trajectory of the developing brain is a critical next step. Here, we report that disrupted signaling mediated MET receptor tyrosine kinase (RTK), an established risk factor for autism spectrum disorders, in the developing hippocampus glutamatergic circuit leads to profound deficits in neural development, synaptic transmission, and plasticity. In cultured hippocampus slices prepared from neonatal mice, pharmacological inhibition of MET kinase activity suppresses dendritic arborization and disrupts normal dendritic spine development. In addition, single-neuron knockdown (RNAi) or overexpression of Met in the developing hippocampal CA1 neurons leads to alterations, opposite in nature, in basal synaptic transmission and long-term plasticity. In forebrain-specific Met conditional knockout mice (Met fx/fx ;emx1 cre ), an enhanced long-term potentiation (LTP) and long-term depression (LTD) were observed at early developmental stages (P12–14) at the Schaffer collateral to CA1 synapses compared with wild-type littermates. In contrast, LTP and LTD were markedly reduced at young adult stage (P56–70) during which wild-type mice show robust LTP and LTD. The altered trajectory of synaptic plasticity revealed by this study indicate that temporally regulated MET signaling as an intrinsic, cell autonomous, and pleiotropic mechanism not only critical for neuronal growth and functional maturation, but also for the timing of synaptic plasticity during forebrain glutamatergic circuits development.

Original languageEnglish (US)
Pages (from-to)36-50
Number of pages15
JournalDevelopmental Neurobiology
Volume79
Issue number1
DOIs
StatePublished - Jan 2019

Keywords

  • MET receptor tyrosine kinase
  • autism
  • hippocampus
  • neurodevelopment
  • synaptic plasticity

ASJC Scopus subject areas

  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience

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