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

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 (Metfx/fx;emx1cre), 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.

Identification and Functional Analysis of Long Non-coding RNAs in Autism Spectrum Disorders

“…Gene ontology (GO) enrichment analysis of genomic neighbors has shown that most of these genes were enriched in a series of immune pathways, including cellular response to interferon-gamma, cellular response to interleukin-1, and positive regulation of the inflammatory response (Figure 2A; Estes and McAllister, 2015). KEGG pathway analysis illustrated the enrichment in the tyrosine metabolism pathway, which was consistent with the fact that MET receptor tyrosine kinase (RTK) is an autism risk factor ( Figure 2B; Ma et al, 2019). Together, these results indicated that ASD-related lncRNAs may be implicated in the pathogenesis of autism partly through immune response processes.…”

Identification and functional analysis of long non-coding RNAs in autism spectrum disorders

“…is an autism risk factor ( Figure 2B) [43]. Together, these results indicate that ASD-related lncRNAs may be implicated in the pathogenesis of autism partly through immune response processes.…”

“…Several brain regions have been reported to be associated with the pathogenesis of ASD, such as cortex, frontal cortex (BA9), anterior cingulate cortex (BA24), cerebellum, hippocampus, hypothalamus and amygdala [6,43,45,46]. So we constructed specific weighted gene co-expression networks for these distinct brain regions, and then performed enrichment analysis using the pipeline described before, respectively.…”

Synaptic Formation, Neural Circuits and Neurodevelopmental Disorders Controlled by Signaling, Translation, and Epigenetic Regulation

“…Both MET and CDKL5 are relevant to ASD. Using conditioned knockout mice and pharmacological inhibition, Ma and colleagues show that MET deficiency suppresses dendritic arborization and impairs dendritic spine formation and, moreover, they reveal that hippocampal plasticity is altered by MET deficits (Ma et al ., ). Thus, MET is critical for neuronal differentiation and maturation.…”