Disruption of MET Receptor Tyrosine Kinase, an Autism Risk Factor, Impairs Developmental Synaptic Plasticity in the Hippocampus
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Final Accepted Manuscript
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Univ Arizona, Coll Med Phoenix, Basic Med SciIssue Date
2019-01-01
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Ma, X. , Chen, K. , Lu, Z. , Piechowicz, M. , Liu, Q. , Wu, J. and Qiu, S. (2019), Disruption of MET Receptor Tyrosine Kinase, an Autism Risk Factor, Impairs Developmental Synaptic Plasticity in the Hippocampus. Develop Neurobiol, 79: 36-50. doi:10.1002/dneu.22645Journal
DEVELOPMENTAL NEUROBIOLOGYRights
© 2018 Wiley Periodicals, Inc.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.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.Note
12 month embargo; published online: 10 October 2018ISSN
1932-846XPubMed ID
30304576Version
Final accepted manuscriptSponsors
National Institute of Mental HealthAdditional Links
https://onlinelibrary.wiley.com/doi/full/10.1002/dneu.22645ae974a485f413a2113503eed53cd6c53
10.1002/dneu.22645
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