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    Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism

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    Author
    Lo, F.-S.
    Erzurumlu, R.S.
    Date
    2018
    Journal
    Molecular Autism
    Publisher
    BioMed Central Ltd.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://dx.doi.org/10.1186/s13229-018-0196-6
    Abstract
    Background: Met receptor tyrosine kinase regulates neurogenesis, differentiation, migration, connectivity, and synaptic plasticity. The human Met gene has been identified as a prominent risk factor for autism spectrum disorder (ASD). Met gene-altered mice serve as useful models for mechanistic studies of ASD. Inactivation of Met in excitatory cortical neurons in mice (Emx1 cre /Met flox mice) yields a phenotype in which significantly decreased GABAA receptor-mediated inhibition shifts the excitation/inhibition (E/I) balance toward excitation in the somatosensory cortex. Further, unlike that seen in wild-type mice, insulin does not increase inhibition in the mutant cortex, suggesting that one of the consequences of kinase inactive Met gene could be desensitization of insulin receptors. To test this hypothesis, we investigated the effects of insulin receptor sensitizer, pioglitazone, on inhibition in the somatosensory thalamocortical circuitry. Methods: We used whole-cell patch clamp electrophysiology and analyzed excitatory and inhibitory responses of cortical layer IV excitatory cells following stimulation of their thalamic input in thalamocortical pathway intact brain slices. We applied insulin alone and insulin + a thiazolidinedione, pioglitazone (PIO), to test the effects of sensitizing insulin receptors on inhibitory responses mediated by GABAA receptors in the somatosensory cortex of Emx1 cre /Met flox mice. Results: In WT brain slices, application of insulin together with PIO did not enhance the effect of insulin alone. In contrast, PIO application induced a much larger inhibition than that of insulin alone in Met-defective cortex. Thus, insulin resistance of GABAA receptor-mediated response in Met mutant mice may result from desensitized insulin receptors. Conclusions: Sporadic clinical studies reported improved behavioral symptoms in children with autism following PIO treatment. We show that PIO can aid in normalization of the E/I balance in the primary somatosensory cortex, a potential physiological mechanism underlying the positive effects of PIO treatment. � 2018 The Author(s).
    Sponsors
    Research supported by NIH/NINDS R01 NS092216
    Keyword
    Barrel cortex
    GABAA receptors
    Homeostatic plasticity
    Met receptor tyrosine kinase
    Pioglitazone
    Thalamocortical circuitry
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85042510437&doi=10.1186%2fs13229-018-0196-6&partnerID=40&md5=40188bab461720d82f6ce43b6352ccde; http://hdl.handle.net/10713/8805
    ae974a485f413a2113503eed53cd6c53
    10.1186/s13229-018-0196-6
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