Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism
Date
2018Journal
Molecular AutismPublisher
BioMed Central Ltd.Type
Article
Metadata
Show full item recordAbstract
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 NS092216Keyword
Barrel cortexGABAA 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/10713/8805ae974a485f413a2113503eed53cd6c53
10.1186/s13229-018-0196-6
Scopus Count
Collections
Related articles
- Insulin-Independent GABAA Receptor-Mediated Response in the Barrel Cortex of Mice with Impaired Met Activity.
- Authors: Lo FS, Erzurumlu RS, Powell EM
- Issue date: 2016 Mar 30
- Altered Forebrain Functional Connectivity and Neurotransmission in a Kinase-Inactive Met Mouse Model of Autism.
- Authors: Tang S, Powell EM, Zhu W, Lo FS, Erzurumlu RS, Xu S
- Issue date: 2019 Jan-Dec
- Enhancement of postsynaptic GABAA and extrasynaptic NMDA receptor-mediated responses in the barrel cortex of Mecp2-null mice.
- Authors: Lo FS, Blue ME, Erzurumlu RS
- Issue date: 2016 Mar
- Imbalance Between Excitatory and Inhibitory Synaptic Transmission in the Primary Somatosensory Cortex Caused by Persistent Nociception in Rats.
- Authors: Cao FL, Xu M, Gong K, Wang Y, Wang R, Chen X, Chen J
- Issue date: 2019 Aug
- Enhanced Thalamocortical Synaptic Transmission and Dysregulation of the Excitatory-Inhibitory Balance at the Thalamocortical Feedforward Inhibitory Microcircuit in a Genetic Mouse Model of Migraine.
- Authors: Tottene A, Favero M, Pietrobon D
- Issue date: 2019 Dec 4