Tactile defensiveness and impaired adaptation of neuronal activity in the Fmr1 knockout mouse model of autism
Abstract
Sensory hypersensitivity is a common symptom in autism spectrum disorders (ASDs), including Fragile X Syndrome (FXS), and frequently leads to tactile defensiveness. In mouse models of ASDs, there is mounting evidence of neuronal and circuit hyperexcitability in several brain regions, which could contribute to sensory hypersensitivity. However, it is not yet known whether or how sensory stimulation might trigger abnormal sensory processing at the circuit level or abnormal behavioral responses in ASD mouse models, especially during an early developmental time when experience-dependent plasticity shapes such circuits. Using a novel assay, we discovered exaggerated motor responses to whisker stimulation in young Fmr1 knockout (KO) mice (postnatal days (P) 14-16), a model of FXS. Adult Fmr1 KO mice actively avoided a stimulus that was innocuous to wild-type controls, a sign of tactile defensiveness. Using in vivo two-photon calcium imaging of Layer 2/3 barrel cortex neurons expressing GCaMP6s, we found no differences between wild-type and Fmr1 KO mice in overall whisker-evoked activity, though 45% fewer neurons in young Fmr1 KO mice responded in a time-locked manner. Notably, we identified a pronounced deficit in neuronal adaptation to repetitive whisker stimulation in both young and adult Fmr1 KO mice. Thus, impaired adaptation in cortical sensory circuits is a potential cause of tactile defensiveness in autism.
Additional Information
© 2017 the authors. Beginning six months after publication the Work will be made freely available to the public on SfN's website to copy, distribute, or display under a Creative Commons Attribution 4.0 International (CC BY 4.0) license (https://creativecommons.org/licenses/by/4.0/). The user may not create, compile, publish, host, enable or otherwise make available a mirror site of The Journal of Neuroscience site. Received: 7 March 2017; Revised: 17 May 2017; Accepted: 24 May 2017; Published: 12 June 2017. Author contributions: C.X.H. and C.P.-C. designed research; C.X.H., D.A.C., W.A.Z., and A.G. performed research; C.X.H., S.S.M., A.G., and C.P.-C. analyzed data; C.X.H. and C.P.-C. wrote the paper. This work was supported by a Paul and Daisy Soros Fellowship for New Americans (C.X.H.), NIH NINDS F30 Fellowship NS093719 (C.X.H.), UCLA Neural Microcircuits Training Grant T32-NS058280 (D.A.C.), a Eugene V. Cota-Robles fellowship (D.A.C.), the UCLA Medical Scientist Training Program (NIH National Institute of General Medical Sciences Training Grant GM08042; C.X.H.), Developmental Disabilities Translational Research Program Grant 20160969 (John Merck Fund; C.P.-C.), Simons Foundation Autism Research Initiative Grant 295438 (C.P.-C.), and NIH National Institute of Child Health and Human Development Grant R01 HD054453 (C.P.-C.).Wethank M. Einstein and P. Golshani (help with behavioral rig design); G. Liu (help with behavioral rig construction); P. Mineault, D. Ringach, D. Dombeck, T.-W. Chen, and K. Svoboda (MATLAB code for imaging analysis); N. Hardy (help with behavioral data analysis); N. Wisniewski (help with statistical analyses); K. Battista (P1 injection illustration); A. Keller (help with curve fitting); D. Buonomano, K. Martin, S. Masmanidis, J. Moore, D. Geschwind, M. Reimers, M. Suchard, and other Portera-Cailliau lab members (helpful discussions); and the Janelia GENIE project (AAV GCaMP6s). The authors declare no competing financial interests.Attached Files
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Additional details
- PMCID
- PMC5511879
- Eprint ID
- 78334
- DOI
- 10.1523/JNEUROSCI.0651-17.2017
- Resolver ID
- CaltechAUTHORS:20170619-135638094
- Paul and Daisy Soros Fellowship
- NS093719
- NIH
- T32-NS058280
- NIH Predoctoral Fellowship
- Eugene V. Cota-Robles Fellowship
- GM08042
- NIH Predoctoral Fellowship
- 20160969
- John Merck Fund
- 295438
- Simons Foundation
- R01 HD054453
- NIH
- Created
-
2017-06-19Created from EPrint's datestamp field
- Updated
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2021-11-15Created from EPrint's last_modified field