Impaired cerebellar plasticity hypersensitizes sensory reflexes in SCN2A-associated ASD.
Children diagnosed with autism spectrum disorder (ASD) commonly present with sensory hypersensitivity or abnormally strong reactions to sensory stimuli. Such hypersensitivity can be overwhelming, causing high levels of distress that contribute markedly to the negative aspects of the disorder. Here, we identify a mechanism that underlies hypersensitivity in a sensorimotor reflex found to be altered in humans and in mice with loss of function in the ASD risk-factor gene SCN2A. The cerebellum-dependent vestibulo-ocular reflex (VOR), which helps maintain one's gaze during movement, was hypersensitized due to deficits in cerebellar synaptic plasticity. Heterozygous loss of SCN2A-encoded NaV1.2 sodium channels in granule cells impaired high-frequency transmission to Purkinje cells and long-term potentiation, a form of synaptic plasticity important for modulating VOR gain. VOR plasticity could be rescued in mice via a CRISPR-activator approach that increases Scn2a expression, demonstrating that evaluation of a simple reflex can be used to assess and quantify successful therapeutic intervention.
Pubmed ID: 38412857 RIS Download
Research resources used in this publication
- KiloSort (RRID:SCR_016422) (data processing software)
- DeepLabCut (RRID:SCR_021391) (software resource)
- MATLAB (RRID:SCR_001622) (software resource)
- LabView (RRID:SCR_014325) (software development tool)
- GraphPad Prism (RRID:SCR_002798) (software resource)
- IGOR Pro (RRID:SCR_000325) (software resource)
- B6.D2-Tg(Gabra6-cre)B1Lfr/Mmucd (RRID:MMRRC_015966-UCD) (organism)
- C57BL/6J (RRID:IMSR_JAX:000664) (organism)
- Guinea pig Anti-Vesicular Glutamate Transporter 1 (VGLUT1) Polyclonal antibody, Unconjugated (RRID:AB_2301751) (antibody)
- Anti-Green Fluorescent Protein Antibody (RRID:AB_2307313) (antibody)
- RFP Antibody Pre-adsorbed (RRID:AB_11182807) (antibody)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Guinea pig Anti-Vesicular Glutamate Transporter 1 (VGLUT1) Polyclonal antibody, Unconjugated (RRID:AB_2301751)
- Anti-Green Fluorescent Protein Antibody (RRID:AB_2307313)
- RFP Antibody Pre-adsorbed (RRID:AB_11182807)
- Goat Anti-Guinea Pig IgG (H+L) Highly Cross-adsorbed Antibody, Alexa Fluor ?? 568 Conjugated (RRID:AB_141954)
- Goat Anti-Chicken IgG (H+L) Antibody, Alexa Fluor ?? 488 Conjugated (RRID:AB_142924)
- Goat anti-Rabbit IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 568 (RRID:AB_143157)
Associated grants
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This is a list of tools and resources that we have found mentioned in this publication.
Guinea pig Anti-Vesicular Glutamate Transporter 1 (VGLUT1) Polyclonal antibody, Unconjugated (antibody)
RRID:AB_2301751
This polyclonal targets VGLUT1
View all literature mentionsAnti-Green Fluorescent Protein Antibody (antibody)
RRID:AB_2307313
This polyclonal targets GFP-1010
View all literature mentionsRFP Antibody Pre-adsorbed (antibody)
RRID:AB_11182807
This polyclonal targets RFP
View all literature mentionsGoat Anti-Guinea Pig IgG (H+L) Highly Cross-adsorbed Antibody, Alexa Fluor ?? 568 Conjugated (antibody)
RRID:AB_141954
This unknown targets Guinea Pig IgG (H+L)
View all literature mentionsGoat Anti-Chicken IgG (H+L) Antibody, Alexa Fluor ?? 488 Conjugated (antibody)
RRID:AB_142924
This unknown targets Chicken IgG (H+L)
View all literature mentionsGoat anti-Rabbit IgG (H+L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 568 (antibody)
RRID:AB_143157
This polyclonal secondary targets IgG (H+L)
View all literature mentionsKiloSort (data processing software)
RRID:SCR_016422
Software tool that implements an integrated template matching framework for detecting and clustering spikes from multi-channel electrophysiological recordings.
View all literature mentionsDeepLabCut (software resource)
RRID:SCR_021391
Open source software package for markerless pose estimation. 2D keypoint detection in animals.
View all literature mentionsMATLAB (software resource)
RRID:SCR_001622
Multi paradigm numerical computing environment and fourth generation programming language developed by MathWorks. Allows matrix manipulations, plotting of functions and data, implementation of algorithms, creation of user interfaces, and interfacing with programs written in other languages, including C, C++, Java, Fortran and Python. Used to explore and visualize ideas and collaborate across disciplines including signal and image processing, communications, control systems, and computational finance.
View all literature mentionsLabView (software development tool)
RRID:SCR_014325
A development environment for engineers and scientists to visualize, create, and code engineering systems. The system design software is integrated with all measurement hardware and contains signal processing IP. Other features include multithreaded execution, software deployment to hardware, and program integration into a single environment.
View all literature mentionsGraphPad Prism (software resource)
RRID:SCR_002798
Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsIGOR Pro (software resource)
RRID:SCR_000325
Software used for visualizing and graphing data, image processing, and programming. It is designed for use by scientists and engineers and supports large data sets, evenly spaced data, and various data import formats. The software includes a suite of image processing operations for image filtering, manipulation, and quantification and is completely programmable.
View all literature mentionsB6.D2-Tg(Gabra6-cre)B1Lfr/Mmucd (organism)
RRID:MMRRC_015966-UCD
Mus musculus with name B6.D2-Tg(Gabra6-cre)B1Lfr/Mmucd from MMRRC.
View all literature mentionsC57BL/6J (organism)
RRID:IMSR_JAX:000664
Mus musculus with name C57BL/6J from IMSR.
View all literature mentionsGuinea pig Anti-Vesicular Glutamate Transporter 1 (VGLUT1) Polyclonal antibody, Unconjugated (antibody)
RRID:AB_2301751
This polyclonal targets VGLUT1
View all literature mentionsAnti-Green Fluorescent Protein Antibody (antibody)
RRID:AB_2307313
This polyclonal targets GFP-1010
View all literature mentionsRFP Antibody Pre-adsorbed (antibody)
RRID:AB_11182807
This polyclonal targets RFP
View all literature mentions
