Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X syndrome
Edited by Mark Nelson, University of Vermont, Burlington, VT; received May 25, 2022; accepted November 11, 2022
Significance
Fragile X syndrome (FXS) is the most commonly known cause of autism spectrum disorders (ASD). We found that while control animals integrate subthreshold feedforward excitatory inputs linearly, this integration is sublinear in FXS mice, a defect that was reversed by genetic manipulation of BK channel activity. The sublinear integration contradicts what would be expected of sensory hypersensitivity classically associated with ASD. These findings instead support a model of FXS encompassing sensory hyposensitivity and predictive hypersensitivity at the level of cortical neurons. Moreover, these results highlight the need to study, in FXS and other forms of ASD, channelopathies in cortical feedforward and feedback pathways independently, their associations, and how cortical pyramidal neurons output is affected, which ultimately shapes behavior.
Abstract
Layer 5 (L5) pyramidal neurons receive predictive and sensory inputs in a compartmentalized manner at their apical and basal dendrites, respectively. To uncover how integration of sensory inputs is affected in autism spectrum disorders (ASD), we used two-photon glutamate uncaging to activate spines in the basal dendrites of L5 pyramidal neurons from a mouse model of Fragile X syndrome (FXS), the most common genetic cause of ASD. While subthreshold excitatory inputs integrate linearly in wild-type animals, surprisingly those with FXS summate sublinearly, contradicting what would be expected of sensory hypersensitivity classically associated with ASD. We next investigated the mechanism underlying this sublinearity by performing knockdown of the regulatory β4 subunit of BK channels, which rescued the synaptic integration, a result that was corroborated with numerical simulations. Taken together, these findings suggest that there is a differential impairment in the integration of feedforward sensory and feedback predictive inputs in L5 pyramidal neurons in FXS and potentially other forms of ASD, as a result of specifically localized subcellular channelopathies. These results challenge the traditional view that FXS and other ASD are characterized by sensory hypersensitivity, proposing instead a hyposensitivity of sensory inputs and hypersensitivity of predictive inputs onto cortical neurons.
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Data, Materials, and Software Availability
All study data are included in the article and/or SI Appendix.
Acknowledgments
We thank Hélène Klein for excellent technical assistance and are grateful to all other members of Roberto Araya’s laboratory for helpful discussions. We thank E. Cook and G. Di Cristo for insightful comments, critical discussion, and reading of the manuscript. Confocal microscopy experiments were carried out at the IRIC Bio-Imaging Core. This work was funded by the Canadian Institutes of Health Research (CIHR) grants MOP-133711 and MOP-377520 to R.A., a Canada Foundation for Innovation (CFI) equipment grant Fonds des leaders 29970 to R.A., a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grant #418113-2012, and a Scottish Rite Charitable Foundation of Canada (SRCFC) research grant to R.A. M.B. was supported by a Herber Jesper postdoctoral fellowship at Université of Montréal. D.E.M. was supported by postdoctoral fellowships from the Fonds de recherche du Québec Santé (FRQS) and the Quebec Autism Research Training (QART) Program.
Author contributions
D.E.M., S.M.-R., and R.A. designed research; D.E.M., S.M.-R., and M.B. performed research; D.E.M., S.M.-R., M.B., and R.A. analyzed data; and D.E.M., S.M.-R., and R.A. wrote the paper.
Competing interest
The authors declare no competing interest.
Supporting Information
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Copyright © 2023 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
Data, Materials, and Software Availability
All study data are included in the article and/or SI Appendix.
Submission history
Received: May 25, 2022
Accepted: November 11, 2022
Published online: January 3, 2023
Published in issue: January 10, 2023
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Acknowledgments
We thank Hélène Klein for excellent technical assistance and are grateful to all other members of Roberto Araya’s laboratory for helpful discussions. We thank E. Cook and G. Di Cristo for insightful comments, critical discussion, and reading of the manuscript. Confocal microscopy experiments were carried out at the IRIC Bio-Imaging Core. This work was funded by the Canadian Institutes of Health Research (CIHR) grants MOP-133711 and MOP-377520 to R.A., a Canada Foundation for Innovation (CFI) equipment grant Fonds des leaders 29970 to R.A., a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grant #418113-2012, and a Scottish Rite Charitable Foundation of Canada (SRCFC) research grant to R.A. M.B. was supported by a Herber Jesper postdoctoral fellowship at Université of Montréal. D.E.M. was supported by postdoctoral fellowships from the Fonds de recherche du Québec Santé (FRQS) and the Quebec Autism Research Training (QART) Program.
Author Contributions
D.E.M., S.M.-R., and R.A. designed research; D.E.M., S.M.-R., and M.B. performed research; D.E.M., S.M.-R., M.B., and R.A. analyzed data; and D.E.M., S.M.-R., and R.A. wrote the paper.
Competing Interest
The authors declare no competing interest.
Notes
This article is a PNAS Direct Submission.
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