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Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X Syndrome

Diana E. Mitchell, Soledad Miranda-Rottmann, Maxime Blanchard, View ORCID ProfileRoberto Araya
doi: https://doi.org/10.1101/2022.03.14.484306
Diana E. Mitchell
1Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, QC, Canada
2The CHU Sainte-Justine Research Center, Montreal, QC, Canada
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Soledad Miranda-Rottmann
1Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, QC, Canada
2The CHU Sainte-Justine Research Center, Montreal, QC, Canada
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Maxime Blanchard
1Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, QC, Canada
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Roberto Araya
1Department of Neurosciences, Faculty of Medicine, University of Montreal, Montreal, QC, Canada
2The CHU Sainte-Justine Research Center, Montreal, QC, Canada
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  • ORCID record for Roberto Araya
  • For correspondence: roberto.araya@umontreal.ca
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ABSTRACT

To uncover how synaptic integration of feedforward sensory inputs is affected in autism spectrum disorders (ASD), we used two-photon uncaging of caged glutamate to activate two clustered spines in the basal dendrites of layer 5 (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 a hyperexcitable cortex typically associated with ASD. Knockdown of the regulatory β4 subunit of BK channels, rescues 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. These results challenge the traditional view that FXS and other ASD are characterized by sensory hypersensitivity, but instead by hyposensitivity of sensory inputs and hypersensitivity of predictive inputs onto cortical neurons.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 15, 2022.
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Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X Syndrome
Diana E. Mitchell, Soledad Miranda-Rottmann, Maxime Blanchard, Roberto Araya
bioRxiv 2022.03.14.484306; doi: https://doi.org/10.1101/2022.03.14.484306
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Altered integration of excitatory inputs onto the basal dendrites of layer 5 pyramidal neurons in a mouse model of Fragile X Syndrome
Diana E. Mitchell, Soledad Miranda-Rottmann, Maxime Blanchard, Roberto Araya
bioRxiv 2022.03.14.484306; doi: https://doi.org/10.1101/2022.03.14.484306

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