Affiliation:
1. Department of Neurosciences, Faculty of Medicine, University of Montreal, Montréal QC H3T 1C5, Canada
2. CHU Ste-Justine Research Center, Montréal, QC H3T 1C5, Canada
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.
Funder
The Canadian Institutes of Health Research
Canada Foundation for Innovation
Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada
Scottish Rite Charitable Foundation of Canada
Fonds de recherche du Québec Santé
Herber Jesper postdoctoral fellowship at Université of Montréal
Publisher
Proceedings of the National Academy of Sciences