Potential Involvement of Impaired BKCa Channel Function in Sensory Defensiveness and Some Behavioral Disturbances Induced by Unfamiliar Environment in a Mouse Model of Fragile X Syndrome

Abstract

In fragile X syndrome (FXS), sensory hypersensitivity and impaired habituation is thought to result in attention overload and various behavioral abnormalities in reaction to the excessive and remanent salience of environment features that would normally be ignored. This phenomenon, termed sensory defensiveness, has been proposed as the potential cause of hyperactivity, hyperarousal, and negative reactions to changes in routine that are often deleterious for FXS patients. However, the lack of tools for manipulating sensory hypersensitivity has not allowed the experimental testing required to evaluate the relevance of this hypothesis. Recent work has shown that BMS-204352, a BK channel agonist, was efficient to reverse cortical hyperexcitability and related sensory hypersensitivity in the Fmr1-KO mouse model of FXS. In the present study, we report that exposing Fmr1-KO mice to novel or unfamiliar environments resulted in multiple behavioral perturbations, such as hyperactivity, impaired nest building and excessive grooming of the back. Reversing sensory hypersensitivity with the BK channel agonist BMS-204352 prevented these behavioral abnormalities in Fmr1-KO mice. These results are in support of the sensory defensiveness hypothesis, and confirm BK as a potentially relevant molecular target for the development of drug medication against FXS/ASD.

Early Retinal Defects in Fmr1−/y Mice: Toward a Critical Role of Visual Dys-Sensitivity in the Fragile X Syndrome Phenotype?

“…Early in life, FXS patients present auditory, olfactory, nociceptive and visual abnormalities (Casamassimo et al, 1986 ; Lachiewicz et al, 1994 ), creating a wide range of phenotypical dysregulations in sensory responses. These sensorial perturbations may participate in occurrence of major behavioral troubles in FXS as suggested recently (Carreno-Munoz et al, 2018 ). According to our hypothesis, the term “sensorial hypersensitivity”, literally suggesting a higher sensorial response, should be avoided.…”

Gamma power abnormalities in a Fmr1-targeted transgenic rat model of fragile X syndrome

“…The present study found that Fmr1 -KO rats showed enhanced locomotor activity for the first 30 min after placement in a novel environment but not at 30–60 min or 60–90 min. Studies using Fmr1 KO mice have reported that the hyperactivity was a reaction to novelty 42 , 43 . Our results from Fmr1 -KO rats suggest that the hyperactivity may be a reaction to novelty, because the significant augmentation in locomotor activity was only observed for the first 30 min after placement in a novel testing field.…”

Physiological Roles and Therapeutic Potential of Ca2+ Activated Potassium Channels in the Nervous System

“…Additionally, direct injection of the activator restored hippocampal glutamate homeostasis and corrected disturbances in social recognition and interaction, non-social anxiety and spatial memory ( Hebert et al, 2014 ). In another study, BMS-204352 efficiently reversed the cortical hyperexcitability and increased acoustic startle seen in FMR1 knockout mice ( Carreno-Munoz et al, 2018 ), suggesting that this treatment could alleviate sensory hypersensitivity symptoms in FXS patients.…”