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. 2018 Feb;43(3):492-502.
doi: 10.1038/npp.2017.149. Epub 2017 Jul 19.

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

Maria Isabel Carreno-Munoz  1   2   3 , Fabienne Martins  1   2 , Maria Carmen Medrano  1   2 , Elisabetta Aloisi  1   2 , Susanna Pietropaolo  4   5 , Corentin Dechaud  1   2 , Enejda Subashi  1   2 , Guillaume Bony  1   2 , Melanie Ginger  1   2 , Abdelmalik Moujahid  3 , Andreas Frick  1   2 , Xavier Leinekugel  1   2
Affiliations

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

Maria Isabel Carreno-Munoz et al. Neuropsychopharmacology. 2018 Feb.

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 BKCa 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 BKCa channel agonist BMS-204352 prevented these behavioral abnormalities in Fmr1-KO mice. These results are in support of the sensory defensiveness hypothesis, and confirm BKCa as a potentially relevant molecular target for the development of drug medication against FXS/ASD.

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Figures

Figure 1
Figure 1
BMS-204352 rescue of the hyperactivity phenotype of Fmr1-KO mice in a novel environment. (a) Single animal (left, WT; right, Fmr1-KO) total trajectory during a 1 h exposure to an open field never visited before. (b–f) Summary plots of locomotor activity during the initial 1 h spent in a novel open field for WT and Fmr1-KO mice pretreated with either vehicle or BMS-204352 (IP injection 30 min before introduction into the open field). WT+Veh, n=16, KO+Veh, n=13, KO+BMS-204352, n=13, WT+BMS-204352, n=15. (b) Total distance moved; (c) total time resting; (d) number of rotations (angle >180°); (e) total time resting in center; and (f) total time in center. *Statistically significant difference compared with all other groups (p<0.05). Note the general hyperactivity of KO mice, rescued by BMS-204352 treatment.
Figure 2
Figure 2
Fmr1-KO mice are not hyperactive in a familiar environment. (a) Single animal (left, WT; right, Fmr1-KO) total trajectory during a 1 h exploration session of an open field after familiarization (1 h/day during 5 days). (b–f) Summary plots of locomotor activity during the 1 h recording period in the familiar open field for WT and Fmr1-KO mice. WT, n=8, KO, n=8. (b) Total distance moved; (c) total time resting; (d) number of rotations (angle >180°); (e) total time resting in center; and (f) total time in center. No statistically significant effect of genotype.
Figure 3
Figure 3
Impaired nest building for Fmr1-KO mice outside home cage. (a) Illustration of nest building performance for individual WT and Fmr1-KO mice in their home cage (left), familiar open field (OF, familiarization 1 h/day during 9 days), and new cage (right). The pictures were taken at the time indicated (between 1 h and 5 h after introduction of the nest building material). Note that the WT mouse had terminated nest building after 90 min in all tested conditions, whereas the KO mouse performed well in its home cage but not in the familiar open field or in a new cage. (b) Summary plots of nest building scores in home cage, new cage, and familiar open field for WT and Fmr1-KO mice. (c) Summary plot of nest building over time for WT and Fmr1-KO mice in a new cage. Note that WT mice complete nest building within 2 to 3 h in any tested condition, whereas KO mice have delayed nest building. (b, c) *Statistically significant effect of genotype (p<0.05).
Figure 4
Figure 4
BMS-204352 but not diazepam rescue of nest building in familiar open field and new cage. (a) Illustration of nest building performance of Fmr1-KO mice after 1 h in a new cage after vehicle (left), BMS-204352 (middle), or diazepam (DZ, right) injection. Summary plots of nest building performance after 1 h, following treatment with either vehicle or BMS-204352 (left, 5 WT+Veh, 5 WT+BMS, 12 Fmr1-KO+Veh, and 9 Fmr1-KO+BMS). The effect on nest building of the anxiolytic DZ, tested against that of vehicle (Veh) on the same animals but on consecutive days (8 WT and 6 Fmr1-KO mice tested consecutively with vehicle, DZ, and for Fmr1-KO mice vehicle again), is illustrated on the right plots. *P<0.05 compared with all other groups. (b) Illustration of nest building performance of Fmr1-KO mice treated either with vehicle (days 10 and 12) or BMS-204352 (day 11) after 2 h in a familiar (1 h/day during 9 days) open field. Summary plot of nest building performance on days 10 (treatment=vehicle), 11 (BMS-204352), and 12 (vehicle) for Fmr1-KO (n=15) mice. Inset, nest building performance on days 10 (treatment=vehicle) and 11 (BMS-204352) for WT mice (n=12). *P<0.05 compared with Veh (day 10) and Veh (day 12). Note the reversible rescue of nest building performance in Fmr1-KO mice with the BMS-204352 treatment.
Figure 5
Figure 5
BMS-204352 prevents excessive self-grooming of the back in Fmr1-KO mice exposed to a novel environment. Wild-type (WT) and Fmr1-KO mice (KO) treated either with vehicle (Veh) or BMS-204352 (BMS) were exposed for 1 h to a novel open field. Total grooming time (a) or specific grooming of the back, belly, nose, or ears (b–d) were quantified (number of animals: 8 WT, 8 Fmr1-KO). (a) Total self-grooming time. (b) Pictures showing the four different types of self-grooming activities quantified in (c, d) (*position of paws). (c) Total time spent in grooming the belly, nose, or ears. (d) Total time (left plot), number (middle), and mean duration (right) of events for grooming the back. *P<0.05 compared with WT+Veh and KO+BMS. Note the excessive grooming of the back in Fmr1-KO mice, an effect fully rescued by BMS-204352.
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