Atypical sensory experience is a core feature of autism spectrum disorder (ASD) and is strongly determinant of other ASD traits. For the vast majority of individuals with ASD, atypical sensory experience represents an important challenge for everyday life. Nonetheless, there is a surprising paucity of neurobiological studies addressing this aspect of ASD pathology, or specifically attempting to target atypical sensory experience for therapeutic rescue. In the current project, Andreas Frick and Stefan Heinemann plan to address this important challenge and to enhance translation between preclinical experiments in mice and clinical studies.
Touch-related sensory information is processed and integrated in the somatosensory cortex in humans and in mice. This brain region is thus eminently suited to the evaluation of sensory-evoked signals in ASD. Frick and colleagues previously described that alterations in the excitability and responsiveness of somatosensory cortex neurons are critically implicated in the atypical processing of touch-related sensory information in the Fmr1 knockout mouse model of fragile X syndrome and ASD1,2. Importantly, these studies also suggested that targeting big-conductance calcium- and voltage-activated potassium (BKCa) channels could be a suitable therapeutic treatment of atypical sensory experience.
Building on a previous SFARI Pilot Award, Frick and Heinemann aim to further investigate how BKCa channel agonists modulate BKCa channels and affect neocortical excitability and sensory experience. Specifically, they plan to characterize the BKCa channel profile of human neurons and use this information to tailor their in vitro expression model, which will be used to study the mode of action of different BKCa agonists (Aim 1).
In parallel, they will evaluate the effect of BKCa agonists on different parameters related to the neocortical processing of touch-related sensory information in genetic mouse models of ASD (including Fmr1, Shank3b and Pten mutant lines). To complement these findings, they will evaluate the effect of BKCa agonists on neuronal excitability in engineered human stem-cell derived neuronal models of ASD (Aim 2).
Lastly, they will explore whether chronic treatment with a BKCa agonist during early postnatal development can correct circuit-level deficits impinging on the processing of touch-related sensory information in Fmr1 knockout mice (Aim 3).
Findings from these studies are expected to lead to a refinement of our understanding of the molecular composition of neuronal BKCa channels in human neurons and the efficacy of different BKCa agonists in modulating these channels and correcting specific aspects of sensory information processing. Since atypical sensory experiences are strongly determinant of other ASD features, any therapeutic approach that can target sensory information processing has the potential to improve multiple ASD challenges.