Development and function of the auditory cortex in a mouse model of autism spectrum disorder
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that is characterised by the core features of impairments in social communication and interaction and repetitive behaviours. In addition to the core features, atypical sensory processing is highly prevalent in people with ASD and in relation to auditory processing, this is associated with impairments in language and communication. The mechanisms underlying the pathophysiology remain unclear, but it is likely that neural networks are altered due to permanent miswiring of neuronal connections during early development, prompted by defective synaptic proteins, such as the Shank3 protein. Previous studies of the Shank3B-/- mouse model of ASD have shown that mutation of the Shank3 gene can adversely affect synapses. In this study, we used in vivo widefield calcium imaging to determine whether functional differences are present in the auditory cortex of neonatal and adult Shank3B-/- and Shank3B+/- mice when compared to age-matched Shank3B+/+ mice. In adult animals (either at 4- 6 weeks or 8-12 weeks old), region-specific and mesoscopic imaging data showed no differences in the average frequency, amplitude, and duration of calcium transients between the genotype groups. However, at post-natal day 8-10, mesoscopic images in Shank3B-/- mice revealed that the calcium transients were less frequent when compared to Shank3B+/+ neonates. Additionally, the fluorescent amplitude was higher when compared to the Shank3B+/+ and Shank3B+/- mice, but no difference in the average duration of calcium transients was observed between the genotype groups. We were not able to determine the tonotopic organisation in region-specific and mesoscopic imaging for all genotype groups. However, mesoscopic imaging showed long-range functional hyper-connectivity in the adult Shank3B-/-mice, which was not seen in the neonatal mice. Together, our data suggests that during development, the absence of Shank3B protein perturbs network activity either by delaying maturation in sensory circuits or by altering neuronal firing properties. Further investigation at the cellular level is required to elucidate which of these possibilities is occurring in Shank3B-/- neonates. Furthermore, it is currently unknown if these observations seen during development are linked to the functional hyper-connectivity we observed in the adult Shank3B-/- mice. Taken together, our data contributes to the ultimate goal of finding a common pathological pathway behind auditory processing abnormalities in a highly heterogeneous disorder with no known pathophysiological mechanism.
Networked Digital Library of Theses and Dissertations