Autism Spectrum Disorder (ASD) is a communication disorder, and recent functional imaging studies have revealed significant abnormalities in the way that the brains of ASD individuals process speech and sound. Specifically, core auditory cortical areas exhibit different patterns of activation compared with typically developed individuals, suggesting that improper wiring in these areas during brain development might lead to later deficits in primary auditory processing. Such faulty wiring could result from abnormal development of the thalamocortical or intracortical connections to layer 4 of core auditory cortex, though this has never been investigated. Mice exposed prenatally to the antiepileptic drug valproic acid (VPA), a translational model of ASD, exhibit several deficits in auditory processing, including the response of core auditory cortical neurons to tones. Our preliminary results indicate that fetal subplate circuits, which are critical for the development o thalamocortical and intracortical connections to layer 4, are disrupted in the primary auditory cortex of VPA- exposed mouse pups. These findings, along with previous studies of subplate disruption in the mammalian brain, lead us to hypothesize that VPA exposure results in underdeveloped thalamocortical connectivity, but increased intracortical connectivity, in layer 4; essentially, layer 4 becomes functionally decoupled from thalamic input. Thus, this proposal will test the hypothesis that, following prenatal exposure to VPA, there is a decoupling of cortica circuits in auditory cortex from thalamic input, leading to abnormal auditory processing. To test this hypothesis, I will use in vivo 2-photon Ca2+ imaging (Aim 1), and in vitro electrophysiology with high resolution circuit mapping techniques (Aim 2), to examine functional thalamocortical and intracortical connectivity in core auditory cortex of adult mice exposed prenatally to VPA. The results of the proposed research have the potential to reveal how early insults to developing auditory circuits can lead to dysfunctional sound processing in ASD.
Autism is a communication disorder, and might be caused by a failure of brain circuits that process sound to correctly assemble in the developing fetus. I propose to use a mouse model of autism to uncover dysfunctional circuits in the auditory cortex using high resolution in vitro and in vivo techniques.
| Nagode, Daniel A; Meng, Xiangying; Winkowski, Daniel E et al. (2017) Abnormal Development of the Earliest Cortical Circuits in a Mouse Model of Autism Spectrum Disorder. Cell Rep 18:1100-1108 |
