Neural Circuits Underlying Autism-Relevant Behaviors in TSC
Abstract
Tuberous sclerosis complex (TSC) is a neurodevelopmental disorder that affects 1:6000 people. One of the major contributors to disability in individuals with TSC is the presence of autism, which affects 50% of individuals with TSC. Yet despite these high rates of autism in TSC, the underlying causes continue to be poorly understood. Studies to this point have ignored the contributions of a certain brain region, the cerebellum, to autism despite the fact that the most consistent pathological feature in autism is cerebellar, despite the fact that isolated cerebellar injury during development conveys a 40-fold increased risk of developing autistic symptoms, and despite the fact that in TSC, when individuals without autism are compared to those with autism, the presence of cerebellar lesions and cerebellar dysfunction is highly correlated with the presence of autism. To address these findings, we developed a mouse model of TSC whereby one of the causative genes responsible for TSC was deleted only in the cerebellum and we for the first time determined that cerebellar dysfunction was sufficient to generate autism-related behaviors in this model of TSC. However, this study has left us with the pressing question of how dysfunction in this brain region results in autism-related behaviors. We hypothesize that the cerebellum communicates with the rest of brain through distinct neural circuits and that there are specific cerebellar derived circuits that communicate with other brain regions and regulate social and repetitive behaviors. In this study, we propose to delineate the specific cerebellar circuits that regulate autism-related behaviors. These studies, thus, will allow us to achieve a better understanding of how the cerebellum regulates autism-related behavior. In addition, identifying these circuits and potential disruptions in these circuits in TSC may also afford an opportunity to better understand the phenotypic heterogeneity of TSC. If dysfunction or disruption of these specific circuits contributes to autism-related behaviors, these neural circuits could provide potential biomarkers to determine risk for developing autism in TSC. Moreover, in this study, we also propose to manipulate these circuits and evaluate whether targeted neuromodulation of these circuits can result in therapeutic benefit for autism-related behaviors. If successful, these studies will thus provide the foundation for developing novel therapeutics for the treatment of autism related to TSC, in addition to potentially providing a therapeutic framework to treat autism unrelated to TSC where cerebellar dysfunction has also been implicated. Combined with the present development of modalities such as non-invasive neuromodulation presently being studied for the treatment of diverse neuropsychiatric disorders as strokes, seizures, and depression, these proposed studies have the potential to rapidly inform clinical studies of treatment of autistic behaviors in TSC. These proposed studies would evaluate efficacy of neuromodulation in preclinical models and thus provide potential therapeutic targets for these modalities, thereby reducing potential side effects of nonspecific neuromodulation. Thus, these proposed studies are both mechanistic and rapidly translational and could provide the framework to develop targeted, neuroanatomic-based therapeutics for the treatment of autism spectrum disorder in individuals with TSC, for whom, at present, no targeted therapies exist.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710238
Entities
People
- Peter T Tsai
Organizations
- United States Army
- University of Texas Southwestern Medical Center