Tuberous Sclerosis: A New Frontier in Targeted Treatment of Autism

Abstract

Tuberous sclerosis complex (TSC) is a genetic disorder with a high prevalence of autism spectrum disorder (ASD). Tremendous progress in understanding the pathogenesis of TSC has been made in recent years, along with initial trials of medical treatment aimed specifically at the underlying mechanism of the disorder. At the cellular level, loss of TSC1 or TSC2 results in upregulation of the mechanistic target of rapamycin (mTOR) pathway. At the circuitry level, TSC and mTOR play crucial roles in axonal, dendritic, and synaptic development and function. In this review, we discuss the molecular mechanism underlying TSC, and how this disease results in aberrant neural connectivity at multiple levels in the central nervous system, leading to ASD symptoms. We then review recent advances in mechanism-based treatments of TSC, and the promise that these treatments provide for future mechanism-based treatment of ASD. Because of these recent advances, TSC represents an ideal model for how to make progress in understanding and treating the mechanisms that underlie ASD in general.

Fig. 1

The multiple levels of neural structure and function affected in tuberous sclerosis complex (TSC). (a) Biochemical: dysregulation of the mechanistic target of rapamycin (mTOR) pathway leads to unchecked cellular growth. (b) Neuronal: cellular overgrowth causes abnormal synaptic excitability and long-term potentitation (LTP), dendritic spine morphology, neuronal structure, and cortical lamination. (c) Brain: cellular overgrowth and abnormal migration results in formation of tubers, abnormal white matter myelination and connectivity, and cerebellar abnormalities. (d) Organism: multiple neural abnormalities result in seizures, abnormal cognition, inflammation, and autism spectrum disorder symptoms. PI3K = phosphoinositide 3-kinse; AMP=adenosine monophosphate; ATP=adenosine triphosphate; AKT=protein kinase B; AMPK=AMP-activated protein kinase; mTORC1 = mTOR complex 1; 4E-BP1 = eIF4E-binding protein 1; S6K1 = p70 S6 kinase 1