The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment

Abstract

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders sharing a core set of symptoms, including impaired social interaction, language deficits, and repetitive behaviors. While ASDs are highly heritable and demonstrate a clear genetic component, the cellular and molecular mechanisms driving ASD etiology remain undefined. The unavailability of live patient-specific neurons has contributed to the difficulty in studying ASD pathophysiology. The recent advent of induced pluripotent stem cells (iPSCs) has provided the ability to generate patient-specific human neurons from somatic cells. The iPSC field has quickly grown, as researchers have demonstrated the utility of this technology to model several diseases, especially neurologic disorders. Here, we review the current literature around using iPSCs to model ASDs, and discuss the notable findings, and the promise and limitations of this technology. The recent report of a nonsyndromic ASD iPSC model and several previous ASD models demonstrating similar results points to the ability of iPSC to reveal potential novel biomarkers and therapeutics.

Fig. 1

Transient receptor potential canonical 6 (TRPC6) signaling pathways. TRPC6 has been implicated in the activation of several important neuronal signaling pathways. Influx of Ca²⁺ via TRPC6 pathways has been demonstrated to induce several signal transduction pathways, including the protein kinase B (Akt), calcium/calmodulin-dependent protein kinase IV (CaMKIV), and extracellular signal-regulated kinase (ERK) pathways. Activation of these pathways eventually leads to the activation of the transcription factor cyclic adenosine monophosphate-response element binding protein phosphorylation (CREB), which has been demonstrated to promote proneuronal effects, including neuronal survival, neuronal plasticity, neurite outgrowth, and synaptogenesis. Several TRPC6 agonists have been demonstrated to stimulate TRPC6 and induce Ca²⁺ influx, including hyperforin and diacyl glycerol (DAG), the endogenous TRPC6 activator. Both the brain-derived neurotrophic factor (BDNF) receptor tropomyosin receptor kinase B (TrkB) and insulin-like growth factor (IGF)-1 receptor can promote downstream signaling that can also activate TRPC6, as well as both the ERK and Akt pathways. Recently, methyl CpG binding protein 2 (MeCP2) has been shown to bind to the promoter region of TRPC6 and to be important for TRPC6 expression