Editors' ChoiceAutism

An epigenetic target for autism

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Science Translational Medicine  18 Apr 2018:
Vol. 10, Issue 437, eaat4476
DOI: 10.1126/scitranslmed.aat4476


A transient 3-day course of treatment with a histone deacetylase inhibitor persistently rescues atypical social behavior in a Shank3-deficiency mouse model of autism.

Autism spectrum disorder (ASD) is a neurodevelopmental condition involving difficulties with communication and social interaction that emerge early in life. ASD is highly heritable, but the genetic etiology is complex—hundreds of genes have been implicated—and targeted medical treatments linked to specific genetic risk factors remain elusive. Mutations in one such gene, SHANK3, encoding a synaptic scaffolding protein, are found in ~0.5 to 2% of cases. The mechanisms linking SHANK3 deficiency, synapse dysfunction, and social behavior are not well understood but are thought to involve complex gene expression changes affecting synaptic homeostasis and transcription regulation. This observation suggests that drugs targeting physiological regulators of gene expression could be promising treatment candidates.

Qin et al. show that romidepsin, a histone deacetylase (HDAC) inhibitor, rescued social behavioral deficits in Shank3-deficient mice by inhibiting excessive HDAC2 activity in the prefrontal cortex. Remarkably, a single three-day treatment course at 5 to 6 weeks of age (corresponding to late adolescence in humans) had rapid effects on social behavior that persisted for up to three weeks. In contrast, treating adult Shank3-deficient mice had modest and transient effects, underscoring the necessity of early intervention. The mechanism linking Shank3 deficiency with excessive HDAC2 activity and atypical social behavior was mediated by β-catenin, a transcriptional regulator and cellular adhesion molecule that normally binds Shank3 within synapses. In Shank3-deficient mice, β-catenin migrates out of synapses, accumulates in the nucleus, and up-regulates the expression of HDAC2. Romidepsin reversed these effects, inhibiting excessive HDAC2 activity and selectively increasing the expression of Grin2a and various actin regulatory genes, which in turn restored excitatory synapse function.

Although the therapeutic effects of romidepsin attenuated over time and did not permanently rescue atypical social behaviors in Shank3-deficient mice, this report identifies a specific, druggable mechanism linking Shank3 deficiency, synapse dysfunction, and social behavior, opening multiple new avenues for developing more targeted interventions. Intervening early in life was critical, and additional studies will be required to define the optimal timing and understand how interactions with neurodevelopmental processes might be leveraged for maximal therapeutic benefit.

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