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Characterizing microRNA-128 as a Therapeutic Target for Vocal Communication Deficits

  • Author(s): Aamodt, Caitlin M
  • Advisor(s): White, Stephanie A
  • et al.
Abstract

Autism spectrum disorder (ASD) prevalence is on the rise, with recent estimates of 1 in 68 children affected (cdc.gov). Although social communication deficits are among the two core criteria for diagnosis there are currently no medications available on the market to enhance the efficacy of speech therapy. Despite the urgent and growing need, progress on therapeutic development has been hindered by a lack of understanding of the molecular mechanisms underlying learned vocal communication. One model for how communication deficits arise is that the molecular mechanisms that constrain critical period plasticity come on too early, closing the plasticity window before the patient has the opportunity to learn speech and language (LeBlanc & Fagiolini 2011). The brain-enriched microRNA miR-128 increases over the course of development in rodent and human brains, peaking in adulthood (Lek-Tan et al. 2012, Bruno et al. 2011). miR-128 is also aberrantly upregulated in postmortem tissue (Wu et al. 2016) and its targets are downregulated in peripheral blood from autism patients (Gazestani et al. 2019). If miR-128 is a negative regulator of vocal learning, then reducing its levels could restore plasticity, or the capacity to learn to speak, in patients with ASD.

Previously our lab generated activity-dependent gene expression networks in the striatopallidal song nucleus known as Area X in adult and juvenile songbirds to identify master regulators of learned vocal behavior (Hilliard et al. 2012, Burkett et al. 2018). Using this dataset, I discovered that the two host genes for miR-128, ARPP21 and R3HDM1, are among the top genes whose expression was correlated to how much the adult bird sang. In humans, multiple single nucleotide polymorphisms that reduce the expression of ARPP21 correlate with higher intelligence scores (Savage et al. 2018). I hypothesized that reducing miR-128 during the critical period for vocal plasticity would enhance vocal learning. To test this, I adapted a miR-128 siRNA sponge for use in songbird Area X from a previously published rodent version developed by Bredy and colleagues (Lin et al. 2011). I injected a viral construct bearing either the siRNA sponge or a control sponge with a scrambled sequence bilaterally into Area X at post-hatch day 30 (30d) using sibling-matched controls, then returned birds to their home cage. After collecting recordings at 45d, 60d, and 75d post-hatch I collected tissue and performed song analysis. Strikingly, miR-128 inhibition in Area X was sufficient to recapitulate the therapeutic rescue of abnormal sequence stereotypy. In human ASD patients, differential gene expression in microglia is correlated to clinical symptom severity (Velmeshev et al. 2019). My results suggest that inhibiting miR-128 could normalize microglia reactivity in autism patients to improve clinical symptom severity. To my knowledge, this study is the first to directly link miR-128 to learned vocal communication and among the first to identify miR-128 as a potential therapeutic target for ASD.

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