Hypothesis-driven investigations of diverse pharmacological targets in two mouse models of autism

Maya A. Rhine, Jennifer M. Parrott, Maria N. Schultz, Tatiana M. Kazdoba, Jacqueline Crawley

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Autism spectrum disorder is a neurodevelopmental syndrome diagnosed primarily by persistent deficits in social interactions and communication, unusual sensory reactivity, motor stereotypies, repetitive behaviors, and restricted interests. No FDA-approved medical treatments exist for the diagnostic symptoms of autism. Here we interrogate multiple pharmacological targets in two distinct mouse models that incorporate well-replicated autism-relevant behavioral phenotypes. Compounds that modify inhibitory or excitatory neurotransmission were selected to address hypotheses based on previously published biological abnormalities in each model. Shank3B is a genetic model of a mutation found in autism and Phelan-McDermid syndrome, in which deficits in excitatory neurotransmission and synaptic plasticity have been reported. BTBR is an inbred strain model of forms of idiopathic autism in which reduced inhibitory neurotransmission and excessive mTOR signaling have been reported. The GABA-A receptor agonist gaboxadol significantly reduced repetitive self-grooming in three independent cohorts of BTBR. The TrkB receptor agonist 7,8-DHF improved spatial learning in Shank3B mice, and reversed aspects of social deficits in BTBR. CX546, a positive allosteric modulator of the glutamatergic AMPA receptor, and d-cycloserine, a partial agonist of the glycine site on the glutamatergic NMDA receptor, did not rescue aberrant behaviors in Shank3B mice. The mTOR inhibitor rapamycin did not ameliorate social deficits or repetitive behavior in BTBR mice. Comparison of positive and negative pharmacological outcomes, on multiple phenotypes, evaluated for replicability across independent cohorts, enhances the translational value of mouse models of autism for therapeutic discovery. GABA agonists present opportunities for personalized interventions to treat components of autism spectrum disorder. Autism Res 2019.

Original languageEnglish (US)
JournalAutism Research
DOIs
StateAccepted/In press - Jan 1 2019

Keywords

  • Autism
  • cognitive
  • GABA
  • medicine
  • mice
  • preclinical
  • repetitive
  • social
  • Trkb

ASJC Scopus subject areas

  • Neuroscience(all)
  • Clinical Neurology
  • Genetics(clinical)

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