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

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, 12: 401–421 © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. Lay Summary Many of the risk genes for autism impair synapses, the connections between nerve cells in the brain. A drug that reverses the synaptic effects of a mutation could offer a precision therapy. Combining pharmacological and behavioral therapies could reduce symptoms and improve the quality of life for people with autism. Here we report reductions in repetitive behavior by a GABA‐A receptor agonist, gaboxadol, and improvements in social and cognitive behaviors by a TrkB receptor agonist, in mouse models of autism.

Evaluation of a TrkB agonist on spatial and motor learning in the Ube3a mouse model of Angelman syndrome

“…Beginning a neurotrophic drug intervention early in life, during a critical period of brain development, may be essential for neurodevelopmental disorders such as Angelman syndrome (Sonzogni et al 2019). Although TrkB agonists have been shown to improve components of social and motor behaviors in adult mice (Simmons et al 2013;Kang et al 2017;Li et al 2017;Nasrallah et al 2019;Rhine et al 2019), brain disorders with structural neuroanatomical abnormalities established during early development, such as reductions in myelination which have been reported for Angelman syndrome (Harting et al 2009;Peters et al 2011;Tiwari et al 2012;Grier et al 2015), may require that neurotrophic interventions begin at a very young age (Silva-Santos et al 2015;Sonzogni et al 2019).…”

“…Each subject mouse was weighed on the morning of each drug treatment, for calculations of dose by body weight. The 7,8-DHF dose was chosen from previous publications on behavioral actions of 7,8-DHF in mice, in which no adverse health effects were reported (Devi and Ohno 2012;Castello et al 2014;Ren et al 2014;Stagni et al 2017;Rhine et al 2019). For all assays, surfaces of the testing chamber were cleaned with 70% ethanol after each subject mouse was tested, with sufficient time for the ethanol odor to dissipate before the start of the next test session.…”

“…BDNF exerts its synaptic actions on promoting LTP through the TrkB receptor (Reichardt 2006;Kron et al 2014;Lin et al 2018). TrkB agonists, including 7,8-dihydroxyflavone (7,8-DHF) and LM22A-4, were reported to improve phenotypes in mouse models of neurodegenerative and neurodevelopmental disorders, including Alzheimer's, autism spectrum disorder, Fragile X, Huntington's, and Rett syndromes (Johnson et al 1985;Devi and Ohno 2012;Jiang et al 2013;Simmons et al 2013;Castello et al 2014;Tian et al 2015;Aytan et al 2018;García-Díaz Barriga et al 2017;Li et al 2017;Nguyen et al 2019;Rhine et al 2019). Importantly, BDNF and TrkB signaling were reported to be defective in Ube3a mice (Cao et al 2013), and treatment with an ampakine which enhances BDNF effectively reversed deficits in LTP and in contextual and cued fear conditioning in 9-to 12-wk-old Ube3a mice (Baudry et al 2012).…”

Changes in the Fluorescence Tracking of NaV1.6 Protein Expression in a BTBR T+Itpr3tf/J Autistic Mouse Model

“…In molecular terms, these mice exhibit deficits in neurotransmission, synaptic plasticity, and neuronal wiring. Behaviorally, they display core features of autistic-like behavior such as compulsive stereotyped repetitive behavior and reduced sociability [4]. In addition to the pharmacologically induced VPA model and the Shank3B genetic model, the BTBR inbred mouse strain is another valid model of ASD that has been used to represent idiopathic autism.…”

Sociability development in mice with cell‐specific deletion of the NMDA receptor NR1 subunit gene

“…[68][69][70][71][72][73] We observed the effects of ablation of NR1 in either excitatory forebrain cells or in a subset of inhibitory cells on behavior in the three-chambered Social Approach Test (SAT), a well-established assay with good reliability and validity in mice, which are highly social animals. [74][75][76][77][78][79][80] 2 | MATERIALS AND METHODS…”