R-Baclofen, a Gabab Agonist, Reduced Stereotyped and Repetitive Behavior in the BTBR and C58 Mouse Models of Autism

Background: A fundamental hypothesis in the search for causes of autism spectrum disorder (ASD) focuses on dysregulation of the excitatory/inhibitory balance in the brain.  Reducing excitatory glutamatergic transmission, and/or elevating GABAergic inhibition, could normalize the excitatory/inhibitory balance.  This theory is supported by electrophysiological studies in mouse models with mutations in risk genes for autism, in which excessive glutamatergic excitation or impairments in synaptic plasticity are common.  Furthermore, clinical trials of positive and negative modulators of glutamatergic and GABAergic receptors are being pursued.

Objectives: The specific objective of this proposal is to test the hypothesis that enhanced inhibitory transmission, via the GABA_B agonist R⁺-baclofen, will reduce high levels of repetitive behavior in two mouse models of non-syndromic autism.  BTBR displays multiple behavioral phenotypes with face validity to both of the diagnostic symptoms of autism, including well-replicated low sociability, low levels of vocalizations in social settings, and high levels of repetitive self-grooming.  R⁺-baclofen was similarly tested in C58/J mice (C58), which display high levels of stereotyped jumping and repetitive grooming.  The control strain, C57BL/6J (B6), displays high sociability and no detectable stereotyped or repetitive behaviors.

Methods: BTBR, C58 and B6 were given an intraperitoneal injection of R⁺-baclofen (1.0 mg/kg, or 3.0 mg/kg) or saline, 30 or 60 minutes before behavioral testing.  BTBR, C58 and B6 were tested in three behavioral tasks: 1) marble burying in an empty mouse cage (Thomas et al., 2012), 2) self-grooming in a clean standard mouse cage for a 10 minute test session (Silverman et al., 2012) and 3) open field locomotor activity, as a control measure to detect confounding drug-induced behavioral sedation.  

Results: R⁺-baclofen reduced repetitive self-grooming and marble burying in two cohorts of BTBR mice.  R⁺-baclofen also reduced stereotyped jumping in C58 mice.  Effective doses of R⁺-baclofen on repetitive or stereotyped behavior in BTBR or C58 mice did not produce signs of sedation, as measured in the open field locomotor exploration test, 1 hour post drug administration.

Conclusions: Two mouse models of non-syndromic ASD provide corroborative preclinical evidence that a GABA_B agonist may be effective for decreasing stereotyped and repetitive and behaviors in autism spectrum disorder.