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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    245—Speech, Language, and Signaling in Autism

    Sunday, November 10, 2013, 1:00 pm - 5:00 pm

    245.17: Enhancement of α2,3-GABAA receptor signaling rescues autistic-like behaviors in a mouse model of autism

    Location: Halls B-H

    *S. HAN, C. TAI, C. J. JONES, T. SCHEUER, W. A. CATTERALL;
    Pharmacol., Univ. of Washington, Seattle, WA

    Abstract Body: Autism spectrum disorder (ASD) may arise from increased ratio of excitatory to inhibitory neurotransmission in the brain. Many pharmacological treatments have been tested in ASD, but only limited success has been achieved. Here we report that BTBR T+tf/J (BTBR) mice, a well-established model of idiopathic autism, have reduced spontaneous GABAergic neurotransmission. Treatment with non-sedating/non-anxiolytic doses of benzodiazepines, which increase inhibitory neurotransmission through positive allosteric modulation of postsynaptic GABAA receptors, completely rescued autistic-like behaviors. Moreover, negative allosteric modulation of GABAA receptors induced autistic-like behaviors in otherwise normal C57BL/6J mice, suggesting a causal role for impaired inhibitory neurotransmission in autistic-like behaviors. The dramatic behavioral improvement after low-dose benzodiazepine treatment was subunit-specific; the α2,3-subunit-selective positive allosteric modulator L-838,417 was effective, but the α1-subunit-selective drug zolpidem exacerbated the social deficits. We propose that impaired GABAergic neurotransmission may contribute to ASD and that α2,3-subunit-selective positive GABAA receptor modulation may be an effective treatment.

    Lay Language Summary: The cause of autism is unknown, but a strong genetic component has been revealed by studies of twins and families with a high frequency of autism. In studies of mice with inherited autistic-like behaviors, we have found that inhibitory neurotransmission is impaired and drugs that enhance inhibitory neurotransmission are effective in treating the core symptoms of autism.
    Nerve cells (neurons) in the brain are either excitatory or inhibitory. Chemical neurotransmitters released from excitatory neurons excite other neurons to which they are connected by nerve fibers and synapses. On the other hand, inhibitory neurons release the neurotransmitter GABA, which inhibits the electrical signaling activity of neurons onto which it is released. The correct balance of excitatory and inhibitory neurotransmission is crucial for all brain circuits. One can think of inhibitory neurons as the traffic cops of electrical signaling in brain circuits. Without the normal electrical signaling of inhibitory neurons to cause release of GABA from their synapses, brain circuits would be jammed like New York City traffic at rush hour without stoplights!
    Recent studies of mice with single gene mutations that cause autistic-like behaviors show that the delicate balance of electrical signaling is tipped in favor of excitatory neurotransmission. This imbalance leads to repetitive behaviors, intense but narrow interests, and social interaction deficits that are characteristic of these animal models of autism.
    Human autism is polygenic rather than monogenic, and many genes are known to be associated with the disease. BTBR T+tf/J (BTBR) mice are a well-established model of polygenic autism. These mice have social interaction deficits, increased repetitive behaviors, and impaired learning and memory of the place in which important events occur. The research that we will report at the Annual Meeting of the Society for Neuroscience shows that these mice have a deficit of inhibitory neurotransmission mediated by GABA. Moreover, inhibition of GABA-A receptors induced autistic-like behaviors in behaviorally normal C57BL/6J mice. These two sets of results suggest a causal role for impaired inhibitory neurotransmission in autistic-like behaviors in BTBR mice.
    Treatment of BTBR mice with low doses of benzodiazepine drugs, which increase inhibitory neurotransmission mediated by GABA by enhancing the responsiveness of GABA-A receptors, completely rescued the autistic-like symptoms, including repetitive behaviors, social interaction, and spatial learning and memory. Beneficial effects required careful optimization of drug dose.
    GABA-A receptors are complexes of five subunits (typically two α subunits, two β subunits, and one γ subunit) and each of these types of subunits have multiple similar forms encoded by different genes. We found the dramatic behavioral improvement after low-dose benzodiazepine treatment was subunit-specific_the α2, α3-subunit-selective GABA enhancer L-838,417 was effective, but the α1-subunit-selective drug zolpidem (Ambien) exacerbated the social interaction deficits. We propose that impaired GABAergic neurotransmission may contribute to core autistic-like symptoms in mice and that α2,3-subunit-selective enhancement of GABA effects on GABA-A receptors may be an effective treatment.
    These basic research studies connect gene defects in mice, disease mechanisms, and new therapeutic approaches for autism. New therapeutic strategies using existing drugs derived from this work could potentially have a positive impact on patient care in the near future.