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Treating enhanced GABAergic inhibition in Down syndrome: use of GABA alpha5-selective inverse agonists

Abstract : Excess inhibition in the brain of individuals carrying an extra copy of chromosome 21 could be responsible for cognitive deficits observed throughout their lives. A change in the excitatory/inhibitory balance in adulthood would alter synaptic plasticity, potentially triggering learning and memory deficits. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system and binds to GABAA receptors, opens a chloride channel, and reduces neuronal excitability. In this review we discuss methods to alleviate neuronal inhibition in a mouse model of Down syndrome, the Ts65Dn mouse, using either an antagonist (pentylenetetrazol) or two different inverse agonists selective for the α5-subunit containing receptor. Both inverse agonists, which reduce inhibitory GABAergic transmission, could rescue learning and memory deficits in Ts65Dn mice. We also discuss safety issues since modulation of the excitatory-inhibitory balance to improve cognition without inducing seizures remains particularly difficult when using GABA antagonists.
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https://hal-cnrs.archives-ouvertes.fr/hal-03236876
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Submitted on : Wednesday, May 26, 2021 - 3:00:18 PM
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Carmen Martinez-Cué, B. Delatour, M. C. Potier. Treating enhanced GABAergic inhibition in Down syndrome: use of GABA alpha5-selective inverse agonists. Neurosci Biobehav Rev, 2014, 46 Pt 2, pp.218-27. ⟨10.1016/j.neubiorev.2013.12.008⟩. ⟨hal-03236876⟩

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