Treating enhanced GABAergic inhibition in Down syndrome: use of GABA α5-selective inverse agonists
- PMID:24412222
- DOI: 10.1016/j.neubiorev.2013.12.008
Treating enhanced GABAergic inhibition in Down syndrome: use of GABA α5-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.
Keywords: Behavior; Convulsion; Down syndrome; Inverse agonist; α5-Subunit containing GABA(A) receptor; γ-Aminobutyric acid.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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