Treating enhanced GABAergic inhibition in Down syndrome: Use of GABA α5-selective inverse agonists

NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS

卷:46

Review

Martinez-Cue, Carmen¹  Delatour, Benoit²  Potier, Marie-Claude² 

[1] Univ Cantabria, Fac Med, Dept Physiol & Pharmacol, E-39005 Santander, Spain

[2] UPMC, Hop Pitie Salpetriere, Inst Cerveau & Moelle Epiniere, CNRS UMR7225,INSERM U1127,IHUA ICM, F-75013 Paris, France

关键词: Down syndrome;    gamma-Aminobutyric acid;    Inverse agonist;    alpha 5-Subunit containing GABA(A) receptor;    Convulsion;    Behavior;   

DOI  :  10.1016/j.neubiorev.2013.12.008

来源: Elsevier

【 摘 要 】

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. gamma-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mature central nervous system and binds to GABA(A) 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 alpha 5-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. (C) 2014 Elsevier Ltd. All rights reserved.

【 授权许可】

Free