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

Carmen Martinez-Cué (1) , B. Delatour (2) , M. C. Potier (3)

1 Department of Physiology and Pharmacology, Faculty of Medicine
2 ICM - Institut du Cerveau = Paris Brain Institute
3 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute

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.

Domaines: Sciences du Vivant [q-bio]

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⟩