title: 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.
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, University of Cantabria, Santander, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Martínez-Cué
authors.affiliation: Institut du Cerveau et de Moelle Epinière, CNRS UMR7225, INSERM U1127, UPMC, IHUA-ICM, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Delatour
authors.affiliation: Institut du Cerveau et de Moelle Epinière, CNRS UMR7225, INSERM U1127, UPMC, IHUA-ICM, Hôpital Pitié-Salpêtrière, Paris, France. Electronic address: marie-claude.potier@upmc.fr.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Potier
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D004314:Down Syndrome / Q000188:drug therapy*; D054314:Drug Inverse Agonism; D058787:GABA-A Receptor Antagonists / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D009433:Neural Inhibition / Q000187:drug effects*; D018697:Nootropic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D010433:Pentylenetetrazole / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D011963:Receptors, GABA-A / Q000378:metabolism*
chemical_list: C542509:3-bromo-10-difluoromethyl-9H-imidazo(1,5-a)(1,2,4)triazolo(1,5-d)(1,4)benzodiazepine; D058787:GABA-A Receptor Antagonists; D007093:Imidazoles; D018697:Nootropic Agents; C531941:PWZ-029; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D010433:Pentylenetetrazole
keywords: Behavior; Convulsion; Down syndrome; Inverse agonist; α5-Subunit containing GABA(A) receptor; γ-Aminobutyric acid