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: Carmen Martínez-Cué, Benoît Delatour, Marie-Claude Potier
• Journal: Neuroscience and biobehavioral reviews (Neurosci Biobehav Rev) Vol. 46 Pt 2 Pg. 218-27 (Oct 2014) ISSN: 1873-7528 [Electronic] United States
• PMID: 24412222 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• 3-bromo-10-difluoromethyl-9H-imidazo(1,5-a)(1,2,4)triazolo(1,5-d)(1,4)benzodiazepine
• GABA-A Receptor Antagonists
• Imidazoles
• Nootropic Agents
• PWZ-029
• Receptors, GABA-A
• Benzodiazepines
• Pentylenetetrazole

Topics

• Animals
• Benzodiazepines (adverse effects, pharmacology, therapeutic use)
• Down Syndrome (drug therapy)
• Drug Inverse Agonism
• GABA-A Receptor Antagonists (adverse effects, pharmacology, therapeutic use)
• Humans
• Imidazoles (adverse effects, pharmacology, therapeutic use)
• Neural Inhibition (drug effects)
• Nootropic Agents (adverse effects, pharmacology, therapeutic use)
• Pentylenetetrazole (adverse effects, pharmacology, therapeutic use)
• Receptors, GABA-A (metabolism)