Reducing GABAA α5 receptor-mediated inhibition rescues functional and neuromorphological deficits in a mouse model of down syndrome.

Abstract

Down syndrome (DS) is associated with neurological complications, including cognitive deficits that lead to impairment in intellectual functioning. Increased GABA-mediated inhibition has been proposed as a mechanism underlying deficient cognition in the Ts65Dn (TS) mouse model of DS. We show that chronic treatment of these mice with RO4938581 (3-bromo-10-(difluoromethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]diazepine), a selective GABA(A) α5 negative allosteric modulator (NAM), rescued their deficits in spatial learning and memory, hippocampal synaptic plasticity, and adult neurogenesis. We also show that RO4938581 normalized the high density of GABAergic synapse markers in the molecular layer of the hippocampus of TS mice. In addition, RO4938581 treatment suppressed the hyperactivity observed in TS mice without inducing anxiety or altering their motor abilities. These data demonstrate that reducing GABAergic inhibition with RO4938581 can reverse functional and neuromorphological deficits of TS mice by facilitating brain plasticity and support the potential therapeutic use of selective GABA(A) α5 NAMs to treat cognitive dysfunction in DS.

• Authors: Carmen Martínez-Cué, Paula Martínez, Noemí Rueda, Rebeca Vidal, Susana García, Verónica Vidal, Andrea Corrales, Juan A Montero, Ángel Pazos, Jesús Flórez, Rodolfo Gasser, Andrew W Thomas, Michael Honer, Frédéric Knoflach, Jose Luis Trejo, Joseph G Wettstein, Maria-Clemencia Hernández
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 33 Issue 9 Pg. 3953-66 (Feb 27 2013) ISSN: 1529-2401 [Electronic] United States
• PMID: 23447605 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 3-bromo-10-difluoromethyl-9H-imidazo(1,5-a)(1,2,4)triazolo(1,5-d)(1,4)benzodiazepine
• Carrier Proteins
• GABA Modulators
• Gabra5 protein, mouse
• Imidazoles
• Ki-67 Antigen
• Membrane Proteins
• Receptors, GABA-A
• Vesicular Inhibitory Amino Acid Transport Proteins
• gephyrin
• vesicular GABA transporter
• Tritium
• Benzodiazepines
• Glutamate Decarboxylase
• glutamate decarboxylase 1
• glutamate decarboxylase 2

Topics

• Acoustic Stimulation
• Analysis of Variance
• Animals
• Benzodiazepines (pharmacology, therapeutic use)
• Biophysics
• Carrier Proteins (metabolism)
• Cell Count
• Cell Proliferation (drug effects)
• Cues
• Disease Models, Animal
• Down Syndrome (complications, drug therapy, pathology)
• Electric Stimulation
• Excitatory Postsynaptic Potentials (drug effects, genetics)
• Exploratory Behavior (drug effects)
• GABA Modulators (pharmacology, therapeutic use)
• Glutamate Decarboxylase (metabolism)
• Hippocampus (drug effects, pathology)
• Hyperkinesis (drug therapy, etiology)
• Imidazoles (pharmacology, therapeutic use)
• Ki-67 Antigen
• Learning Disabilities (drug therapy, etiology)
• Long-Term Potentiation (drug effects, genetics)
• Male
• Maze Learning (drug effects)
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurogenesis (drug effects, genetics)
• Neurons (drug effects, physiology)
• Protein Binding (drug effects, genetics)
• Psychomotor Performance (drug effects)
• Reaction Time (drug effects)
• Receptors, GABA-A (metabolism)
• Reflex (drug effects, genetics)
• Reflex, Startle (drug effects)
• Rotarod Performance Test
• Seizures (etiology)
• Sensory Gating (drug effects)
• Tritium (pharmacokinetics)
• Vesicular Inhibitory Amino Acid Transport Proteins (metabolism)