Cerebral Cortex Advance Access published online on September 11, 2008
Cerebral Cortex, doi:10.1093/cercor/bhn159
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Downregulation of Tonic GABAergic Inhibition in a Mouse Model of Fragile X Syndrome
1 Montreal Neurological Institute and Department of Neurology and Neurosurgery, McGill University, Montreal, Canada H3A 2B4, 2 Department of Biology, Ecole Normale Superieure, 75005, Paris, France, 3 Department of Experimental Medicine, Sapienza Università di Roma, 00100, Rome, Italy
Address correspondence to Massimo Avoli, MD, PhD, 3801 University Street, Room 794, Montreal, Quebec H3A 2B4, Canada. Email: massimo.avoli{at}mcgill.ca.
The absence of fragile X mental retardation protein results in the fragile X syndrome (FXS), a common form of mental retardation associated with attention deficit, autistic behavior, and epileptic seizures. The phenotype of FXS is reproduced in fragile X mental retardation 1 (fmr1) knockout (KO) mice that have region-specific altered expression of some 
-aminobutyric acid (GABAA) receptor subunits. However, little is known about the characteristics of GABAergic inhibition in the subiculum of these animals. We employed patch-clamp recordings from subicular pyramidal cells in an in vitro slice preparation. In addition, semiquantitative polymerase chain reaction and western blot experiments were performed on subiculum obtained from wild-type (WT) and KO mice. We found that tonic GABAA currents were downregulated in fmr1 KO compared with WT neurons, whereas no significant differences were observed in phasic GABAA currents. Molecular biology analysis revealed that the tonic GABAA receptor subunits 
5 and 
were underexpressed in the fmr1 KO mouse subiculum compared with WT. Because the subiculum plays a role in both cognitive functions and epileptic disorders, we propose that altered tonic inhibition in this structure contributes to the behavioral deficits and epileptic activity seen in FXS patients. This conclusion is in line with evidence implicating tonic GABAA inhibition in learning and memory.
Key Words: fragile X • GABA • patch-clamp • subiculum • tonic inhibition
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