Cerebral Cortex Advance Access published online on July 5, 2007
Cerebral Cortex, doi:10.1093/cercor/bhm100
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Intracortical Hyperexcitability in Humans with a GABAA Receptor Mutation
1 Department of Medicine, The University of Melbourne, Heidelberg, Victoria, Australia, 2 Department of Neurology, Austin Health Heidelberg, Victoria, Australia, 3 Neurogenetics Laboratory, Istituto di Neuropsichiatria Infantile, IRCSS Fondazione Stella Maris, Pisa, Italy, 4 Southern Clinical School, Monash University, Clayton, Victoria, Australia
Address correspondence to David C. Reutens, MD, FRACP, Department of Medicine, Level 5 Block E, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria 3168, Australia. Email: David.Reutens{at}med.monash.edu.au.
A missense mutation of the 
2 subunit of the -aminobutyric acid A (GABAA) receptor has been linked to an inherited human generalized epilepsy. As synaptic inhibition in the human brain is largely mediated by the GABAA receptor, we tested the hypothesis that the GABRG2(R43Q) mutation alters cortical excitability. Fourteen subjects affected by the GABRG2(R43Q) mutation (5 males, mean age: 44 ± 15 years) and 24 controls (11 males, mean age: 38 ± 11 years) were studied with transcranial magnetic stimulation (TMS). To assess the specificity of the effect of the mutation, 4 additional family members unaffected by the GABRG2(R43Q) mutation (2 males, mean age: 41 ± 16 years) were included. Subjects affected by the GABRG2(R43Q) mutation demonstrated reduced net short-interval intracortical inhibition and increased intracortical facilitation assessed with paired-pulse stimulation. Subjects with the mutation had similar motor thresholds to controls both at rest and with weak voluntary activation. No significant differences were noted between groups in the cortical silent period. Our findings provide in vivo evidence for increased intracortical excitability in subjects affected by the GABRG2(R43Q) mutation. These findings are also likely to represent an important clue to the mechanisms linking this gene defect and the epilepsy phenotype.
Key Words: cortical excitability • epilepsy • GABAA receptor and GABRG2(R43Q) • transcranial magnetic stimulation
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