Probing epilepsy’s molecular sparksMay. 10, 2012, 2:05 PM
Mutations in GABA-A receptors – a family of receptors that normally inhibit neuronal activity – are associated with some inherited forms of epilepsy. To explore how mutations contribute to epilepsy development, graduate student Mengnan Tian and Robert Macdonald, professor of neurology, characterized the functional consequences of a particular GABA-A receptor mutation.
The mutation – in the gamma-2 subunit of the GABA-A receptor – was identified in an Australian family with childhood absence epilepsy and febrile seizures. The researchers expressed normal or mutated gamma-2 subunits in cultured cells and transgenic mice. They report in the April 25 Journal of Neuroscience that the mutation altered how the gamma subunit was spliced, resulting in a mutant mRNA that was either degraded or translated into a stable, but shortened, form of the protein.
The study suggests that the mutation reduces surface GABA-A receptor levels, which would reduce the receptor’s ability to “quiet” excited neuronal chatter and make the brain more susceptible to epilepsy. The findings could offer new directions for targeted epilepsy therapies.
This research was supported by a National Institutes of Health grant from the National Institute of Neurological Disorders and Stroke and by a fellowship from the Epilepsy Foundation.