Objective: The most common neurological symptom of tuberous sclerosis complex (TSC) and focal cortical dysplasia (FCD) is early life refractory epilepsy. As previous studies have shown enhanced excitatory glutamatergic neurotransmission in TSC and FCD brains, we hypothesized that neurons associated with these lesions may also express altered γ-aminobutyric acid (GABA) A receptor (GABA AR)-mediated inhibition. Methods: Expression of the GABA AR subunits α1 and α4, and the Na +-K +-2Cl - (NKCC1) and the K +-Cl - (KCC2) transporters, in human TSC and FCD type II specimens were analyzed by Western blot and double label immunocytochemistry. GABA AR responses in dysplastic neurons from a single case of TSC were measured by perforated patch recording and compared to normal-appearing cortical neurons from a non-TSC epilepsy case. Results: TSC and FCD type IIb lesions demonstrated decreased expression of GABA AR α1, and increased NKCC1 and decreased KCC2 levels. In contrast, FCD type IIa lesions showed decreased α4, and increased expression of both NKCC1 and KCC2 transporters. Patch clamp recordings from dysplastic neurons in acute slices from TSC tubers demonstrated excitatory GABA AR responses that were significantly attenuated by the NKCC1 inhibitor bumetanide, in contrast to hyperpolarizing GABA AR-mediated currents in normal neurons from non-TSC cortical slices. Interpretation: Expression and function of GABA ARs in TSC and FCD type IIb suggest the relative benzodiazepine insensitivity and more excitatory action of GABA compared to FCD type IIa. These factors may contribute to resistance of seizure activity to anticonvulsants that increase GABAergic function, and may justify add-on trials of the NKCC1 inhibitor bumetanide for the treatment of TSC and FCD type IIb-related epilepsy. Copyright

Annals of Neurology
Department of Neuroscience

Talos, D.M. (Delia M.), Sun, H, Kosaras, B. (Bela), Joseph, A. (Annelise), Folkerth, R.D. (Rebecca D.), Poduri, A. (Annapurna), … Jensen, F.E. (Frances E.). (2012). Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Annals of Neurology, 71(4), 539–551. doi:10.1002/ana.22696