Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia
Version of Record online: 23 MAR 2012
Copyright © 2012 American Neurological Association
Annals of Neurology
Volume 71, Issue 4, pages 539–551, April 2012
How to Cite
Talos, D. M., Sun, H., Kosaras, B., Joseph, A., Folkerth, R. D., Poduri, A., Madsen, J. R., Black, P. M. and Jensen, F. E. (2012), Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Ann Neurol., 71: 539–551. doi: 10.1002/ana.22696
- Issue online: 20 APR 2012
- Version of Record online: 23 MAR 2012
- Accepted manuscript online: 16 DEC 2011 06:56AM EST
- Manuscript Accepted: 9 DEC 2011
- Manuscript Revised: 17 NOV 2011
- Manuscript Received: 22 JUL 2011
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 (GABAAR)-mediated inhibition.
Expression of the GABAAR 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. GABAAR 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.
TSC and FCD type IIb lesions demonstrated decreased expression of GABAAR 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 GABAAR responses that were significantly attenuated by the NKCC1 inhibitor bumetanide, in contrast to hyperpolarizing GABAAR-mediated currents in normal neurons from non-TSC cortical slices.
Expression and function of GABAARs 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. ANN NEUROL 2012