title: Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia.
abstract: 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(A)R)-mediated inhibition.
  
  
  METHODS
  Expression of the GABA(A)R 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(A) R 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(A)R 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(A)R responses that were significantly attenuated by the NKCC1 inhibitor bumetanide, in contrast to hyperpolarizing GABA(A)R-mediated currents in normal neurons from non-TSC cortical slices.
  
  
  CONCLUSIONS
  Expression and function of GABA(A)Rs 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.
authors.affiliation: Department of Neurology, Children's Hospital Boston, MA, USA. delia.talos@nyumc.org
authors.forename: Delia M
authors.initials: DM
authors.lastname: Talos
authors.forename: Hongyu
authors.initials: H
authors.lastname: Sun
authors.forename: Bela
authors.initials: B
authors.lastname: Kosaras
authors.forename: Annelise
authors.initials: A
authors.lastname: Joseph
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Folkerth
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Madsen
authors.forename: Peter M
authors.initials: PM
authors.lastname: Black
authors.forename: Frances E
authors.initials: FE
authors.lastname: Jensen
mesh_terms: D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001927:Brain Diseases / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D054220:Malformations of Cortical Development / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D065703:Malformations of Cortical Development, Group I; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D018079:Receptors, GABA / Q000096:biosynthesis; D028021:Sodium-Potassium-Chloride Symporters / Q000096:biosynthesis; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters / Q000096:biosynthesis; D014402:Tuberous Sclerosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D055815:Young Adult; D000096922:K Cl- Cotransporters
chemical_list: D018079:Receptors, GABA; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D000096922:K Cl- Cotransporters; C578877:SLC12A2 protein, human