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Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia
Author(s) -
Talos Delia M.,
Sun Hongyu,
Kosaras Bela,
Joseph Annelise,
Folkerth Rebecca D.,
Poduri Annapurna,
Madsen Joseph R.,
Black Peter M.,
Jensen Frances E.
Publication year - 2012
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.22696
Subject(s) - cortical dysplasia , excitatory postsynaptic potential , glutamatergic , tuberous sclerosis , epilepsy , immunocytochemistry , neuroscience , bumetanide , patch clamp , inhibitory postsynaptic potential , gabaa receptor , chemistry , neurotransmission , endocrinology , medicine , electrophysiology , biology , receptor , pathology , glutamate receptor , ion transporter , biochemistry , membrane
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. Interpretation: 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. ANN NEUROL 2012