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Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia

Authors

  • Delia M. Talos MD,

    Corresponding author
    1. Department of Neurology, Children's Hospital Boston
    2. Harvard Medical School, Boston, Children's Hospital Boston, Boston
    Current affiliation:
    1. NYU Comprehensive Epilepsy Center, Department of Neurology, 223 East 34th Street, New York, NY 10016
    • Children's Hospital, CLS 14073, Department of Neurology, 300 Longwood Avenue, Boston, MA 02115
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  • Hongyu Sun MD, PhD,

    1. Department of Neurology, Children's Hospital Boston
    2. Harvard Medical School, Boston, Children's Hospital Boston, Boston
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  • Bela Kosaras MD,

    1. Department of Neurology, Children's Hospital Boston
    2. Harvard Medical School, Boston, Children's Hospital Boston, Boston
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  • Annelise Joseph BS,

    1. Department of Neurology, Children's Hospital Boston
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  • Rebecca D. Folkerth MD,

    1. Harvard Medical School, Boston, Children's Hospital Boston, Boston
    2. Department of Pathology (Neuropathology), Children's Hospital Boston
    3. Department of Pathology, Brigham and Women's Hospital Boston
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  • Annapurna Poduri MD,

    1. Department of Neurology, Children's Hospital Boston
    2. Harvard Medical School, Boston, Children's Hospital Boston, Boston
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  • Joseph R. Madsen MD,

    1. Harvard Medical School, Boston, Children's Hospital Boston, Boston
    2. Department of Neurosurgery, Children's Hospital Boston
    3. Department of Neurosurgery, Brigham and Women's Hospital Boston
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  • Peter M. Black MD, PhD,

    1. Harvard Medical School, Boston, Children's Hospital Boston, Boston
    2. Department of Neurosurgery, Children's Hospital Boston
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  • Frances E. Jensen MD

    1. Department of Neurology, Children's Hospital Boston
    2. Harvard Medical School, Boston, Children's Hospital Boston, Boston
    3. Program in Neuroscience, Harvard Medical School, Boston, MA
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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 (GABAAR)-mediated inhibition.

Methods:

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.

Results:

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.

Interpretation:

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

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