Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia

Department of Neurology, Children's Hospital Boston, MA, USA.
Annals of Neurology (Impact Factor: 9.98). 04/2012; 71(4):539-51. DOI: 10.1002/ana.22696
Source: PubMed


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.
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.
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.
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.

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    • "In this paper we will review the patterns of subunit composition of the main glutamate [í µí»¼-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-Daspartate (NMDA)] and gamma-aminobutyric acid (GABA) receptors during development [7–13]. We will also review the subunit composition of neurotransmitter receptors that mirrors that of the immature brain, facilitating further seizures and the development of pathologic neuronal networks [14] [15] [16] [17] [18] [19] [20] [21]. Finally, we will discuss the novel therapeutic targets that are being revealed by studying the subunit composition of the neurotransmitter receptors and potential therapeutic translation into clinical practice [3] [4] [5] [6] "
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    • "Immunocytochemical and western blots experiments have demonstrated that this disorder is associated with a decrease of α1 GABAA receptor subunits and reduced and enhanced levels of KCC2 and NKCC1, respectively, in tubers. Changes in the expression of KCC2 and NKCC1 account for the excitatory action of GABA revealed with patch clamp in slices from Tuberous sclerosis tubers (96). However, electrophysiological data are still preliminary and should be taken with caution since they refer only to experiments from cortical slices obtained from tubers of a single patient. "
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    • "Many reports indicate that seizures may alter GABA A R signaling in immature and mature periods. Following the report of depolarizing GABA A R responses in human epileptic subiculum (Cohen et al., 2002), multiple studies confirmed or extended these findings that suggest abnormal CCC expression and depolarizing GABA A R in human epileptic tissues (Aronica et al., 2007; Cepeda et al., 2007; Conti et al., 2011; Huberfeld et al., 2007; Jansen et al., 2010; Munakata et al., 2007; Munoz et al., 2007; Palma et al., 2006; Talos et al., 2012a). Several animal studies also indicated that seizures or the epileptic state in adult rodents may lead to re-appearance of depolarizing GABA A R due to either increase in NKCC1 or decrease in KCC2 activity (Benini and Avoli, 2006; Okabe et al., 2002,c 2003; Pathak et al., 2007; Rivera et al., 2002). "
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