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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Available from: Joseph R Madsen, Oct 10, 2015
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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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    ABSTRACT: Neuronal activity is critical for synaptogenesis and the development of neuronal networks. In the immature brain excitation predominates over inhibition facilitating the development of normal brain circuits, but also rendering it more susceptible to seizures. In this paper, we review the evolution of the subunit composition of neurotransmitter receptors during development, how it promotes excitation in the immature brain, and how this subunit composition of neurotransmission receptors may be also present in the epileptic brain. During normal brain development, excitatory glutamate receptors peak in function and gamma-aminobutiric acid (GABA) receptors are mainly excitatory rather than inhibitory. A growing body of evidence from animal models of epilepsy and status epilepticus has demonstrated that the brain exposed to repeated seizures presents a subunit composition of neurotransmitter receptors that mirrors that of the immature brain and promotes further seizures and epileptogenesis. Studies performed in samples from the epileptic human brain have also found a subunit composition pattern of neurotransmitter receptors similar to the one found in the immature brain. These findings provide a solid rationale for tailoring antiepileptic treatments to the specific subunit composition of neurotransmitter receptors and they provide potential targets for the development of antiepileptogenic treatments.
    BioMed Research International 09/2014; 2014:301950. DOI:10.1155/2014/301950 · 2.71 Impact Factor
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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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    ABSTRACT: γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter in the adult brain, early in postnatal life exerts a depolarizing and excitatory action. This depends on accumulation of chloride inside the cell via the cation-chloride importer NKCC1, being the expression of the chloride exporter KCC2 very low at birth. The developmentally regulated expression of KCC2 results in extrusion of chloride with age and a shift of GABA from the depolarizing to the hyperpolarizing direction. The depolarizing action of GABA leads to intracellular calcium rise through voltage-dependent calcium channels and/or N-methyl-d-aspartate receptors. GABA-mediated calcium signals regulate a variety of developmental processes from cell proliferation migration, differentiation, synapse maturation, and neuronal wiring. Therefore, it is not surprising that some forms of neuro-developmental disorders such as autism spectrum disorders (ASDs) are associated with alterations of GABAergic signaling and impairment of the excitatory/inhibitory balance in selective neuronal circuits. In this review, we will discuss how changes of GABAA-mediated neurotransmission affect several forms of ASDs including the Fragile X, the Angelman, and Rett syndromes. Then, we will describe various animal models of ASDs with GABAergic dysfunctions, highlighting their behavioral deficits and the possibility to rescue them by targeting selective components of the GABAergic synapse. In particular, we will discuss how in some cases, reverting the polarity of GABA responses from the depolarizing to the hyperpolarizing direction with the diuretic bumetanide, a selective blocker of NKCC1, may have beneficial effects on ASDs, thus opening new therapeutic perspectives for the treatment of these devastating disorders.
    Frontiers in Pediatrics 07/2014; 2:70. DOI:10.3389/fped.2014.00070
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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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    ABSTRACT: Seizures are very common in the early periods of life and are often associated with poor neurologic outcome in humans. Animal studies have provided evidence that early life seizures may disrupt neuronal differentiation and connectivity, signaling pathways, and the function of various neuronal networks. There is growing experimental evidence that many signaling pathways, like GABAA receptor signaling, the cellular physiology and differentiation, or the functional maturation of certain brain regions, including those involved in seizure control, mature differently in males and females. However, most experimental studies of early life seizures have not directly investigated the importance of sex on the consequences of early life seizures. The sexual dimorphism of the developing brain raises the question that early seizures could have distinct effects in immature females and males that are subjected to seizures. We will first discuss the evidence for sex-specific features of the developing brain that could be involved in modifying the susceptibility and consequences of early life seizures. We will then review how sex-related biological factors could modify the age-specific consequences of induced seizures in the immature animals. These include signaling pathways (e.g., GABAA receptors), steroid hormones, growth factors. Overall, there are very few studies that have specifically addressed seizure outcomes in developing animals as a function of sex. The available literature indicates that a variety of outcomes (histopathological, behavioral, molecular, epileptogenesis) may be affected in a sex-, age-, region- specific manner after seizures during development. Obtaining a better understanding for the gender-related mechanisms underlying epileptogenesis and seizure comorbidities will be necessary to develop better gender and age appropriate therapies.
    Neurobiology of Disease 05/2014; 72. DOI:10.1016/j.nbd.2014.05.021 · 5.08 Impact Factor
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