Interneurons, GABAA currents, and subunit composition of the GABAA receptor in type I and type II cortical dysplasia

Intellectual and Developmental Disabilities Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
Epilepsia (Impact Factor: 4.57). 07/2010; 51 Suppl 3(s3):166-70. DOI: 10.1111/j.1528-1167.2010.02634.x
Source: PubMed


Interneurons, gamma-aminobutyric acid (GABA)(A) receptor density, and subunit composition determine inhibitory function in pyramidal neurons and control excitability in cortex. Abnormalities in GABAergic cells or GABA(A) receptors could contribute to seizures in malformations of cortical development. Herein we review data obtained in resected cortex from pediatric epilepsy surgery patients with type I and type II cortical dysplasia (CD) and non-CD pathologies. Our studies found fewer interneurons immunolabeled for glutamic acid decarboxylase (GAD) in type II CD, whereas there were no changes in tissue from type I CD. GAD-labeled neurons had larger somata, and GABA transporter (VGAT and GAT1) staining showed a dense plexus surrounding cytomegalic neurons in type II CD. Functionally, neurons from type I CD tissue showed GABA currents with increased half maximal effective concentration compared to cells from the other groups. In type II CD, cytomegalic pyramidal neurons showed alterations in GABA currents, decreased sensitivity to zolpidem and zinc, and increased sensitivity to bretazenil. In addition, pyramidal neurons from type II CD displayed higher frequency of spontaneous inhibitory post synaptic currents. The GABAergic system is therefore, altered differently in cortex from type I and type II CD patients. Alterations in zolpidem, zinc, and bretazenil sensitivity and spontaneous inhibitory postsynaptic currents (IPSCs) suggest that type II CD neurons have altered GABA(A) receptor subunit composition and receive dense GABA inputs. These findings support the hypothesis that patients with type I and type II CD will respond differently to GABA receptor-mediated antiepileptic drugs and that cytomegalic neurons have features similar to immature neurons.

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Available from: Carlos Cepeda, Oct 10, 2015
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    • "Furthermore, a number of studies have suggested that failure to remove regions of dysplasia results in continued seizure occurrence (Wagner et al., 2011). Slice electrophysiologic investigations have been carried out on regions of cortical dysplasia removed at surgery, and investigators have suggested that these tissue samples are hyperexcitable (and may generate spontaneous epileptiform events) (Avoli et al., 1999; D'Antuono et al., 2004; Calcagnotto et al., 2005; Andre et al., 2010). However, recordings from individual neurons that appear to have aberrant morphologic characteristics (as seen with intracellular staining) suggest that the most abnormal-appearing cells are relatively silent, and unlikely to serve as a basis for seizure generation. "
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    ABSTRACT: Cortical dysplasia of various types, reflecting abnormalities of brain development, have been closely associated with epileptic activities. Yet, there remains considerable discussion about if/how these structural lesions give rise to seizure phenomenology. Animal models have been used to investigate the cause-effect relationships between aberrant cortical structure and epilepsy. In this article, we discuss three such models: (1) the Eker rat model of tuberous sclerosis, in which a gene mutation gives rise to cortical disorganization and cytologically abnormal cellular elements; (2) the p35 knockout mouse, in which the genetic dysfunction gives rise to compromised cortical organization and lamination, but in which the cellular elements appear normal; and (3) the methylazoxymethanol-exposed rat, in which time-specific chemical DNA disruption leads to abnormal patterns of cell formation and migration, resulting in heterotopic neuronal clusters. Integrating data from studies of these animal models with related clinical observations, we propose that the neuropathologic features of these cortical dysplastic lesions are insufficient to determine the seizure-initiating process. Rather, it is their interaction with a more subtly disrupted cortical "surround" that constitutes the circuitry underlying epileptiform activities as well as seizure propensity and ictogenesis.
    Epilepsia 06/2012; 53 Suppl 1(s1):35-44. DOI:10.1111/j.1528-1167.2012.03473.x · 4.57 Impact Factor
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    ABSTRACT: Focal cortical dysplasia (FCD) and other localized malformations of cortical development represent common causes of intractable pediatric epilepsy. Insights into the cellular and molecular pathogenesis of focal cortical malformations may reveal information about associated mechanisms of epileptogenesis and suggest new therapies for seizures caused by these developmental lesions. In animal models and human studies of FCD and the related disease of Tuberous Sclerosis Complex (TSC), the mammalian target of rapamycin (mTOR) pathway has been implicated in mediating cellular and molecular changes leading to the formation of the cortical malformations and the expression of epilepsy. The use of mTOR inhibitors may represent a rational therapeutic strategy for treating or even preventing epilepsy due to FCD and TSC.
    Experimental Neurology 10/2011; 244. DOI:10.1016/j.expneurol.2011.10.002 · 4.70 Impact Factor
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    ABSTRACT: 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.
    Annals of Neurology 04/2012; 71(4):539-51. DOI:10.1002/ana.22696 · 9.98 Impact Factor
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