Altered GABA Signaling in Early Life Epilepsies

Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Kennedy Center Rm 306, Bronx, NY 10461, USA.
Neural Plasticity (Impact Factor: 3.58). 07/2011; 2011(3):527605. DOI: 10.1155/2011/527605
Source: PubMed


The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABA(A) signaling by reshuffling the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABA(A) receptor currents. Such effects may not result in epileptogenesis as frequently as they do in adults. Given the central role of GABA(A) signaling in brain function and development, perturbation of its physiological role may interfere with neuronal morphology, differentiation, and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and sex-appropriate development of the brain.

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    • "However, when extrapolated to other brain regions affected in EPM1, alterations in GABAergic signaling could also contribute to hyperexcitability, manifested as severe myoclonus and seizures. In the cerebral cortex, alterations in GABA signaling may cause seizures, and vice versa, seizures can alter GABA signaling [23], [24]. Many GABA-related mutations are known to cause epilepsy in early life, and for example the analysis of a conditional mutant with disrupted GABAA signaling has implied a developmental period when disrupted GABA signaling may be critical for later ictogenesis and epileptogenesis in addition to having developmental consequences [25]. "
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    PLoS ONE 02/2014; 9(2):e89321. DOI:10.1371/journal.pone.0089321 · 3.23 Impact Factor
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    • "First, some GABA A R subunits, expressing only in the neocortex, could suffer molecular damage. We confirmed no genetic mutations of GABA A R subunits α1, α2, α3, α4, α5, γ1, γ2 and γ3, possibly expressing in the human neocortex [12] [39]. Second, her intractable epilepsy, showing various clinical and EEG features, started within 1 week after birth and continued until death. "
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    • "where ti = 2 days indicates the onset of the inflammatory state and tf = 12.5 days the end. Only two interneurons were submitted to the transient changes, since in the DG not all inhibitory synapses are GABAa [31]. The weight of the two interneuron connections was altered for the connection to 22 granule cells. "
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