Differences in Cortical versus Subcortical GABAergic Signaling: A Candidate Mechanism of Electroclinical Uncoupling of Neonatal Seizures

Abstract

Electroclinical dissociation of neonatal seizures refers to electrographic seizure activity that is not clinically manifest. Dissociation increases after treatment with Phenobarbital, which increases the GABAA receptor (GABAAR) conductance. The effects of GABAAR activation depend on the intracellular Cl− concentration ([Cl−]i) that is determined by the inward Cl− transporter NKCC1 and the outward Cl− transporter KCC2. Differential maturation of Cl− transport observed in cortical vs. subcortical regions should alter the efficacy of GABA-mediated inhibition. In perinatal rat pups, most thalamic neurons maintained low [Cl−]i, and were inhibited by GABA. Phenobarbital suppressed thalamic seizure activity. Most neocortical neurons maintained higher [Cl−]i, and were excited by GABAAR activation. Phenobarbital had insignificant anticonvulsant responses in the neocortex until NKCC1 was blocked. Regional differences in the ontogeny of Cl− transport may thus explain why seizure activity in the cortex is not suppressed by anticonvulsants that block the transmission of seizure activity through subcortical networks.

Autistic characteristics in adults with epilepsy

“…Individuals with infantile seizures often present with TLE later in life. Therefore, one explanation may be that as infantile seizures are often clinically invisible, missed diagnosis in early-life have resulted in adulthood diagnosis of epilepsy (Glykys et al, 2009). For some of the adult participants in this experiment however, onset of epilepsy was 'acquired' through a head injury, and a normal developmental period was assumed.…”

“…Although developing countries report generally higher incidence rates, socio-economic deprivation has been identified as one predominant factor. Seizures are more commonly found in the newborn neonatal stage of life than at any other time (Glykys et al, 2009). …”

Depolarizing Actions of GABA in Immature Neurons Depend Neither on Ketone Bodies Nor on Pyruvate

“…Agents that alter tissue pH alter intracellular chloride (Kaila and Voipio, 1987;Kaila et al, 1993;Chesler, 2003;Glykys et al, 2009;Kim and Trussell, 2009), neuronal excitability, and seizures (Roos and Boron, 1981;Aram and Lodge, 1987;Balestrino and Somjen, 1988;Jarolimek et al, 1989;Kaila, 1994;Bonnet et al, 2000;Dulla et al, 2005Dulla et al, , 2009Ziemann et al, 2008). Propionate, D-and L-lactate reduce GDPs, although only L-lactate is metabolically active (Roos and Boron, 1981;Dulla et al, 2005;Ruussuvori et al, 2010).…”

A Single Seizure Episode Leads to Rapid Functional Activation of KCC2 in the Neonatal Rat Hippocampus

“…In an analogous manner, depolarizing shifts in E GABA that take place during neuronal epilepsy and trauma have been associated with a decrease in the total amount of KCC2 protein (e.g., Khalilov et al, 2003;Rivera et al, 2004;Munoz et al, 2007, Huberfeld et al, 2007Glykys et al, 2009). In view of the widely recognized but poorly understood differences in neonatal and adult epilepsies (Moshe and Galanopoulou, 2002;Ben Ari and Holmes, 2006;Rennie and Boylan, 2007), it is intriguing that recurrent seizures at postnatal day (P) 4 -6 lead to a precocious hyperpolarizing E GABA shift in CA1 pyramidal neurons of male rats 3-5 d after seizure induction, paralleled by an increase in KCC2 expression (Galanopoulou, 2008).…”