Biochemistry and Molecular Biology

The developmental hyperexcitability of the all subtypes of glutamate receptors (49, 73) may be a function of their developmentally regulated subunit composition (74). The AMPA subtype of glutamate receptors may change their subunit composition during development from calcium-permeable isoforms in the immature brain to calcium-impermeable isoforms in adulthood (75). In this scenario, it is possible that the enhanced calcium influx into the immature neurons via fast excitatory receptor channels may be a powerful source of depolarization. Similarly, there are significant developmental differences in the expression of GABAa receptor subunit messenger RNAs (mRNAs), which also suggest age-specific composition of GABAA receptors (76). The striking correlation between the seizure-specific function and the distribution of certain GABAA receptor subunit mRNAs in certain brain areas suggests the existence of developmentally regulated GABAA receptor isoforms that may affect seizures in an opposite way compared to adult GABAA receptor iso-forms (77). Molecular biology studies also indicate that ionic transporter systems such as NKCC1 and KCC2 go through maturational processes, which may affect excitatory and inhibitory features of the neurotransmit-ter receptors, particularly GABAA responses (78-80). One of the functional features that may comprise both the differential composition of GABAA receptors and the ionic (chloride) environment inside the neurons is GABA-mediated tonic inhibition (81). It has been demonstrated that the spillover of GABA outside the synaptic cleft acts on extrasynaptic GABAA receptors. Addition of bicuculline would block these receptors as well as the chloride currents they control. This tonic inhibition, which may be age-specific, presets excitability of the neuronal plasma membrane and modulates the gain of the transmission (82). These extrasynaptic receptors exhibit a high affinity for GABA (hence low ambient concentrations of GABA are sufficient), and do not inactivate rapidly, thus producing a tonic form of inhibition (83). Unlike the syn-aptic (phasic) receptors, they do not bind benzodiazepines (84, 85). Recent studies indicate that during this "excitatory GABA" developmental period, tonic and phasic GABA activation in immature neurons may play a critical role in their synaptic integration, which is activity dependent. This process takes place in both the immature brain and newly born neurons in the adult brain (86-88).

The relatively delayed maturation of other neu-romodulatory systems may contribute to the increased epileptogenicity of the immature brain. In adult rats, norepinephrine depletion accelerates the rate of kindling, decreases the intensity of postictal refractoriness levels, and permits the development of multiple seizure foci (89-91). In this respect, the norepinephrine-depleted adult rats resemble developing 2-week-old rats in which the norepinephrine transmission has not reached adult levels (29).

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