John Libbey Eurotext

Developmental pharmacology of benzodiazepines under normal and pathological conditions Volume 16, numéro spécial 1, October 2014

Figure 1

Developmental changes in GABAAR composition and postsynaptic currents. (A) GABAARs are pentameric ligand-gated Cl- channels that are typically comprised of 2α and 2β subunits, in addition to a fifth subunit which is usually a γ subunit, although other subunit combinations have been described. The GABA binding pocket lies between the α and β subunits, whereas the benzodiazepine binding site is between the α and γ subunits, with the α1γ2 combination exhibiting greatest affinity. (B-D) During development, a gradual shift in the subunit composition of GABAARs has been described in several brain regions. Whole-cell patch clamp recordings from GABAergic SNR neurons are shown here to demonstrate that in older age groups, the kinetics of post-synaptic GABAAR inhibitory currents acquire faster kinetics (faster rise and decay times) (B) and become more frequent (C). This can be explained by the gradual replacement of α3 subunits (highly present in immature neurons) and α1 subunits (highly expressed in mature neurons), as shown in the substantia nigra neurons (D), by performing immunochemistry specific to either α1 or α3 subunits.

Permission to reproduce panels B-D from Chudomel et al. (2009) was obtained by Elsevier.

Figure 2

Developmental changes in the physiology of GABAARs. GABAAR can normally elicit depolarising or hyperpolarising postsynaptic responses depending upon the electrochemical gradient of Cl-, between the intra- and extra-cellular space. In immature neurons, there are abundant cation chloride cotransporters that import Cl- (e.g. NKCC1) and scarce cation chloride cotransporters that export Cl- (e.g. KCC2), creating relatively high intracellular Cl- concentrations ([Cl-]i). As a result, opening of GABAARs leads to efflux of Cl-, depolarising these neurons. GABA depolarisations are necessary early in life as they support calcium-sensitive processes that are important for neuronal proliferation, migration, differentiation, and synaptic growth and integration. GABA depolarisations are not necessarily excitatory, as they do not necessarily trigger action potentials. In the face of excessive neuronal excitation (e.g. during seizures), the open GABAAR channels can still shunt excitatory currents, contributing a weak form of inhibition (shunting inhibition). In mature neurons, there is greater activity of KCC2 than NKCC1, which lowers [Cl-]i and permits the hyperpolarising GABAAR currents to emerge, once GABAARs open. This suggests that the efficacy of inhibitory effects of benzodiazepines may be enhanced in older age groups.

Figure 3

GABAAR expression and functional changes during normal development and pathological states. Various factors contribute to the variable functions of GABAARs and strength of GABAAR inhibition under normal conditions, including age, sex, cell type, brain region, and subunit types expressed. In addition, seizures, underlying pathological states (aetiology), age at seizure induction, time after seizures, the presence of epileptic state, and other stressors or drugs may further diversify the function of GABAARs. As a result, the end effect and efficacy of benzodiazepines may vary across brain regions, subjects, and under different normal or pathological states.