Maturation of the GABAergic transmission in normal and pathologic motoneurons

Abstract

γ-aminobutyric acid (GABA) acting on Cl(-)-permeable ionotropic type A (GABA(A)) receptors (GABA(A)R) is the major inhibitory neurotransmitter in the adult central nervous system of vertebrates. In immature brain structures, GABA exerts depolarizing effects mostly contributing to the expression of spontaneous activities that are instructive for the construction of neural networks but GABA also acts as a potent trophic factor. In the present paper, we concentrate on brainstem and spinal motoneurons that are largely targeted by GABAergic interneurons, and we bring together data on the switch from excitatory to inhibitory effects of GABA, on the maturation of the GABAergic system and GABA(A)R subunits. We finally discuss the role of GABA and its GABA(A)R in immature hypoglossal motoneurons of the spastic (SPA) mouse, a model of human hyperekplexic syndrome.

Figure 1

Development of the GABA_AR-mediated inhibitory transmission in mouse lumbar spinal MNs. From top to bottom: schematic drawings (frontal views) depict the transient expression of GABA in spinal ventral interneurons (in green), while horizontal bars indicate the permanent KCC2 (in blue) and transient NKCC1 activity (in violet). The color intensity encodes the level of activity. NKCC1 inactivation combined to KCC2 activity leads to a significant decrease in [Cl⁻]_i and a disappearance of GABA_AR-mediated excitatory effects. In parallel to the maturation of the chloride cotransporters KCC2 and NKCC1, the spinal cord starts to convey first synaptic activity at E12.5 that is GABAergic (green horizontal bar). Bottom: maturation of the chloride equilibrium potential (E _Cl), spike threshold and resting membrane potential (Vrest) across the embryonic stages of developmental. Note the drop of E _Cl at E16.5 that accounts for the “shunting” GABA_AR-mediated effect (modified from [47, 56, 66]).

Figure 2

(a) Developmental changes in the proportions of GABAergic and glycinergic synaptic activity in various areas of the central nervous system. (b) Examples of individual glycinergic (left) GABAergic (middle) and mixed (right) miniature inhibitory postsynaptic currents (mIPSCs) recorded in a hypoglossal motoneuron at P15, in the presence of tetrodotoxin (a blocker of voltage-gated sodium channels). Note the slower decay phase of the GABAergic mIPSC compared to the glycinergic mIPSC. Decay phase of GABAergic and glycinergic events is better fitted with a single exponential function, while a double exponential function is required to fit the decay phase of mixed events. (c) Relative proportions of glycinergic, GABAergic and mixed mIPSCs at P3–P5 (black bars) and at P15 (white bars) in wild-type mice. (d) Relative proportions of glycinergic, GABAergic and mixed miniature postsynaptic events at P5–P7 (black bars) and at P15–P18 (white bars) in SPA mice. (Adapted from [118, 126]).