Functional role of ambient GABA in refining neuronal circuits early in postnatal development

Giada Cellot,Enrico Cherubini

doi:10.3389/fncir.2013.00136

Abstract

Early in development, γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mature brain, depolarizes and excites targeted neurons by an outwardly directed flux of chloride, resulting from the peculiar balance between the cation-chloride importer NKCC1 and the extruder KCC2. The low expression of KCC2 at birth leads to accumulation of chloride inside the cell and to the equilibrium potential for chloride positive respect to the resting membrane potential. GABA exerts its action via synaptic and extrasynaptic GABAA receptors mediating phasic and tonic inhibition, respectively. Here, recent data on the contribution of “ambient” GABA to the refinement of neuronal circuits in the immature brain have been reviewed. In particular, we focus on the hippocampus, where, prior to the formation of conventional synapses, GABA released from growth cones and astrocytes in a calcium- and SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor)-independent way, diffuses away to activate in a paracrine fashion extrasynaptic receptors localized on distal neurons. The transient increase in intracellular calcium following the depolarizing action of GABA leads to inhibition of DNA synthesis and cell proliferation. Tonic GABA exerts also a chemotropic action on cell migration. Later on, when synapses are formed, GABA spilled out from neighboring synapses, acting mainly on extrasynaptic α5, β2, β3, and γ containing GABAA receptor subunits, provides the membrane depolarization necessary for principal cells to reach the window where intrinsic bursts are generated. These are instrumental in triggering calcium transients associated with network-driven giant depolarizing potentials which act as coincident detector signals to enhance synaptic efficacy at emerging GABAergic and glutamatergic synapses.

Highlights

In development, γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mature brain, depolarizes and excites targeted neurons by an outwardly directed flux of chloride, resulting from the peculiar balance between the cation-chloride importer NKCC1 and the extruder KCC2
We focus on the hippocampus, where, prior to the formation of conventional synapses, GABA released from growth cones and astrocytes in a calcium- and sensitive-factor attachment protein receptor (SNARE)-independent way, diffuses away to activate in a paracrine fashion extrasynaptic receptors localized on distal neurons
Later on, when synapses are formed, GABA spilled out from neighboring synapses, acting mainly on extrasynaptic α5, β2, β3, and γ containing GABAA receptor subunits, provides the membrane depolarization necessary for principal cells to reach the window where intrinsic bursts are generated. These are instrumental in triggering calcium transients associated with network-driven giant depolarizing potentials which act as coincident detector signals to enhance synaptic efficacy at emerging GABAergic and glutamatergic synapses

Summary

Cellot and Cherubini

GABAA-mediated tonic conductance in development different subunits. the introduction of single molecule imaging technique has enabled measuring individual receptor movements in the plane of the plasma membrane (Triller and Choquet, 2005; Jacob et al, 2008; Luscher et al, 2011). The entire hippocampal network possesses the capacity to generate GDPs, the CA3 area is centrally involved because: (i) in this area GABAergic interneurons with large axonal arborizations operate as functional hubs to synchronize large ensembles of cells (Bonifazi et al, 2009; Picardo et al, 2011; Allene et al, 2012); (ii) principal cells are connected by extensive glutamatergic recurrent collaterals; (iii) principal cells give rise to intrinsic bursts that drive other neurons to fire (Sipilä et al, 2005; Safiulina et al, 2008) In this context, GABAA-mediated tonic inhibition provides the membrane depolarization needed for principal cells to reach the window where intrinsic bursts are generated (Figure 1; Sipilä et al, 2007; Ben-Ari et al, 2012). Differences in tonic currents between D1- and D2-positive cells observed in juvenile animals may be crucial for regulating MSNs excitability and motor output

CONCLUSION

Depolarizing Depolarizing Depolarizing Hyperpolarizing Unknown Unknown Unknown