Excitatory actions of gaba during development: the nature of the nurture

Key Points The sculpting of neuronal connections during brain development depends on a precise balance between inhibition and excitation — an excess of GABA (γ-aminobutyric acid)-mediated inhibition might prevent growth or synapse formation, whereas an excess of glutamatergic excitation could lead to toxicity. This review describes a sequence of events that might provide a solution. First, GABA is initially excitatory. Second, GABA synapses are formed before glutamatergic ones. Third, the excitatory actions of GABA generate a primitive pattern of activity, which helps to modulate neuronal growth and synapse formation. Activation of GABA synapses in young neurons produces depolarization instead of the characteristic hyperpolarization, because of a relatively high concentration of intracellular chloride ions ([Cl − ] i ). The intracellular accumulation of chloride seems to be generated by a delay in the expression of the chloride exporter KCC2. GABA-expressing interneurons become postmitotic at an earlier stage than glutamatergic pyramidal neurons, and they originate from a different source and follow a different migration pathway. In the rodent hippocampus in utero , all the activity is provided by GABA synapses that are formed between interneurons, and the first glutamatergic synapses are also established on GABA interneurons. Early ongoing activity in the brain is dominated by long-lasting, recurrent potentials known as giant depolarizing potentials (GDPs). The excitatory actions of GABA have a central role in the generation of GDPs. GDPs are key players in the modulation by electrical activity of various functions, including neuronal migration and growth, synapse formation and plasticity of developing GABA synapses. The formation of excitatory GABA synapses and the GABA–glutamate developmental sequence have been conserved throughout evolution, and they might constitute a fundamental step in the construction of a functional cortical network and in its reinforcement by neuronal activity.