Is there more to gaba than synaptic inhibition?

Key Points The amino acid GABA (γ-aminobutyric acid) was first identified in the mammalian brain over 50 years ago, and during the 1950s and 1960s, strong evidence accumulated that it acts as an inhibitory neurotransmitter in both vertebrate and invertebrate nervous systems. GABA is synthesized from glutamate and is loaded into synaptic vesicles, from which it is released by calcium-dependent exocytosis. Non-vesicular forms of GABA secretion have also been described, and these might be particularly important during brain development. In developing neurons, GABA has been shown to act as an excitatory neurotransmitter. This is largely due to a relatively high intracellular chloride concentration in immature neurons, which decreases as development proceeds, allowing GABA to become progressively inhibitory. The first indication that GABA might act as a trophic substance during nervous system development came from studies showing that GABA could promote neurite growth in the rat superior cervical ganglia. Subsequently, GABA has also been shown to regulate neuronal proliferation and migration in the developing cortex. Examination of mice with mutations in key genes of the GABA pathway has revealed surprisingly few developmental abnormalities in the central nervous system. However, developing cells might be promiscuous in their use of transmitter signals, so it is possible that any system that induces membrane depolarization could be used to influence developmental programmes. In the mature brain, GABA (γ-aminobutyric acid) functions primarily as an inhibitory neurotransmitter. But it can also act as a trophic factor during nervous system development to influence events such as proliferation, migration, differentiation, synapse maturation and cell death. GABA mediates these processes by the activation of traditional ionotropic and metabotropic receptors, and probably by both synaptic and non-synaptic mechanisms. However, the functional properties of GABA receptor signalling in the immature brain are significantly different from, and in some ways opposite to, those found in the adult brain. The unique features of the early-appearing GABA signalling systems might help to explain how GABA acts as a developmental signal.