Chemical synapses can be classified according to the neurotransmitter that the presynaptic neuron is utilizing. GABAergic presynaptic axon terminals release Gamma aminobutyric acid, which acts on postsynaptic GABAA receptors, opening an intrinsic chloride channel. This action usually inhibits the postsynaptic neuron by hyperpolarizing the cell membrane.
Neurons are incapable of de novo synthesis of Glutamate or Gamma aminobutyric acid. Instead, they take up glutamine released from Astrocytes, which is then converted to glutamate by Glutaminase. GABAergic neurons and their axon terminals can be identified by visualising Glutamic acid decarboxylase. This enzyme catalyses the subsequent Decarboxylation of glutamate to GABA. GABA is then taken up into Synaptic vesicles by the Vesicular GABA transporter (VGAT). Action potentials invading the axon terminal trigger the release machinery, causing synaptic GABA concentration to rise transiently to millimolar concentrations. Released GABA is rapidly cleared by GABA transporters (GAT 1 to 3), of which GAT1 is mainly expressed presynaptically, and GAT3 on astrocytes. GAT1 and GAT3 can also operate in reverse mode and thus regulate GABAergic tone.
The presynaptic terminal of a GABAergic neuron takes up Glutamine released from neighbouring astrocytes, where it was converted from glutamate by Glutamate synthetase. Glutamine is then metabolised into Gamma aminobutyric acid through Glutaminase and Glutamic acid decarboxylase (GAD). The Vesicular GABA transporter (VGAT) translocates GABA into synaptic vesicles, from where it is released into the Synaptic cleft. Here, GABA can act on synaptic GABAA receptors or Metabotropic GABAB receptors, and can also diffuse away to reach peri- and extrasynaptic GABAA receptors. GABA reuptake is mediated mainly by the transporters GAT1 on presynaptic terminals and GAT3 on astrocytes.
Within astrocytes, degradation of GABA is catalysed by GABA transaminase to succinate semialdehyde (SSA), and further by SSA dehydrogenase to Succinic acid, which is fed into the Tricarboxylic acid cycle. Synaptic GABAA receptors bind to the scaffolding protein Gephyrin, but can also diffuse out of synaptic sites, where exo-/endocytosis takes place.
Comparison to excitatory synapses
Basic numbers on GABAergic transmission are most readily available for the Hippocampus. In this region, about 15-20 % of all neurons use GABA as their main neurotransmitter. Similarly, the majority of hippocampal synapses are glutamatergic and the relative number of inhibitory synapses remains low: Pyramidal neurons and Basket cells receive about 6 % inhibitory versus 94 % excitatory inputs, while other interneuron types can have 20-30 % inhibitory inputs. Because of architectonic similarities, these estimates are likely to be in the same range also for the cortex. Two factors help explain why, despite these numbers, excitation and inhibition can still be at balance in the brain, allowing network operations to be under interneuron control: (i) several types of interneurons including basket and chandelier cells are characterised by considerably faster spiking rates when compared to principal neurons (in the order of 15 Hz versus 1 Hz , and (ii) tonic inhibition mediated by extrasynaptic GABAARs is quantitatively important, with a three to four times larger total charge transfer compared to synaptic inhibition .