GABA · Grey Matter

GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter of the adult brain: released by interneurons, it makes the next neuron less likely to fire, and it is the brake that keeps excitation from running away.

GABA. GABA (gamma-aminobutyric acid) is the main inhibitory neurotransmitter of the adult brain: released by interneurons, it makes the next neuron less likely to fire, and it is the brake that keeps excitation from running away.

It acts through two receptor families that differ in speed. GABA-A receptors are ion channels for chloride; when GABA binds they open within milliseconds, chloride flows in (in a mature neuron), and the membrane is held at or below rest. Even when the voltage barely moves, the open channels short-circuit excitatory currents, an effect called shunting inhibition. GABA-B receptors are metabotropic: through G proteins they open potassium channels (the GIRK family) on the receiving cell and close calcium channels on terminals, producing an inhibition that is slower and lasts longer.

Inhibition shapes timing as much as it lowers activity. Interneurons fire onto the cell body and the axon's first segment of many pyramidal cells at once, which opens and closes short windows in which those cells can fire together; this is how rhythms such as gamma are paced.

Many drugs that calm the brain act on GABA-A receptors. Benzodiazepines and barbiturates bind sites on the receptor that make GABA's effect stronger, which is why they can stop seizures and also cause sedation.

In the developing brain GABA can depolarise, because immature neurons hold more chloride inside; the inhibitory role described here is that of the mature cortex.

Inhibition is the reason a network of mostly excitatory cells does not ignite.

A minority of GABA cells, wired locally and firing fast, sets both how much and when the majority can fire.

Questions: What do glutamate and GABA each do to the same neuron's membrane? Glutamate opens AMPA channels that let sodium in, so the membrane moves toward threshold within a millisecond; if the cell is already depolarised, NMDA receptors also lose their magnesium block and admit calcium. GABA works the other way: GABA-A receptors open chloride channels that hold the membrane at or below rest and short-circuit excitatory currents, and GABA-B receptors, more slowly, open potassium channels through G proteins. The neuron fires or stays silent according to the running sum of the two, which is why the same cell can be pushed either way within a few milliseconds. How can GABA inhibit a neuron even when it barely changes the voltage? When the chloride equilibrium potential sits close to the resting voltage, opening GABA-A channels moves the voltage little, but the open channels still make the membrane leakier. Excitatory current arriving at the same moment then escapes through that leak instead of charging the membrane, so an input that would have reached threshold falls short. This is shunting inhibition: it divides the effect of excitation more than it subtracts from the voltage. It is strongest when the GABA synapses sit between the excitatory inputs and the spike initiation zone, on the soma or the axon initial segment. How can a minority of GABA interneurons hold back a majority of excitatory cells? Each interneuron contacts many pyramidal cells, fires fast without tiring, and often synapses on the cell body or the start of the axon, where it has the most control over whether a spike is produced. Interneurons are driven by the same inputs as their targets, so inhibition arrives a millisecond or two after excitation and scales with it, which keeps the ratio of the two roughly constant. GABA-A inhibition also works by shunting: open chloride channels cancel excitatory currents even when the voltage barely moves. Interneurons make up roughly a fifth to a quarter of neocortical neurons in rodents and a larger share in humans. How does inhibition set the pace of fast brain rhythms? When a group of fast-spiking interneurons fires, the GABA-A inhibition it delivers silences the pyramidal cells around it for a few milliseconds. As that inhibition wears off, the pyramidal cells that are being driven fire together in the short window that opens, excite the interneurons again, and the cycle repeats. The decay time of GABA-A inhibition sets the period, which is why such loops oscillate in the gamma range, roughly 30 to 90 Hz. Because these rhythms come from the inhibitory side of the circuit, gamma is often read as a sign of how well inhibition is working.