GABA switch · Grey Matter

The GABA switch is the developmental change that turns GABA from a depolarising signal in immature neurons into the inhibitory transmitter of the mature brain, by lowering the chloride inside neurons, and it explains why the same transmitter can excite a newborn's neurons.

GABA switch. The GABA switch is the developmental change that turns GABA from a depolarising signal in immature neurons into the inhibitory transmitter of the mature brain, by lowering the chloride inside neurons, and it explains why the same transmitter can excite a newborn's neurons.

What GABA does depends on chloride. The GABA-A receptor is a chloride channel, so opening it pulls the membrane toward the chloride equilibrium potential. Immature neurons express a lot of NKCC1, a transporter that loads chloride into the cell; with chloride high inside, opening GABA-A channels lets chloride flow out and the membrane depolarises. As neurons mature they express KCC2, which extrudes chloride with potassium; internal chloride falls, its equilibrium potential drops below rest, and GABA now hyperpolarises or shunts. In rodents the switch happens over the first one to two postnatal weeks; in humans KCC2 rises steeply around full-term birth, with regional differences continuing after.

Early depolarising GABA is useful. It drives the spontaneous activity that wires young networks and acts as a growth signal for migrating and maturing neurons.

It can come back. After injury, in some epileptic tissue and after intense activity, KCC2 falls or chloride accumulates, and GABA becomes less inhibitory or even exciting, which weakens the brake exactly when it is needed.

It complicates drugs. Treatments that enhance GABA-A work less well where chloride is high, one reason why seizures in newborns can resist benzodiazepines and phenobarbital; trials of the NKCC1 blocker bumetanide in neonates have not shown clear benefit.

Whether GABA brakes or accelerates is decided by a chloride pump.

The receptor is the same at every age; the transporter that sets chloride inside the cell decides the sign.

Questions: What does the chloride inside neurons have to do with seizures? Inhibition through GABA-A receptors works only while chloride inside neurons is kept low by KCC2. In the newborn brain, where the switch from NKCC1 to KCC2 is still under way, GABA inhibits weakly, which is one explanation for why neonatal seizures often resist drugs that enhance GABA-A receptors. In adult epileptic tissue and after intense activity, KCC2 can fall or chloride can build up, so GABA loses part of its brake when it is needed most. Restoring the chloride gradient is therefore studied as a treatment strategy, though blocking NKCC1 with bumetanide has not shown clear benefit in newborns. Why can GABA excite the neurons of a newborn's brain? GABA opens a chloride channel, and whether that inhibits depends on how much chloride is inside the cell. Immature neurons express the transporter NKCC1, which loads chloride in, so when GABA-A channels open chloride flows out and the membrane depolarises, sometimes enough to help fire the cell. As neurons mature they express KCC2, which pumps chloride out; internal chloride falls and GABA becomes hyperpolarising or shunting. In rodents the switch happens over the first one to two postnatal weeks, and in humans KCC2 rises steeply around full-term birth, so the newborn brain sits close to the transition.