Switching channels

Although GABA (γ-aminobutyric acid) is best known as the main inhibitory neurotransmitter in the adult brain, it can actually excite neurons during embryonic brain development, and in structures such as the hippocampus, neocortex and hypothalamus, its inhibitory properties only emerge after birth. The GABA_A receptor is a chloride channel, and the balance between its excitatory and inhibitory properties depends largely on the Cl⁻ gradient across the cell membrane. During postnatal development, the switch of GABA-mediated synaptic transmission from excitation to inhibition coincides with the upregulation of expression of the K⁺-Cl⁻ co-transporter KCC2. One consequence of this upregulation is that more Cl⁻ ions are pumped out of the cell, lowering the resting intracellular Cl⁻ concentration. But what causes the upregulation of KCC2? A new study by Ganguly et al. provides evidence that it might be GABA itself.

The authors isolated neurons from the rat hippocampus just before birth (embryonic day 18), and cultured the cells over a 13-day period. This protocol had previously been shown to accurately replicate the maturation of neurons in vivo over the same time period. They then measured the percentage of neurons in which the intracellular Ca²⁺ concentration increased in response to GABA. As the cells matured, they became increasingly unresponsive, indicating that the decrease in the excitatory action of GABA could also be found in culture. Blocking the GABA_A channels with antagonists inhibited this change in responsiveness, and also prevented the switch from GABA-mediated excitation to inhibition. Conversely, the switch was accelerated when GABA_A receptor activation was increased by treating the cells with KCl to induce synaptic GABA release. The authors also observed that GABA regulates the levels of KCC2 mRNA expression, and they suggest a mechanism for this. They propose that depolarizing GABA-mediated potentials activate voltage-dependent calcium channels, setting off a signalling cascade that culminates in the upregulation of KCC2 gene expression. This is further supported by the observation that blocking L-type calcium channels also delayed the switch.

So, Ganguly et al. have provided strong evidence that a causal relationship exists between excitatory GABA-mediated transmission and the levels of KCC2. In this way, GABA could indirectly regulate the Cl⁻ gradient across the cell membrane, leading to a switch in the transmission properties of its own receptor.