From Excitatory to Inhibitory

Abstract

In the vertebrate central nervous system, γ-aminobutyric acid (GABA) acting at the ionotropic GABA A receptor is a classic inhibitory neurotransmitter. However, very early in postnatal development GABA exerts an excitatory effect in certain regions of the nervous system, which changes to an inhibitory response a few days after birth. The GABA A receptor is a chloride channel, and thus the cellular response will depend on the chloride gradient across the membrane. Ganguly et al. show in hippocampal neurons in culture that the basis of this switch is a change in the reversal potential for GABA (E GABA ). This change in E GABA is accompanied by an increase in the expression of the K + -coupled Cl - transporter KCC2 and a decrease in the depolarization-induced elevation of intracellular calcium mediated by voltage-gated calcium channels in response to GABA signaling. It is surprising that the spontaneous release of GABA and activation of calcium channels, but not the induction of action potentials, was required for the switch. Inhibition of GABA A receptor signaling blocked the developmental switch, the increase in KCC2 expression, and the change in voltage-gated calcium channel activity. Thus, GABA appears to be able to regulate GABAergic synaptic activity and act as a self-limiting trophic factor. K. Ganguly, A. F. Schinder, S. T. Wond, M.-m. Poo, GABA itself promotes the developmental switch of neuronal GABAergic responses from excitation to inhibition. Cell 105 , 521-532 (2001). [Online Journal]