Low expression of the CIC-2 chloride channel during postnatal development:a mechanism for the paradoxical depolarizing action of GABA and glycine inthe hippocampus

In early postnatal development, during the period of synapse formation, gam ma-aminobutyric acid (GABA) and glycine, the main inhibitory transmitters i n the adult brain! paradoxically excite and depolarize neuronal membranes b y an outward flux of chloride. The mechanisms of chloride homeostasis are n ot fully understood. It is known chat in adult neurons intracellular chlori de accumulation is prevented by a particular type of chloride channel, the ClC-2. This channel strongly rectifies in the inward direction at potential s negative to E-Cl thus ensuring chloride efflux. We have tested the hypoth esis that in the developing hippocampus, a differential expression or regul ation of ClC-2 channels may contribute to the depolarizing action of GABA a nd glycine. We have cloned a truncated form of ClC-2 (ClC-2nh) from the neo natal hippocampus which lacks the 157 bp corresponding to exon 2. In situ h ybridization experiments show that ClC-2nh is the predominant form of ClC-2 mRNA in the neonatal brain. ClC-2nh mRNA is unable to encode a full-length protein due to a frameshift, consequently it does not induce any currents upon injection into Xenopus oocytes. Low expression of the full-length ClC- 2 channel, could alter chloride homeostasis, lead to accumulation of [Cl-]( i) and thereby contribute to the depolarizing action of GABA and glycine du ring early development.