Low expression of the ClC-2 chloride channel during postnatal development: a mechanism for the paradoxical depolarizing action of GABA and glycine in the hippocampus.
In early postnatal development, during the period of synapse formation, gamma-aminobutyric acid (GABA) and glycine, the main inhibitory transmitters in the adult brain, paradoxically excite and depolarize neuronal membranes by an outward flux of chloride. The mechanisms of chloride homeostasis are not fully understood. It is known that in adult neurons intracellular chloride accumulation is prevented by a particular type of chloride channel, the ClC-2. This channel strongly rectifies in the inward direction at potentials negative to ECl thus ensuring chloride efflux. We have tested the hypothesis that in the developing hippocampus, a differential expression or regulation of ClC-2 channels may contribute to the depolarizing action of GABA and glycine. We have cloned a truncated form of ClC-2 (ClC-2nh) from the neonatal hippocampus which lacks the 157 bp corresponding to exon 2. In situ hybridization 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 during early development.
INFM Unit, International School for Advanced Studies (SISSA), Trieste, Italy.
M
M
Mladinić
A
A
Becchetti
F
F
Didelon
A
A
Bradbury
E
E
Cherubini
D000375:Aging / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D003001:Cloning, Molecular; D005260:Female; D018507:Gene Expression Regulation, Developmental; D015723:Gene Library; D005998:Glycine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D017403:In Situ Hybridization; D008969:Molecular Sequence Data; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D018118:Chloride Channels; D012333:RNA, Messenger; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D005998:Glycine