KCC K+/Cl- cotransporters

Over a decade, we have also worked on electroneutral KCC K-Cl cotransporters that stoichiometrically couple the movement of chloride to that of potassium. This coupling leads generally to a lowering of the cytoplasmic Cl^- concentration.  In neurons, this concentration determines whether the response to the neurotransmitters GABA and glycine is inhibitory (as in most adult neurons) or excitatory (as early in development). ClC-2 is thought to play a role in this regulation, but the disruption of this Cl- channel led to male infertility, blindness and leukodystrophy rather than to CNS hyperexcitability. By contrast, the disruption of the neuronal K-Cl cotransporter KCC2 led to perinatal death due to the inability to breathe and to a spastic phenotype [22]. This was indeed due to an increase in intracellular chloride in motoneurons. The knock-out of KCC4 led to a rapid hearing loss that was associated with renal tubular acidosis [23], whereas the disruption of KCC3 led to a degeneration of the nervous system, deafness, and hypertension [24, 25]. Finally, we have shown that KCC1 and KCC3 co-operate in regulating the volume of red blood cells [26]. Genetic elimination of both transporters partially alleviates the symptoms of sickle-cell anemia.

Later we have used ‘floxed’ Kcc2 mice to disrupt Kcc2 only in a subset of specific neurons like cerebellar granule and Purkinje cells [27]. In both cell types, KCC2 ablation significantly increased the cytoplasmic Cl- concentration. It nearly abolished GABA-ergic hyperpolarization of Purkinje cells and increased the excitability of granule cells (GCs) through depolarization. Ablation of Kcc2 from GCs impaired consolidation of long-term phase learning of the vestibulo-ocular reflex, revealing a previously unknown role of GC excitability in consolidation of phase learning [27]. Specific disruption of Kcc2 in mitral and tufted cells of the olfactory bulb revealed the importance of precise GABAergic siganling in the processing of olfactory information. It disrupted the separration of odour-induced activity patterns and disturbed the dscrimination of closely related odors [38].