The absence of ClC-3 leads to hippocampal degeneration. Photograph courtesy of Thomas Jentsch, ZMNH, Hamburg University, Germany.

Neuroscientists seldom talk about anion channels. With the notable exception of GABAA (and occasionally glycine) receptors, advances in the study of cation channels — be they voltage- or ligand-gated — tend to receive much more attention. But Stobrawa and her colleagues are determined to change this status quo after showing that the absence of ClC-3, a chloride channel expressed on synaptic vesicles, leads to retinal and hippocampal degeneration.

ClC channels are present in many species, from bacteria to humans. Their main structural peculiarity is that each ClC channel seems to form two pores in the membrane, like a double-barrelled gun. Although several ClC proteins (for example, ClC-3 and ClC-4) exist in the brain, the functional relevance of this family of channels is best exemplified in other organs. For instance, mutations in ClC-1 produce myotonia, and loss of ClC-5 function causes Dent's disease, a renal disorder in which abnormal amounts of protein appear in the urine.

What is the function of ClC channels in the nervous system? Stobrawa et al. tackled this question by generating ClC-3 knockout mice and looking for any ensuing brain changes. They didn't have to look too hard; the absence of ClC-3 caused the complete loss of the hippocampus, which started to vanish two weeks after birth. The knockout mice were also blind, as another effect of the mutation was the progressive degeneration of the retina.

The authors also found that ClC-3 localized to synaptic vesicles and that its absence impaired vesicle acidification and changed glutamate uptake, phenotypes that could be related to the degeneration. However, as ClC-3 is ubiquitously expressed in the brain and other ClC channels were not upregulated by the mutation, the selectivity of the damage is hard to understand and opens a new avenue of research. So, like in every murder mystery, we have a weapon — a double-barrelled gun — and two victims, but we are still missing the motive. Stay tuned for the next episode.