Disruption of CIC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus

Several plasma membrane chloride channels are well characterized, but much less is known about the molecular identity and function of intracellular Cl - channels. ClC-3 is thought to mediate swelling-activated plasma membrane currents, but we now show that this broadly expressed chloride channel is p resent in endosomal compartments and synaptic vesicles of neurons. While sw elling-activated currents are unchanged in mice with disrupted ClC-3, acidi fication of synaptic vesicles is impaired and there is severe postnatal deg eneration of the retina and the hippocampus. Electrophysiological analysis of juvenile hippocampal slices revealed no major functional abnormalities d espite slightly increased amplitudes of miniature excitatory postsynaptic c urrents. Mice almost lacking the hippocampus survive and show several behav ioral abnormalities but are still able to acquire motor skills.