Disruption of ClC-3-mediated 2Cl^-/H⁺ exchange leads to behavioural deficits and thalamic atrophy.

ABSTRACT: CLCN3 encodes ClC-3, an endosomal 2Cl⁻/H⁺ exchanger, with pathogenic variants causing a neurodevelopmental condition marked by developmental delays, intellectual disability, seizures, hyperactivity, anxiety, and brain and retinal abnormalities. Clcn3^-/- mice show hippocampal and retinal degeneration, recapitulating key symptoms observed in humans. ClC-3 forms homodimers (ClC-3/ClC-3) and heterodimers with ClC-4 (ClC-3/ClC-4), with overlapping brain expression. This suggests distinct functional roles for homo- and heterodimeric assemblies and raises the question of which brain regions specifically depend on ClC-3/ClC-3 rather than ClC-3/ClC-4 complexes. Using ex vivo PET tracer analyses, Clcn3^-/- and Clcn3^td/td mice, we found neurodegeneration in the hippoca

SUBMITTER: Balduin C 

PROVIDER: S-EPMC12479943 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature