RT Journal Article
SR Electronic
T1 Loss of Neuronal Potassium/Chloride Cotransporter 3 (KCC3) Is Responsible for the Degenerative Phenotype in a Conditional Mouse Model of Hereditary Motor and Sensory Neuropathy Associated with Agenesis of the Corpus Callosum
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3865
OP 3876
DO 10.1523/JNEUROSCI.3679-11.2012
VO 32
IS 11
A1 Masoud Shekarabi
A1 Randal X. Moldrich
A1 Sarah Rasheed
A1 Adéle Salin-Cantegrel
A1 Janet Laganière
A1 Daniel Rochefort
A1 Pascale Hince
A1 Karine Huot
A1 Rébecca Gaudet
A1 Nyoman Kurniawan
A1 Susana G. Sotocinal
A1 Jennifer Ritchie
A1 Patrick A. Dion
A1 Jeffrey S. Mogil
A1 Linda J. Richards
A1 Guy A. Rouleau
YR 2012
UL http://www.jneurosci.org/content/32/11/3865.abstract
AB Disruption of the potassium/chloride cotransporter 3 (KCC3), encoded by the SLC12A6 gene, causes hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder affecting both the peripheral nervous system and CNS. However, the precise role of KCC3 in the maintenance of ion homeostasis in the nervous system and the pathogenic mechanisms leading to HMSN/ACC remain unclear. We established two Slc12a6 Cre/LoxP transgenic mouse lines expressing C-terminal truncated KCC3 in either a neuron-specific or ubiquitous fashion. Our results suggest that neuronal KCC3 expression is crucial for axon volume control. We also demonstrate that the neuropathic features of HMSN/ACC are predominantly due to a neuronal KCC3 deficit, while the auditory impairment is due to loss of non-neuronal KCC3 expression. Furthermore, we demonstrate that KCC3 plays an essential role in inflammatory pain pathways. Finally, we observed hypoplasia of the corpus callosum in both mouse mutants and a marked decrease in axonal tracts serving the auditory cortex in only the general deletion mutant. Together, these results establish KCC3 as an important player in both central and peripheral nervous system maintenance.