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Abstract The potassium chloride cotransporter, KCC3, is an electroneutral cotransporter expressed in the peripheral and central nervous system. KCC3 is responsible for the efflux of K+ and Cl− in neurons to help maintain cell volume and intracellular chloride levels. A loss-of-function (LOF) of KCC3 causes Hereditary Motor Sensory Neuropathy with Agenesis of the Corpus Callosum (HMSN/ACC) in a population of individuals in the Charlevoix/Lac-Saint-Jean region of Quebec, Canada. A variety of mouse models have been created to understand the physiological and deleterious effects of a KCC3 LOF. Though this KCC3 LOF in mouse models has recapitulated the peripheral neuropathy phenotype of HMSN/ACC, we still know little about the development of the disease pathophysiology. Interestingly, the most recent KCC3 mouse model that we created recapitulated a peripheral neuropathy-like phenotype originating from a KCC3 gain-of-function (GOF). Despite the past two decades of research in attempting to understand the role of KCC3 in disease, we still do not understand how dysfunction of this cotransporter can lead to the pathophysiology of peripheral neuropathy. This review focuses on the function of KCC3 in neurons and its role in human and health and disease. Highlights • Disruption in KCC3 leads to a hereditary sensory motor neuropathy disorder. • Both loss and gain of KCC3 function lead to locomotor deficits. • KCC3 is a protein that functions to maintain and regulate cell volume. • KCC3 LOF results in nerve fiber swelling whereas KCC3 GOF results in their shrinkage. • Loss of KCC3 in sensory proprioceptive neurons leads to a locomotor phenotype. [ABSTRACT FROM AUTHOR]

We have previously reported CNS and locomotor deficits in KCC3 knockout mice, an animal model of agenesis of the corpus callosum associated with peripheral neuropathy (ACCPN) [Howard, H.C., Mount, D.B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.B., Prevost, C., Horst, J., Simonati, A., Lemcke, B., Welch, R., England, R., Zhan, F.Q., Mercado, A., Siesser, W.B., George, A.L., Jr., McDonald, M.P., Bouchard, J.P., Mathieu, J., Delpire, E., Rouleau, G.A., 2002. The K–Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat. Genet. 32, 384–392]. To assess the role of KCC3 in peripheral axon and/or myelin development and maintenance, we determined its expression and performed a detailed morphometric analysis of sciatic nerves. Sciatic nerves of juvenile wild-type mice, but not of adult, express KCC3. In the knockout, Schwann cell/myelin development appears normal at P3, but axons are swollen. At P8 and into P30, some fibers accumulate fluid periaxonally. These initial swelling pathologies are followed by axon and myelin degeneration in adult nerves, leading to reduction in nerve conduction velocity. Mutant mice also exhibit decreased sensitivity to noxious pain. This evidence for fluid-related axonopathy, which ultimately result in neurodegeneration, implicates cell volume regulation as a critical component of peripheral nerve maintenance.

Abstract: We have previously reported CNS and locomotor deficits in KCC3 knockout mice, an animal model of agenesis of the corpus callosum associated with peripheral neuropathy (ACCPN) [Howard, H.C., Mount, D.B., Rochefort, D., Byun, N., Dupre, N., Lu, J., Fan, X., Song, L., Riviere, J.B., Prevost, C., Horst, J., Simonati, A., Lemcke, B., Welch, R., England, R., Zhan, F.Q., Mercado, A., Siesser, W.B., George, A.L., Jr., McDonald, M.P., Bouchard, J.P., Mathieu, J., Delpire, E., Rouleau, G.A., 2002. The K–Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat. Genet. 32, 384–392]. To assess the role of KCC3 in peripheral axon and/or myelin development and maintenance, we determined its expression and performed a detailed morphometric analysis of sciatic nerves. Sciatic nerves of juvenile wild-type mice, but not of adult, express KCC3. In the knockout, Schwann cell/myelin development appears normal at P3, but axons are swollen. At P8 and into P30, some fibers accumulate fluid periaxonally. These initial swelling pathologies are followed by axon and myelin degeneration in adult nerves, leading to reduction in nerve conduction velocity. Mutant mice also exhibit decreased sensitivity to noxious pain. This evidence for fluid-related axonopathy, which ultimately result in neurodegeneration, implicates cell volume regulation as a critical component of peripheral nerve maintenance. [Copyright &y& Elsevier]