Deletion of KCC3 in parvalbumin neurons leads to locomotor deficit in a conditional mouse model of peripheral neuropathy associated with agenesis of the corpus callosum

Behav Brain Res. 2014 Nov 1;274:128-36. doi: 10.1016/j.bbr.2014.08.005. Epub 2014 Aug 10.


Hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC or ACCPN) is an autosomal recessive disease caused by the disruption of the SLC12A6 gene, which encodes the K-Cl cotransporter-3 (KCC3). A ubiquitous deletion of KCC3 in mice leads to severe locomotor deficits similar to ACCPN patients. However, the underlying pathological mechanism leading to the disease remains unclear. Even though a recent study suggests that the neuropathic features of ACCPN are mostly due to neuronal loss of KCC3, the specific cell type responsible for the disease is still unknown. Here we established four tissue specific KCC3 knockout mouse lines to explore the cell population origin of ACCPN. Our results showed that the loss of KCC3 in parvalbumin-positive neurons led to significant locomotor deficit, suggesting a crucial role of these neurons in the development of the locomotor deficit. Interestingly, mice in which KCC3 deletion was driven by the neuron-specific enolase (NSE) did not develop any phenotype. Furthermore, we demonstrated that nociceptive neurons targeted with Nav1.8-driven CRE and Schwann cells targeted with a desert hedgehog-driven CRE were not involved in the development of ACCPN. Together, these results establish that the parvalbumin-positive neuronal population is an important player in the pathogenic development of ACCPN.

Keywords: Behavior; K–Cl cotransport; Locomotion; Neuropathy; Parvalbumin; Sensory neuron.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Agenesis of Corpus Callosum* / complications
  • Agenesis of Corpus Callosum* / genetics
  • Agenesis of Corpus Callosum* / pathology
  • Analysis of Variance
  • Animals
  • Disease Models, Animal
  • Exploratory Behavior / physiology
  • Ganglia, Spinal / metabolism*
  • Ganglia, Spinal / pathology
  • Mice
  • Mice, Transgenic
  • Motor Activity / genetics
  • Movement Disorders / etiology*
  • Movement Disorders / genetics
  • Neurons / metabolism*
  • Parvalbumins / metabolism*
  • Peripheral Nervous System Diseases* / complications
  • Peripheral Nervous System Diseases* / genetics
  • Peripheral Nervous System Diseases* / pathology
  • Phosphopyruvate Hydratase / metabolism
  • Psychomotor Performance / physiology
  • Reaction Time / genetics
  • Spinal Cord / pathology
  • Symporters / deficiency*
  • Symporters / genetics


  • Parvalbumins
  • Slc12a6 protein, mouse
  • Symporters
  • Phosphopyruvate Hydratase

Supplementary concepts

  • Corpus callosum agenesis neuronopathy