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

Abstract

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 4 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.

KCC3 axonopathy: neuropathological features in the central and peripheral nervous system

“…11 Intriguingly, parvalbumin-specific knockdown of KCC3 has also led to locomotor deficit phenotypes in mice, which supports our previous findings of KCC3 expression in these neurons. 16,17 Although this disease announces itself as a peripheral neuropathy, our findings of ongoing axonal atrophy in the white matter of the nervous system at the time of death indicate widespread ongoing axonal disease in the cerebral hemispheres as well. Intra-hemispheric disconnection and telencephalic spheroids may explain the psychotic symptomatology in this disease.…”

K-Cl cotransporters, cell volume homeostasis, and neurological disease

“…However, whether these effects are driven by disrupted RVD in neurons or glia had remained unclear until two recent reports demonstrated that neuron-specific knockdown of KCC3 sufficed to recapitulate the neuropathology [63,64]. In the first study, CRE recombinase-mediated KCC3 deletion was driven by the synapsin promoter, thus targeting all neurons [63].…”

The KCC3 cotransporter as a therapeutic target for peripheral neuropathy

“…First, Shekarabi et al showed that specific targeting of KCC3 deletion in neurons (using synapsin I-CRE) was sufficient to recapitulate the phenotype of the global knockout [10]. Second, we demonstrated that deletion of KCC3 in proprioceptive sensory neurons (driven by parvalbumin-CRE) also recapitulated the proprioceptive and locomotor deficits observed in the global and synapsin I CRE-induced knockout mice [11]. In agreement with a neuronal origin, driving CRE specifically in Schwann cells by using desert hedgehog-CRE did not result in any observable phenotype [11].…”

“…Second, we demonstrated that deletion of KCC3 in proprioceptive sensory neurons (driven by parvalbumin-CRE) also recapitulated the proprioceptive and locomotor deficits observed in the global and synapsin I CRE-induced knockout mice [11]. In agreement with a neuronal origin, driving CRE specifically in Schwann cells by using desert hedgehog-CRE did not result in any observable phenotype [11]. The fact that phosphorylation of K-Cl cotransporter leads to inhibition while dephosphorylation leads to its activation is well appreciated in the field since the early 1990s [12].…”

“…The demonstration that targeted deletion of KCC3 in proprioceptive sensory neurons produces the locomotor phenotype of the global knockout [11] strongly indicates that peripheral sensory neurons participate in the pathology. In contrast, the predominant motor deficit observed in the KCC3-T991A patient points to the participation of motor neurons as well.…”