Potassium Chloride Cotransporter‐3 (KCC3) in Motor Neurons

다국어 초록 (Multilingual Abstract)

The K‐Cl cotransporter KCC3 is an electroneutral membrane transporter of the SLC12A gene family. It uses the K+ gradient established by the Na+/K+ ATPase to efflux K+, Cl−, and obligatory water from cells. KCC3 loss‐of‐function (LOF) mutations have been found to cause the disease Agenesis of the Corpus Callosum with Peripheral Neuropathy (ACCPN). ACCPN patients suffer from intellectual disability, dysmorphic features, hallucinations, degrading ambulation, and a severe, progressive sensorimotor neuropathy. Previous literature has confirmed that both global KCC3 knock‐out mice and neuron‐specific knock‐out (KO) mice recapitulate the severe sensorimotor deficits seen in patients. Furthermore, mice with KCC3 deleted in a subset of sensory neurons (parvalbumin‐positive proprioceptive neurons) also show a locomotor deficit. Thus, KCC3 dysfunction in sensory neurons may be a key to ACCPN pathogenesis; however, it is unknown if KCC3 dysfunction in sensory neurons could account for the entire range of patient symptoms, that is, both sensory and motor neuropathy. From the spinal cord, motor neurons extend their axons to the periphery where they synapse onto skeletal muscles. Reciprocally, sensory neurons, specifically proprioceptive neurons, bring information from muscles back to the spinal cord, where they synapse onto motor neurons and interneurons. Therefore, KCC3 LOF directly in motor neurons, in sensory neurons, or in both types of neurons could be responsible for the ACCPN phenotype.
To investigate the participation of motor neurons, we used a mouse line that expresses the CRE recombinase under the control of the HB9 promoter. HB9 is a transcription factor expressed during peak motor neuron development at mouse embryonic days E9.5–10.5. We crossed HB9‐CRE mice with a KCC3‐floxed line to generate mice with KCC3 deleted in motor neurons (HB9‐CRE x KCC3‐flox). We then subjected cohorts of HB9‐positive KCC3‐flox mice versus HB9‐negative KCC3‐flox mice to locomotor tests. The HB9‐positive KCC3‐flox mice did not show any deficits in the accelerated rotarod test, which assesses balance and overall locomotion performance, nor in the elevated balance beam task, which assesses finer movement coordination. Absence of a phenotype indicates that targeting KCC3 deletion in motor neurons does not contribute to the development of neuropathy. These data suggest that the motor phenotype observed in ACCPN patients might be secondary to the sensory deficit. Such an indirect effect is possible as motor neurons need proper sensory feedback from muscles to appropriately coordinate posture and movement.
This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.