Astrocytic K+ clearance during disease progression in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder in which patients lose motor functions due to progressive loss of motor neurons in the cortex, brainstem, and spinal cord. Whilst the loss of neurons is central to the disease, it is becoming clear that glia, specifically astrocytes, contribute to the onset and progression of neurodegeneration. Astrocytes play an important role in maintaining ion homeostasis in the extracellular milieu and regulate multiple brain functions by altering their extracellular concentrations. In this study, we have investigated the ability of astrocytes to maintain K⁺ homeostasis in the brain via direct measurement of the astrocytic K⁺ clearance rate in the motor and somatosensory cortices of an ALS mouse model (SOD1^G93A ). Using electrophysiological recordings from acute brain slices, we show region-specific alterations in the K⁺ clearance rate, which was significantly reduced in the primary motor cortex but not the somatosensory cortex. This decrease was accompanied by significant changes in astrocytic morphology, impaired conductivity via Kir4.1 channels and low coupling ratio in astrocytic networks in the motor cortex, which affected their ability to form the K⁺ gradient needed to disperse K⁺ through the astrocytic syncytium. These findings indicate that the supportive function astrocytes typically provide to motoneurons is diminished during disease progression and provides a potential explanation for the increased vulnerability of motoneurons in ALS.

Keywords: K+ spatial buffering; SOD1; amyotrophic lateral sclerosis; astrocytes; excitability.