Astrocytic K+ clearance during disease progression in amyotrophic lateral sclerosis.

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 (SOD1G93A ). 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.

Neuromodulation of Astrocytic K+ Clearance.

Potassium homeostasis is fundamental for brain function. Therefore, effective removal of excessive K+ from the synaptic cleft during neuronal activity is paramount. Astrocytes play a key role in K+ clearance from the extracellular milieu using various mechanisms, including uptake via Kir channels and the Na+-K+ ATPase, and spatial buffering through the astrocytic gap-junction coupled network. Recently we showed that alterations in the concentrations of extracellular potassium ([K+]o) or impairments of the astrocytic clearance mechanism affect the resonance and oscillatory behavior of both the individual and networks of neurons. These results indicate that astrocytes have the potential to modulate neuronal network activity, however, the cellular effectors that may affect the astrocytic K+ clearance process are still unknown. In this study, we have investigated the impact of neuromodulators, which are known to mediate changes in network oscillatory behavior, on the astrocytic clearance process. Our results suggest that while some neuromodulators (5-HT; NA) might affect astrocytic spatial buffering via gap-junctions, others (DA; Histamine) primarily affect the uptake mechanism via Kir channels. These results suggest that neuromodulators can affect network oscillatory activity through parallel activation of both neurons and astrocytes, establishing a synergistic mechanism to maximize the synchronous network activity.

Selective hippocampal cell damage and mossy fiber sprouting induced by chronic intracerebral injections of 2-deoxy-D-glucose.

A reduction in glucose consumption has been shown in both patients with acquired epilepsy and in animal epilepsy models. However, the question remains whether the disturbance of glucose metabolism is the driving force of epileptogenesis. We have recently reported that a chronic partial inhibition of brain glycolysis by the non-metabolizable glucose analogue 2-deoxy-D-glucose (2-DG) triggers epileptogenesis in initially healthy rats. In this study, we further investigated whether chronic 2-DG treatment caused a cellular loss in the dorsal hippocampus and mossy fiber sprouting in the dentate gyrus. We found that prolonged (four weeks) treatment with 2-DG induced a neuronal loss in the CA1 field and the dentate hilus. We also found mossy fibers reorganization in the 2-DG group. In addition, we showed that pentylenetetrazole-induced convulsions were considerably strengthened and prolonged in 2-DG-treated rats. Our results demonstrate that the chronically impaired brain glucose metabolism likely leads to a structural remodeling resembling epileptogenesis and has a proconvulsive effect.

Neuromodulation of Glial Function During Neurodegeneration.

Glia, a non-excitable cell type once considered merely as the connective tissue between neurons, is nowadays acknowledged for its essential contribution to multiple physiological processes including learning, memory formation, excitability, synaptic plasticity, ion homeostasis, and energy metabolism. Moreover, as glia are key players in the brain immune system and provide structural and nutritional support for neurons, they are intimately involved in multiple neurological disorders. Recent advances have demonstrated that glial cells, specifically microglia and astroglia, are involved in several neurodegenerative diseases including Amyotrophic lateral sclerosis (ALS), Epilepsy, Parkinson's disease (PD), Alzheimer's disease (AD), and frontotemporal dementia (FTD). While there is compelling evidence for glial modulation of synaptic formation and regulation that affect neuronal signal processing and activity, in this manuscript we will review recent findings on neuronal activity that affect glial function, specifically during neurodegenerative disorders. We will discuss the nature of each glial malfunction, its specificity to each disorder, overall contribution to the disease progression and assess its potential as a future therapeutic target.