Glutamate and ATP at the Interface Between Signaling and Metabolism in Astroglia: Examples from Pathology

Abstract

Glutamate is the main excitatory transmitter in the brain, while ATP represents the most important energy currency in any living cell. Yet, these chemicals play an important role in both processes, enabling them with dual-acting functions in metabolic and intercellular signaling pathways. Glutamate can fuel ATP production, while ATP can act as a transmitter in intercellular signaling. We discuss the interface between glutamate and ATP in signaling and metabolism of astrocytes. Not only do glutamate and ATP cross each other's paths in physiology of the brain, but they also do so in its pathology. We present the fabric of this process in (patho)physiology through the discussion of synthesis and metabolism of ATP and glutamate in astrocytes as well as by providing a general description of astroglial receptors for these molecules along with the downstream signaling pathways that may be activated. It is astroglial receptors for these dual-acting molecules that could hold a key for medical intervention in pathological conditions. We focus on two examples disclosing the role of activation of astroglial ATP and glutamate receptors in pathology of two kinds of brain tissue, gray matter and white matter, respectively. Interventions at the interface of metabolism and signaling show promise for translational medicine.

Age-Related Changes in Axonal and Mitochondrial Ultrastructure and Function in White Matter

“…We also observed increased nodal and internodal lengths with aging, despite previous reports of shorter internodal distances in aging spinal cord (Lasiene et al, 2009) and primate CNS (Peters, 2009). A majority of aging axon profiles exhibited diffuse Nav1.6 immunoreactivity with prominent elongation of Caspr labeling, as described previously (Hinman et al, 2006;Lasiene et al, 2009;.…”

“…Although loss of myelin in humans (Kemper, 1994) and myelin changes characterized by splitting, ballooning, and exuberant formation (Feldman and Peters, 1998;Peters et al, 2000;Sandell and Peters, 2002) in brain and optic nerves with aging have been reported, overproduction of myelin allows sheaths to enlarge and accommodate the subsequent increases in the diameters of enclosed axons. Moreover, during aging, the activity of genes involved in myelin synthesis is upregulated (Blalock et al, 2003), so more myelin is added to an axon and the myelin sheath gets thicker and begins to occupy an increasing proportion of the surrounding volume (Lasiene et al, 2009). These results suggest that oligodendrocytes remain active during aging and continue to add lamella to the myelin sheaths of intact nerve fibers so that the myelin becomes thicker (Peters, 2009;Bowley et al, 2010).…”

“…All chemicals used for electron microscopy (EM) were purchased from Electron Microscopy Sciences except for aspartic acid (SigmaAldrich). The sources for chemicals for electrophysiology experiments have been described previously (Baltan et al, 2008;Uo et al, 2009). The Thy-1 mito-CFP mice (Misgeld et al, 2007) were originally received by the senior author at the University of Washington and were later brought to and bred in the Cleveland Clinic animal facility.…”

“…ATP extraction was performed as described previously (Khan, 2003) and modified for optic nerve (Baltan et al, 2010(Baltan et al, , 2011. Briefly, a MON was cut and placed in 75 l of 10% perchloric acid (HClO 4 ).…”

“…Aging is associated with an increased incidence of ocular diseases, including glaucoma and macular degeneration, as well as ocular complications that are part of systemic diseases such as hypertension and diabetes mellitus (Heflin and Lum, 2008). Moreover, because the optic nerve is a pure CNS WM tract, it has been extensively used to investigate WM injury mechanisms during aglycemia, stretch injury, anoxia, and ischemia (Baltan et al, 2008;Baltan, 2012;Murphy et al, 2014). We studied axon function responses to ischemia as a function of age by exposing mouse optic nerves (MONs) to oxygen and glucose deprivation (OGD) and showed that aging, specifically at 12 months of age, marks the onset of a prominent vulnerability of axon function to ischemia (Baltan et al, 2008;Baltan, , 2012.…”