pH modulation of glial glutamate transporters regulates synaptic transmission in the nucleus of the solitary tract

Abstract

The nucleus of the solitary tract (NTS) is the major site for termination of visceral sensory afferents contributing to homeostatic regulation of, for example, arterial pressure, gastric motility, and breathing. Whereas much is known about how different neuronal populations influence these functions, information about the role of glia remains scant. In this article, we propose that glia may contribute to NTS functions by modulating excitatory neurotransmission. We found that acidification (pH 7.0) depolarizes NTS glia by inhibiting K(+)-selective membrane currents. NTS glia also showed functional expression of voltage-sensitive glutamate transporters, suggesting that extracellular acidification regulates synaptic transmission by compromising glial glutamate uptake. To test this hypothesis, we evoked glutamatergic slow excitatory potentials (SEPs) in NTS neurons with repetitive stimulation (20 pulses at 10 Hz) of the solitary tract. This SEP depends on accumulation of glutamate following repetitive stimulation, since it was potentiated by blocking glutamate uptake with dl-threo-β-benzyloxyaspartic acid (TBOA) or a glia-specific glutamate transport blocker, dihydrokainate (DHK). Importantly, extracellular acidification (pH 7.0) also potentiated the SEP. This effect appeared to be mediated through a depolarization-induced inhibition of glial transporter activity, because it was occluded by TBOA and DHK. In agreement, pH 7.0 did not directly alter d-aspartate-induced responses in NTS glia or properties of presynaptic glutamate release. Thus acidification-dependent regulation of glial function affects synaptic transmission within the NTS. These results suggest that glia play a modulatory role in the NTS by integrating local tissue signals (such as pH) with synaptic inputs from peripheral afferents.

Sea Water Acidification Affects Osmotic Swelling, Regulatory Volume Decrease and Discharge in Nematocytes of the JellyfishPelagia noctiluca

“…The inhibition of discharge capability, underlying Cnidaria survival, is in line with previous reports describing that prey/predator relationships may be compromised by marine water pollution [23]. In fact, the role of glutamate in synaptic transmission in the nucleus of the solitary tract (NTS) is dependent on pH [35]. It has also been demonstrated that acidity causes the nematocyst wall to collapse, which may contribute to decreased discharge capacity [41].…”

“…Acid-base balance in cells is directly related to the intracellular concentration of free H + , which is finely regulated to avoid cellular damage. Therefore, pH is a relevant homeostatic parameter, and the relationship between pH maintenance and cell function is well established in mammals, especially in neuronal cells [33,34,35]. …”

Conditional depletion of methyl-CpG-binding protein 2 in astrocytes depresses the hypercapnic ventilatory response in mice

“…Activation of glial sodium/bicarbonate cotransporters leading to depolarization has also been proposed as one putative mechanism underlying their CO 2 chemosensitivity (39). In addition, studies in the nucleus of the solitary tract have proposed that extracellular acidification regulates synaptic transmission by compromising glial glutamate uptake (29).…”

Astrocytic glutamate transport regulates a Drosophila CNS synapse that lacks astrocyte ensheathment

“…The linear I-V relationship, indicating passive membrane conductance as first noted by Kuffler and Nicholls (1966), has emerged as a common property of astrocytes across species (humans: Schroder et al, 2000;Han et al, 2013;rat: Steinhauser et al, 1994;Kressin et al, 1995;Bergles and Jahr, 1997;Clark and Barbour, 1997;Kimelberg, 2000, 2001;Zhang et al, 2009;Uwechue et al, 2012;Huda et al, 2013; mouse: Matthias et al, 2003;Lalo et al, 2006;caiman: Zayas-Santiago et al, 2014). Much like the astrocyte membranes in each of these species, the fly astrocyte has a resting membrane potential that is similar to or more negative than the potassium equilibrium potential, low membrane resistance, and high membrane capacitance.…”