Abstract
Expression of the large extracellular glycan, polysialic acid (polySia), is restricted in the adult, to brain regions exhibiting high levels of plasticity or remodeling, including the hippocampus, prefrontal cortex, and the nucleus of the solitary tract (NTS). The NTS, located in the dorsal brainstem, receives constant viscerosensory afferent traffic as well as input from central regions controlling sympathetic nerve activity, respiration, gastrointestinal functions, hormonal release, and behavior. Our aims were to determine the ultrastructural location of polySia in the NTS and the functional effects of enzymatic removal of polySia, both in vitro and in vivo polySia immunoreactivity was found throughout the adult rat NTS. Electron microscopy demonstrated polySia at sites that influence neurotransmission: the extracellular space, fine astrocytic processes, and neuronal terminals. Removing polySia from the NTS had functional consequences. Whole-cell electrophysiological recordings revealed altered intrinsic membrane properties, enhancing voltage-gated K+ currents and increasing intracellular Ca2+ Viscerosensory afferent processing was also disrupted, dampening low-frequency excitatory input and potentiating high-frequency sustained currents at second-order neurons. Removal of polySia in the NTS of anesthetized rats increased sympathetic nerve activity, whereas functionally related enzymes that do not alter polySia expression had little effect. These data indicate that polySia is required for the normal transmission of information through the NTS and that changes in its expression alter sympathetic outflow. polySia is abundant in multiple but discrete brain regions, including sensory nuclei, in both the adult rat and human, where it may regulate neuronal function by mechanisms identified here.SIGNIFICANCE STATEMENT All cells are coated in glycans (sugars) existing predominantly as glycolipids, proteoglycans, or glycoproteins formed by the most complex form of posttranslational modification, glycosylation. How these glycans influence brain function is only now beginning to be elucidated. The adult nucleus of the solitary tract has abundant polysialic acid (polySia) and is a major site of integration, receiving viscerosensory information which controls critical homeostatic functions. Our data reveal that polySia is a determinant of neuronal behavior and excitatory transmission in the nucleus of the solitary tract, regulating sympathetic nerve activity. polySia is abundantly expressed at distinct brain sites in adult, including major sensory nuclei, suggesting that sensory transmission may also be influenced via mechanisms described here. These findings hint at the importance of elucidating how other glycans influence neural function.
Highlights
The extracellular space is complex, filled with molecularly diverse matrix, a dynamic structure that influences neuronal function (Venstrom and Reichardt, 1993; Theodosis et al, 2008)
The labeling pattern is consistent with the punctate rings of immunoreactivity that surround some neuronal cell bodies identified by light microscopy (Fig. 1Bi,Bii). Polysialic acid (polySia)-ir was found on the rough endoplasmic reticulum and Golgi apparatus of some neuronal cell bodies (Fig. 2A) where it may be produced before being transported extracellularly to the cell surface (Theodosis et al, 1999). polySia-ir was present adjacent to some synapses and in a subset of dendrites and axon terminals (Fig. 2B–E), consistent with the close association of polySia and synaptophysin revealed using immunofluorescence (Fig. 1Ci,Cii)
As endo-N-acetyl-neuraminidase F (endoNF) evoked smaller and slower sympathoexcitation, little to no effect on mean arterial pressure (MAP) was seen acutely (15 min: 98.24 Ϯ 9.11 vs 87.75 Ϯ 7.32 mmHg, t(13) ϭ 0.713, p ϭ 0.97, n ϭ 6; Fig. 9Ci) or at 60 min (95.02 Ϯ 6.38 vs 92.5 Ϯ 7.5 mmHg, t(13) ϭ 0.301, p Ͼ 0.99, n ϭ 6; Fig. 9Cii). Together these results demonstrate that removal of polySia in the nucleus of the solitary tract (NTS) increases sympathetic nerve activity, which is consistent with a net disfacilitation in the NTS or experimental visceral deafferentation (Iggo and Vogt, 1962; Fagius et al, 1985)
Summary
The extracellular space is complex, filled with molecularly diverse matrix, a dynamic structure that influences neuronal function (Venstrom and Reichardt, 1993; Theodosis et al, 2008). In adult CNS, polySia expression is restricted to discrete regions that exhibit high levels of synaptic remodeling, including the hippocampus, cortex, and hypothalamus (Bonfanti et al, 1992; Rutishauser and Landmesser, 1996; Bonfanti, 2006; Hildebrandt and Dityatev, 2015) In these regions, polySia modulates synaptic plasticity and efficacy via a range of postulated mechanisms, including interactions with cell adhesion complexes, binding of neurotransmitter/neurotrophic substances, or via actions at glutamate receptors (Rutishauser and Landmesser, 1996; Rutishauser, 2008; Schnaar et al, 2014; Hildebrandt and Dityatev, 2015). The precise location and function/s exerted by polySia in the NTS are unknown
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