Dramatically Amplified Thoracic Sympathetic Postganglionic Excitability and Integrative Capacity Revealed with Whole-Cell Patch-Clamp Recordings

Abstract

Thoracic paravertebral sympathetic postganglionic neurons (tSPNs) comprise the final integrative output of the distributed sympathetic nervous system controlling vascular and thermoregulatory systems. Considered a non-integrating relay, what little is known of tSPN intrinsic excitability has been determined by sharp microelectrodes with presumed impalement injury. We thus undertook the first electrophysiological characterization of tSPN cellular properties using whole-cell recordings and coupled results with a conductance-based model to explore the principles governing their excitability in adult mice of both sexes. Recorded membrane resistance and time constant values were an order of magnitude greater than values previously obtained, leading to a demonstrable capacity for synaptic integration in driving recruitment. Variation in membrane resistivity was the primary determinant controlling cell excitability with vastly lower currents required for tSPN recruitment. Unlike previous microelectrode recordings in mouse which observed inability to sustain firing, all tSPNs were capable of repetitive firing. Computational modeling demonstrated that observed differences are explained by introduction of a microelectrode impalement injury conductance. Overall, tSPNs largely linearly encoded injected current magnitudes over a broad frequency range with distinct subpopulations differentiable based on repetitive firing signatures. Thus, whole-cell recordings reveal tSPNs have more dramatically amplified excitability than previously thought, with greater intrinsic capacity for synaptic integration and with the ability for maintained firing to support sustained actions on vasomotor tone and thermoregulatory function. Rather than acting as a relay, these studies support a more responsive role and possible intrinsic capacity for tSPNs to drive sympathetic autonomic function.

Heightened sympathetic neuron activity and altered cardiomyocyte properties in spontaneously hypertensive rats during the postnatal period

“…The altered central activity contributes to increased peripheral sympathetic drive, such as is seen in the SHR (Briant et al, 2014). Ultimately, however, the level of sympathetic drive to peripheral organs is determined by the input-output properties of the ganglionic neurons (Springer et al, 2015;McKinnon et al, 2019), which are modulated by peripheral factors (Luther et al, 2013;Enes et al, 2020). This modulation is likely to be altered in hypertensive SHRs, as is seen in whole ganglion recordings of compound action potentials that show increased output in SHR, compared to WKY rats (Magee and Schofield, 1994).…”

“…Sympathetic drive to the periphery depends upon the normal development and function of ganglionic sympathetic neurons. Development of this system takes place through a set of coordinated processes that include the patterning of target organ innervation (Habecker et al, 2008), the establishment of neurotransmitter identity and release properties (Furshpan et al, 1986;Lockhart et al, 1997), and the excitability and synaptic properties of sympathetic neurons (Luther and Birren, 2009;Luther et al, 2013;McKinnon et al, 2019). Disruption in these early processes has the potential to contribute to the chronic increases in the sympathetic drive that precede and contribute to the development of hypertension in humans and in animal models (Shanks et al, 2013;Grassi et al, 2015).…”

“…The level of peripheral sympathetic activity is set both by the strength of the central inputs driving ganglionic sympathetic neuron activity (McLachlan et al, 1998;Bratton et al, 2010), and by the output properties of the ganglionic neurons themselves (Springer et al, 2015;McKinnon et al, 2019). Sympathetic neuron activity is regulated by local ganglionic and peripheral factors, including target-derived neurotrophic factors that modulate the intrinsic and synaptic properties of sympathetic output neurons (Luther et al, 2013;Lehigh et al, 2017;Enes et al, 2020).…”

An unusual presentation of spontaneous spinal epidural hematoma

“…Increased sympathetic tone will result in decreased venous return from the right upper extremity in the face of vasodilation. Given the absence of evidence of acute arterial occlusion of the right upper extremity, compression of the right cervical sympathetic chain ganglion secondary to the hematoma is a more plausible explanation for the right hand digit cyanosis 6–7 . The patient was also taking low‐dose aspirin.…”

“…[3][4][5] Recall the physiology of the to the hematoma is a more plausible explanation for the right hand digit cyanosis. [6][7] The patient was also taking low-dose aspirin. There have been only a few cases of spontaneous spinal epidural hematoma reported in patients taking aspirin.…”