Virtual leak channels modulate firing dynamics and synaptic integration in rat sympathetic neurons: implications for ganglionic transmission in vivo

Abstract

Key pointsr The synaptic organization of paravertebral sympathetic ganglia enables them to relay activity from the spinal cord to the periphery and thereby control autonomic functions, including blood pressure and body temperature.r The present experiments were done to reconcile conflicting observations in tissue culture, intact isolated ganglia and living animals. By recording intracellularly from dissociated neurons and intact ganglia, we found that when electrode damage makes cells leaky it could profoundly distort cellular excitability and the integration of synaptic potentials.r The experiments relied on the dynamic clamp method, which allows the creation of virtual ion channels by injecting current into a cell based upon a mathematical model and using rapid feedback between the model and cell.r The results support the hypothesis that sympathetic ganglia can produce a 2.4-fold amplification of presynaptic activity. This could aid understanding of the neural hyperactivity that is believed to drive high blood pressure in some patients. AbstractThe excitability of rat sympathetic neurons and integration of nicotinic EPSPs were compared in primary cell culture and in the acutely isolated intact superior cervical ganglion using whole cell patch electrode recordings. When repetitive firing was classified by Hodgkin's criteria in cultured cells, 18% displayed tonic class 1 excitability, 36% displayed adapting class 2 excitability and 46% displayed phasic class 3 excitability. In the intact ganglion, 71% of cells were class 1 and 29% were class 2. This diverges from microelectrode reports that nearly 100% of superior cervical ganglion neurons show phasic class 3 firing. The hypothesis that the disparity between patch and microelectrode data arises from a shunt conductance was tested using the dynamic clamp in cell culture. Non-depolarizing shunts of 3-10 nS converted cells from classes 1 and 2 to class 3 dynamics with current-voltage relations that replicated microelectrode data. Primary and secondary EPSPs recorded from the intact superior cervical ganglion were modelled as virtual synapses in cell culture using the dynamic clamp. Stimulating sympathetic neurons with virtual synaptic activity, designed to replicate in vivo recordings of EPSPs in muscle vasoconstrictor neurons, produced a 2.4-fold amplification of presynaptic activity. This gain in postsynaptic output did not differ between neurons displaying the three classes of excitability. Mimicry of microelectrode damage by virtual leak channels reduced and eventually obliterated synaptic gain by inhibiting summation of subthreshold EPSPs. These results provide a framework for interpreting sympathetic activity recorded from intact animals and support the hypothesis that paravertebral ganglia function as activity-dependent amplifiers of spinal output from preganglionic circuitry.

Changes in excitability and ion channel expression in neurons of the major pelvic ganglion in female type II diabetic mice

“…The most salient of these properties was the increase of the probability of firing 2 or more spikes. As shown in Figure 3A and also previously documented (Suzuki and Rogawski 1989; Tompkins et al 2013), MPG neurons can spike once or many times, a phenomena observed in many other autonomic neuron types (Cassell et al 1986; Malin and Nerbonne 2001; Springer et al 2015). One obvious possible mechanism for generating multiple spikes is the activation of a depolarizing current with somewhat slower kinetics that can maintain depolarization above threshold to allow for the generation of multiple spikes.…”

Fifty years of microneurography: learning the language of the peripheral sympathetic nervous system in humans

“…The ganglia are proposed to exhibit the ability to amplify the preganglionic signal by distributing axons that produce suprathreshold (i.e., "strong") excitatory postsynaptic potentials from one preganglionic to multiple (e.g., 2-15) postganglionic neurons (Bahr et al 1986;Jänig and Häbler 2000;McLachlan 2003;Purves et al 1986;Wang et al 1995). Furthermore, computational and advanced dynamic clamping methods (Horn and Kullmann 2007;Rimmer and Horn 2010;Springer et al 2015) suggest the ability to enhance the firing probabilities of any postganglionic neuron through convergent synapses from multiple preganglionic neurons that individually produce subthreshold excitatory postsynaptic potentials but, depending on their timing, could summate to cause a postganglionic discharge. How these concepts apply to different ganglia or postganglionic axons of varying size and/or varying targets, or in human ganglia, remain to be studied.…”

The role of the paravertebral ganglia in human sympathetic neural discharge patterns

“…Also, patterns of pre‐to‐post ganglionic convergent innervation have been observed in rodent and amphibian models (Rimmer & Horn, ; Springer et al . ). As the degree of convergence appears to scale with neuron size in mammals (Purves & Lichtman, ; Purves et al .…”