Neurons from neonatal hypertensive rats exhibit abnormal membrane properties in vitro

Jubelin, Bruno; Kannan, Mathur

doi:10.1152/ajpcell.1990.259.3.c389

Cited by 23 publications

(9 citation statements)

References 21 publications

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“…Previous work in the SHR model has reported repetitive firing in neurons of the SCG. 13 , 14 , 30 Support for the role for K Ca currents was based upon increased firing rate following K Ca reduction using the SK inhibitor apamin or nonselective K + channel inhibitor Tetraethylammonium. 14 Similarly, we report a role for SK calcium-activated channels in fine-tuning SHR stellate neuron firing rates, as shown by the increased firing rate after apamin inhibition of SK channels (Figure S2), although our data suggest that this is not a disease causative mechanism.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of M Current Is Coupled to Membrane Excitability in Sympathetic Neurons Before the Onset of Hypertension

2020

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Neurohumoral activation is an early hallmark of cardiovascular disease and contributes to the etiology of the pathophysiology. Stellectomy has reemerged as a positive therapeutic intervention to modify the progression of dysautonomia, although the biophysical properties underpinning abnormal activity of this ganglia are not fully understood in the initial stages of the disease. We investigated whether stellate ganglia neurons from prehypertensive SHRs (spontaneously hypertensive rats) are hyperactive and describe their electrophysiological phenotype guided by singlecell RNA sequencing, molecular biology, and perforated patch clamp to uncover the mechanism of abnormal excitability. We demonstrate the contribution of a plethora of ion channels, in particular inhibition of M current to stellate ganglia neuronal firing, and confirm the conservation of expression of key ion channel transcripts in human stellate ganglia. We show that hyperexcitability was curbed by M-current activators, nonselective sodium current blockers, or inhibition of Na v 1.1-1.3, Na v 1.6, or I NaP . We conclude that reduced activity of M current contributes significantly to abnormal firing of stellate neurons, which, in part, contributes to the hyperexcitability from rats that have a predisposition to hypertension. Targeting these channels could provide a therapeutic opportunity to minimize the consequences of excessive sympathetic activation.

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Section: Discussionmentioning

confidence: 99%

“…Early work has reported enhanced electrical excitability in another sympathetic ganglia (superior cervical ganglia [SCG]) in the SHR (spontaneously hypertensive rat), although conflicting reports suggest the neural phenotype might be related to changes in either K Ca or A-type potassium current. 13 , 14 …”

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Downregulation of M Current Is Coupled to Membrane Excitability in Sympathetic Neurons Before the Onset of Hypertension

2020

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“…However these channels make a small contribution to the nicotinic-evoked ganglionic action potential [53]. More importantly, a lack of this conductance in SCG neurons from SHR has been reported [54]; therefore, it is more likely that bicuculline action is limited to GABA-A receptor blockade.…”

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confidence: 99%

Ganglionic Long-Term Potentiation in Prehypertensive and Hypertensive Stages of Spontaneously Hypertensive Rats Depends on GABA Modulation

2019

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The sympathetic nervous system (SNS) regulates body functions in normal and pathological conditions and is characterized by the presence of a neuroplastic phenomenon, termed ganglionic long-term potentiation (gLTP). In hypertension, either in spontaneously hypertensive rats (SHR) or in humans, sympathetic hyperfunction, such as elevated SNS outflow and changes in synaptic plasticity have been described. Because enhanced SNS outflow is detected in the hypertensive stage and, more importantly, in the prehypertensive phase of SHR, here we explored whether synaptic plasticity, particularly gLTP, was modified in the superior cervical ganglia (SCG) of prehypertensive SHR. Furthermore, considering that GABA modulates sympathetic synaptic transmission and gLTP in Wistar rats, we studied whether GABA might modulate gLTP expression in SHR. We characterized gLTP in the SCG of young prehypertensive 6-week-old (wo) and adult hypertensive (12 wo) SHR and in the SCG of Wistar Kyoto (WKy) normotensive control rats of the same ages. We found that gLTP was expressed in 6 wo SHR, but not in 12 wo rats. By contrast, in WKy, gLTP was expressed in 12 wo, but not in 6 wo rats. We also found that gLTP depends on GABA modulation, as blockade of GABA-A subtype receptors with its antagonist bicuculline unmasked gLTP expression in adult SHR and young WKy. We propose that (1) activity-dependent changes in synaptic efficacy are altered not only during hypertension but also before its onset and (2) GABA may play a modulatory role in the changes in synaptic plasticity in SHR, because the blockade of GABA-A receptors unmasked the expression of gLTP. These early changes in neuroplasticity and GABA modulation of gLTP could be part of the sympathetic hyperfunction observed in hypertension.

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“…For example, spike accommodation is compromised in adult and neonatal superior cervical ganglion (SCG) neurons from SHR. 9 - 10 In addition, an increase in the stimulation-induced release of, and a hyperresponsiveness to, norepinephrine exist at the SHR sympathetic neuroeffector junction. 1112 Alterations in the concentration and turnover of catecholamines in many central cardiovascular areas and sympathetic ganglia have also been observed in SHR.…”

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“…Ganglia from SHR have been shown to possess a hyperexcitable membrane, 9 -10 decreased concentrations of the inhibitory transmitter dopamine, and an increased production of catecholamines in response to cholinergic stimulation. 41416 Thus, both membrane alterations and synaptic modifications have been observed in these ganglia; however, the effects of these alterations on transmission of neuronal activity through sympathetic ganglia have not been conclusively established.…”

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Neurotransmission through sympathetic ganglia of spontaneously hypertensive rats.

Magee

Schofield

1992

Hypertension

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Transmission of neuronal activity was assessed by recording preganglionic and postganglionic compound action potentials in superior cervical ganglia isolated from adult spontaneously hypertensive rats (SHR), Wlstar-Kyoto (WKY) rats, and Wistar rats as well as young SHR and WKY rats to determine if previously observed alterations of membrane excitability, synaptic transmission, or both, have an effect on the transmission of preganglionic activity in SHR. Single stimuli induced more postganglionic neurons to fire over a wide range of preganglionic stimulation intensities in superior cervical ganglia from adult SHR as compared with those from adult normotensive controls. Short stimulation trains confirmed that SHR are able to maintain this greater number of active postganglionic neurons during low-frequency stimulation (1-20 Hz). However, by the end of a train of high-frequency stimulation (70-100 Hz) fewer neurons fired in ganglia from SHR compared with those from normotensive controls. These differences in transmission were not observed in the young rats. The results from the present study demonstrate that physiological frequencies of preganglionic activity are more effectively transmitted through sympathetic ganglia from adult SHR compared with those from normotensive controls, and this enhanced transmission through ganglia may contribute to the elevated sympathetic activity and the consequent hypertension seen in this model. (Hypertension 1992;2(h367-373) KEY WORDS • ganglia, sympathetic • hypertension, essential • sympathetic nervous system • rats, inbred SHR A enhanced basal and environmentally evoked sympathetic nerve activity (SNA) has been implicated in the development and maintenance of the hypertension observed in experimental animal models such as the spontaneously hypertensive rat (SHR) as well as in essential hypertension itself. In support of this hypothesis, increased plasma catecholamine and dopamine-0-hydroxylase activity, 1 enhanced SNA response to hypothalamic stimulation," increased cyclic nucleotide levels in sympathetic ganglia, 4 sympathetic hyperreactivity to stressful stimuli, 5 -6 and direct recordings of exaggerated basal SNA have been reported in SHR. -8The neuronal alterations responsible for the enhanced SNA observed in SHR are still under study. The elevation of SNA could be the manifestation of an intrinsic membrane alteration that elevates the firing frequency of sympathetic neurons or of a modification in synaptic transmission that increases the probability of postsynaptic action potential generation, or both. For example, spike accommodation is compromised in adult and neonatal superior cervical ganglion (SCG) neurons from SHR. -10 In addition, an increase in the stimulation-induced release of, and a hyperresponsiveness to, From the Department of Physiology, Tulane University Medical School, New Orleans, La.Supported by grant HL-43656 from the National Heart, Lung, and Blood Institute, National Institutes of Health.Address for correspondence: Dr. Geoffrey G. Schofield, Departm...

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Neurons from neonatal hypertensive rats exhibit abnormal membrane properties in vitro

Cited by 23 publications

References 21 publications

Downregulation of M Current Is Coupled to Membrane Excitability in Sympathetic Neurons Before the Onset of Hypertension

Downregulation of M Current Is Coupled to Membrane Excitability in Sympathetic Neurons Before the Onset of Hypertension

Ganglionic Long-Term Potentiation in Prehypertensive and Hypertensive Stages of Spontaneously Hypertensive Rats Depends on GABA Modulation

Neurotransmission through sympathetic ganglia of spontaneously hypertensive rats.

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