Cardiovascular Research

Extracellular sodium modulates the excitability of cultured hippocampal pyramidal cells.

Authors: Xianghong Arakaki|||Hailey Foster|||Lei Su|||Huy Do|||Andrew J Wain|||Alfred N Fonteh|||Feimeng Zhou|||Michael G Harrington

Affiliations: + Expand

Abstract

Recent studies demonstrated a photophobia mechanism with modulation of nociceptive, cortico-thalamic neurons by retinal ganglion cell projections; however, little is known about how their neuronal homeostasis is disrupted. Since we have found that lumbar cerebrospinal fluid (CSF) sodium increases during migraine and that cranial sodium increases in a rat migraine model, the purpose of this study was to examine the effects of extracellular sodium ([Na(+)](o)) on the intrinsic excitability of hippocampal pyramidal neurons. We monitored excitability by whole cell patch using a multiplex micropipette with a common outlet to change artificial CSF (ACSF) [Na(+)](o) at cultured neurons accurately (SD<7 mM) and rapidly (<5s) as determined by a sodium-selective micro-electrode of the same size and at the same location as a neuronal soma. Changing [Na(+)](o) in ACSF from 100 to 160 mM, choline-balanced at 310-320 mOsm, increased the action potential (AP) amplitude, decreased AP width, and augmented firing rate by 28%. These effects were reversed on returning the ACSF [Na(+)](o) to 100mM. Testing up to 180 mM [Na(+)](o) required ACSF with higher osmolarity (345-355 mOsm), at which the firing rate increased by 36% between 100 and 180 mM [Na(+)](o), with higher amplitude and narrower APs. In voltage clamp mode, the sodium and potassium currents increased significantly at higher [Na(+)](o). These results demonstrate that fluctuations in [Na(+)](o) modulate neuronal excitability by a sodium current mechanism and that excessively altered neuronal excitability may contribute to hypersensitivity symptoms.

---

Chemical List

Sodium

---

Reference List

Agata N, Tanaka H, Shigenobu K. Effects of tetrodotoxin and low-sodium on action potential plateau of ventricular myocardium from neonatal and adult guinea-pigs. Comp Biochem Physiol Comp Physiol. 1994;107:459–61.|||Alkondon M, Pereira EF, Cortes WS, Maelicke A, Albuquerque EX. Choline is a selective agonist of alpha7 nicotinic acetylcholine receptors in the rat brain neurons. Eur J Neurosci. 1997;9:2734–42.|||Alshuaib WB, Hasan SM, Cherian SP, Mathew MV, Hasan MY, Fahim MA. Reduced potassium currents in old rat CA1 hippocampal neurons. J Neurosci Res. 2001;63:176–84.|||Amir R, Michaelis M, Devor M. Membrane potential oscillations in dorsal root ganglion neurons: role in normal electrogenesis and neuropathic pain. J Neurosci. 1999;19:8589–96.|||Azouz R, Alroy G, Yaari Y. Modulation of endogenous firing patterns by osmolarity in rat hippocampal neurones. J Physiol. 1997;502(Pt 1):175–87.|||Carriere JL, El-Fakahany EE. Choline is a full agonist in inducing activation of neuronal nitric oxide synthase via the muscarinic M1 receptor. Pharmacology. 2000;60:82–9.|||Costa LG, Murphy SD. Interaction of choline with nicotinic and muscarinic cholinergic receptors in the rat brain in vitro. Clin Exp Pharmacol Physiol. 1984;11:649–54.|||Evans MS, Collings MA, Brewer GJ. Electrophysiology of embryonic, adult and aged rat hippocampal neurons in serum-free culture. J Neurosci Methods. 1998;79:37–46.|||Filippov V, Krishtal O. The mechanism gated by external potassium and sodium controls the resting conductance in hippocampal and cortical neurons. Neuroscience. 1999;92:1231–42.|||Forsythe ID, Redman SJ. The dependence of motoneurone membrane potential on extracellular ion concentrations studied in isolated rat spinal cord. J Physiol. 1988;404:83–99.|||Fowler JC. Choline substitution for sodium triggers glutamate and adenosine release from rat hippocampal slices. Neurosci Lett. 1995;197:97–100.|||Harrington MG, Fonteh AN, Biringer RG, AF RH, Cowan RP. Prostaglandin D synthase isoforms from cerebrospinal fluid vary with brain pathology. Dis Markers. 2006a;22:73–81.|||Harrington MG, Fonteh AN, Cowan RP, Perrine K, Pogoda JM, Biringer RG, Huhmer AF. Cerebrospinal fluid sodium increases in migraine. Headache. 2006b;46:1128–35.|||Harrington MG, Chekmenev EY, Schepkin V, Fonteh AN, Arakaki X. Sodium MRI in a rat migraine model and a NEURON simulation study support a role for sodium in migraine. Cephalalgia. 2011 In press.|||Hess D, Nanou E, El Manira A. Characterization of Na+-activated K+ currents in larval lamprey spinal cord neurons. J Neurophysiol. 2007;97:3484–93.|||Hodgkin AL, Katz B. The effect of sodium ions on the electrical activity of giant axon of the squid. J Physiol. 1949;108:37–77.|||Hodgkin AL. The Ionic Basis of Nervous Conduction. Science. 1964;145:1148–54.|||Hoener MC. Role played by sodium in activity-dependent secretion of neurotrophins - revisited. Eur J Neurosci. 2000;12:3096–106.|||Huxley AF, Stampfli R. Effect of potassium and sodium on resting and action potentials of single myelinated nerve fibers. J Physiol. 1951;112:496–508.|||Huxley AF. Excitation and Conduction in Nerve: Quantitative Analysis. Science. 1964;145:1154–9.|||Johnston JK, Freeman DE, Gillette D, Soma LR. Effects of superoxide dismutase on injury induced by anoxia and reoxygenation in equine small intestine in vitro. Am J Vet Res. 1991;52:2050–4.|||Kobayashi M, Irisawa H. Effect of Sodium Deficiency on the Action Potential of the Smooth Muscle of Ureter. Am J Physiol. 1964;206:205–10.|||Kunkler PE, Kraig RP. Hippocampal spreading depression bilaterally activates the caudal trigeminal nucleus in rodents. Hippocampus. 2003;13:835–44.|||Kuo CC, Liao SY. Facilitation of recovery from inactivation by external Na+ and location of the activation gate in neuronal Na+ channels. J Neurosci. 2000;20:5639–46.|||Matzner O, Devor M. Na+ conductance and the threshold for repetitive neuronal firing. Brain Res. 1992;597:92–8.|||Matzner O, Devor M. Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na+ channels. J Neurophysiol. 1994;72:349–59.|||Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, Burstein R. A neural mechanism for exacerbation of headache by light. Nat Neurosci. 2010;13:239–45.|||Pantoni L, Lamassa M, Inzitari D. Transient global amnesia: a review emphasizing pathogenic aspects. Acta Neurol Scand. 2000;102:275–83.|||Seyama I, Irisawa H. The effect of high sodium concentration on the action potential of the skate heart. J Gen Physiol. 1967;50:505–17.|||Shah MM, Javadzadeh-Tabatabaie M, Benton DC, Ganellin CR, Haylett DG. Enhancement of hippocampal pyramidal cell excitability by the novel selective slow-afterhyperpolarization channel blocker 3-(triphenylmethylaminomethyl)pyridine (UCL2077) Mol Pharmacol. 2006;70:1494–502.|||Stinner B, Krohn E, Gebhard MM, Bretschneider HJ. Intracellular sodium activity and Bretschneider’s cardioplegia: continuous measurement by ion-selective microelectrodes at initial equilibration. Basic Res Cardiol. 1989;84:197–207.|||Stracciari A, Fonti C, Guarino M. When the past is lost: focal retrograde amnesia. Focus on the “functional” form. Behav Neurol. 2008;20:113–25.|||Xing C, Yin Y, He X, Xie Z. Effects of insulin-like growth factor 1 on voltage-gated ion channels in cultured rat hippocampal neurons. Brain Res. 2006;1072:30–5.|||Xu T, Gregory CA, Molnar P, Cui X, Jalota S, Bhaduri SB, Boland T. Viability and electrophysiology of neural cell structures generated by the inkjet printing method. Biomaterials. 2006;27:3580–8.|||Xu T, Molnar P, Gregory C, Das M, Boland T, Hickman JJ. Electrophysiological characterization of embryonic hippocampal neurons cultured in a 3D collagen hydrogel. Biomaterials. 2009;30:4377–83.