Hypotonic exposure enhances synaptic transmission and triggers spreading depression in rat hippocampal tissue slices

doi:10.1016/0006-8993(95)00778-O

Brain Research

Volume 695, Issue 2, 16 October 1995, Pages 203-216

https://doi.org/10.1016/0006-8993(95)00778-O Get rights and content

Abstract

Low extracellular osmotic pressure (π_o) is known to enhance CNS resposiveneess and the chance of seizures, but the mechanism of the hyperexcitability is not clear. We recorded evoked potentials in st. radiatum and st. pyramidale of CA1. Tissue electrical resistance (R_o) was determined from the voltage drop (V_Ro) evoked by constant current pulses. Lowering of π_o by reducing [NaCl] caused a concentration-dependent increase of amplitude and duration of extracellular excitatory postsynaptic potentials (fEPSPs). fEPSPs increased much more than didV_Ro, but antiddromic population spikes increased in proportion toV_Ro. fEPSP increased also in isosmotic low NaCl (fructose or mannitol substituted) olutions, but not as much as in low π_o. In moderately hypotonic solutions orthodromic population spikes increased as expected from the augmented fEPSP, but in strong hypotonia input-output curves shifted to the left and single stimuli evoked multiple population spikes, indicating lowering of threshold of postsynaptic neurons. Blocking N-methyl-d-aspartate (NMDA) receptors did not diminish the enhancement of fEPSP amplitude. Spreading depression (SD) erupted in most slices in very low π_o, but not in isosmotic low [NaCl] solutions. We conclude that the hypotonic enhancement of EPSPs depends, in part, on the lowering of [Na⁺]_o and/or of [Cl⁻]_o, and it may be augmented by dendritic swelling favoring electrotonic spread of EPSPs from dendrites to somata, and buildup of transmitter concentration due to swelling of perisynaptic glia. SD can be initiated by cell swelling, but the depolarization associated with SD is probably not caused by the opening of stretch-gated ion channels.

Reference (53)

AitkenP.G.
Kainic acid and penicillin: differential effects on excitatory and inhibitory interactions in the CA1 region of the hippocampal slice
Brain Res.
(1985)
AitkenP.G. et al.
NMDA antagonists: lack of protective effect against hypoxic damage in CA1 region of hippocampal slices
Neurosci. Lett.
(1988)
AndrewR.D.
Seizure and acute osmotic change: clinical and neurophysiological aspects
J. Neurol. Sci.
(1991)
AndrewR.D. et al.
Seizure susceptibility and the osmotic state
Brain Res.
(1989)
AndrewR.D. et al.
Imaging cell volume changes and neuronal excitation in the hippocampal slice
Neuroscience
(1994)
ArieffA.I. et al.
Effects on the central nervous system of hypernatremic and hyponatremic states
Kidney Int.
(1976)
BalestrinoM. et al.
The effects of moderate changes of extracellular K⁺ and Ca²⁺ on synaptic and neural function in the CA1 region of the hippocampal slice
Brain Res.
(1986)
CzéhG. et al.
Membrane currents in CA1 hippocampal cells during spreading depression (SD) and SD-like hypoxic depolarization
Brain Res.
(1993)
DudekF.E. et al.
Osmolality-induced changes in extracellular volume alter epileptiform bursts independently of chemical synapses in the rat: importance of non-synaptic mechanisms in hippocampal epileptogenesis
Neurosci. Lett.
(1990)
HerrerasO. et al.
Analysis of potential shifts associated with recurrent spreading depression and prolonged unstable SD induced by microdialysis of elevated K+ in hippocampus of anesthetized rats
Brain Res.
(1993)

HoeltzellP.B. et al.

Conductivity in the somatosensory cortex of the cat — Evidence for cortical anisotropy

Brain Res.

(1979)

HuangR. et al.

The extent and mechanism of the loss of function caused by strongly hypotonic solutions in rat hippocampal tissue slices

Brain Res.

(1995)

KimelbergH.K. et al.

Swelling-induced changes in electrophysiological properties of cultured astrocytes and oligodendrocytes. II. Whole-cell currents

Brain Res.

(1990)

KimelbergH.K. et al.

Swelling-induced changes in electrophysiological properties of cultured astrocytes and oligodendrocytes. I. Effects on membrane potentials, input impedance and cell-cell coupling

Brain Res.

(1990)

KonnerthA. et al.

Effects of GABA on presumed presynaptic calcium entry in hippocampal slices

Brain Res.

(1983)

NicholsonC. et al.

Diffusion from an iontophoretic point source in the brain: role of tortuosity and volume fraction

Brain Res.

(1979)

RosenA.S. et al.

Osmotic effects upon excitability in rat neocortical slices

Neuroscience

(1990)

RothmanS.M. et al.

Excitotoxicity and the NMDA receptor

Trends Neurosci.

(1987)

SomjenG.G. et al.

Channel shutdown: a response of hippocampal neurons to adverse environments

Brain Res.

(1993)

TraynelisS.F. et al.

Modification of potassium-induced interictal bursts and electrographic seizures by divalent cations

Neurosci. Lett.

(1989)

YoungJ.N. et al.

Suppression of presynaptic calcium currents by hypoxia in hippocampal tissue slices

Brain Res.

(1992)

AndersenP. et al.

Mode of activation of hippocampal pyramidal cells by excitatory synapses on dendrites

Exp. Brain Res.

(1966)

BakerL.E. et al.

Factors affecting the measurement of current density distribution of living tissue

BalestrinoM.

Studies on anoxic depolarization

BallykB.A. et al.

Osmotic effects on the CA1 neuronal population in hippocampal slices with special reference to glucose

J. Neurophysiol.

(1991)

BenoitP.R. et al.

Modification of transmitter release by ions which prolong the presynaptic action potential

J. Physiol.

(1970)

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¹: Present address: Department of Pharmacology, Federal University of Rio de Janeiro, Cidade Universitária, 21949 Rio de Janeiro, RJ, Brazil.

²: Present address: Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.

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Hypotonic exposure enhances synaptic transmission and triggers spreading depression in rat hippocampal tissue slices

Abstract

Brain Res.

Neurosci. Lett.

J. Neurol. Sci.

Brain Res.

Neuroscience

Kidney Int.

Brain Res.

Brain Res.

Neurosci. Lett.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Neuroscience

Trends Neurosci.

Brain Res.

Neurosci. Lett.

Brain Res.

Mode of activation of hippocampal pyramidal cells by excitatory synapses on dendrites

Exp. Brain Res.

Factors affecting the measurement of current density distribution of living tissue

Studies on anoxic depolarization

Osmotic effects on the CA1 neuronal population in hippocampal slices with special reference to glucose

J. Neurophysiol.

Modification of transmitter release by ions which prolong the presynaptic action potential

J. Physiol.