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The Role of Cell Volume in the Dynamics of Seizure, Spreading Depression, and Anoxic Depolarization.

ABSTRACT: Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little of how cell volume affects neuronal dynamics. We here performed the first detailed study of the effects of cell volume on neuronal dynamics. By incorporating cell swelling together with dynamic ion concentrations and oxygen supply into Hodgkin-Huxley type spiking dynamics, we demonstrate the spontaneous transition between epileptic seizure and spreading depression states as the cell swells and contracts in response to changes in osmotic pressure. Our use of volume as an order parameter further revealed a dynamical definition for the experimentally described physiological ceiling that separates seizure from spreading depression, as well as predicted a second ceiling that demarcates spreading depression from anoxic depolarization. Our model highlights the neuroprotective role of glial K buffering against seizures and spreading depression, and provides novel insights into anoxic depolarization and the relevant cell swelling during ischemia. We argue that the dynamics of seizures, spreading depression, and anoxic depolarization lie along a continuum of the repertoire of the neuron membrane that can be understood only when the dynamic ion concentrations, oxygen homeostasis,and cell swelling in response to osmotic pressure are taken into consideration. Our results demonstrate the feasibility of a unified framework for a wide range of neuronal behaviors that may be of substantial importance in the understanding of and potentially developing universal intervention strategies for these pathological states.

SUBMITTER: Ullah G

PROVIDER: S-EPMC4537206 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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The Role of Cell Volume in the Dynamics of Seizure, Spreading Depression, and Anoxic Depolarization.

Ullah Ghanim G Wei Yina Y Dahlem Markus A MA Wechselberger Martin M Schiff Steven J SJ

PLoS computational biology 20150814 8

Cell volume changes are ubiquitous in normal and pathological activity of the brain. Nevertheless, we know little of how cell volume affects neuronal dynamics. We here performed the first detailed study of the effects of cell volume on neuronal dynamics. By incorporating cell swelling together with dynamic ion concentrations and oxygen supply into Hodgkin-Huxley type spiking dynamics, we demonstrate the spontaneous transition between epileptic seizure and spreading depression states as the cell ...[more]

PMID: 26273829

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Project description:Sudden unexpected death in epilepsy (SUDEP) is a fatal complication of epilepsy in which brainstem spreading depolarization may play a pivotal role, as suggested by animal studies. However, patiotemporal details of spreading depolarization occurring in relation to fatal seizures have not been investigated. In addition, little is known about behavioural and neurophysiological features that may discriminate spontaneous fatal from non-fatal seizures. Transgenic mice carrying the missense mutation S218L in the α1A subunit of Cav2.1 (P/Q-type) Ca2+ channels exhibit enhanced excitatory neurotransmission and increased susceptibility to spreading depolarization. Homozygous Cacna1aS218L mice show spontaneous non-fatal and fatal seizures, occurring throughout life, resulting in reduced life expectancy. To identify characteristics of fatal and non-fatal spontaneous seizures, we compared behavioural and electrophysiological seizure dynamics in freely-behaving homozygous Cacna1aS218L mice. To gain insight on the role of brainstem spreading depolarization in SUDEP, we studied the spatiotemporal distribution of spreading depolarization in the context of seizure-related death. Spontaneous and electrically-induced seizures were investigated by video monitoring and electrophysiological recordings in freely-behaving Cacna1aS218L and wild-type mice. Homozygous Cacna1aS218L mice showed multiple spontaneous tonic-clonic seizures and died from SUDEP in adulthood. Death was preceded by a tonic-clonic seizure terminating with hindlimb clonus, with suppression of cortical neuronal activity during and after the seizure. Induced seizures in freely-behaving homozygous Cacna1aS218L mice were followed by multiple spreading depolarizations and death. In wild-type or heterozygous Cacna1aS218L mice, induced seizures and spreading depolarization were never followed by death. To identify temporal and regional features of seizure-induced spreading depolarization related to fatal outcome, diffusion-weighted MRI was performed in anaesthetized homozygous Cacna1aS218L and wild-type mice. In homozygous Cacna1aS218L mice, appearance of seizure-related spreading depolarization in the brainstem correlated with respiratory arrest that was followed by cardiac arrest and death. Recordings in freely-behaving homozygous Cacna1aS218L mice confirmed brainstem spreading depolarization during spontaneous fatal seizures. These data underscore the value of the homozygous Cacna1aS218L mouse model for identifying discriminative features of fatal compared to non-fatal seizures, and support a key role for cortical neuronal suppression and brainstem spreading depolarization in SUDEP pathophysiology.

Project description:Spreading depolarization is assumed to be the mechanism of migraine with aura, which is accompanied by an initial predominant hyperaemic response followed by persistent vasoconstriction. Cerebral blood flow responses are impaired in patients and in experimental animals after spreading depolarization. Understanding the regulation of cortical blood vessels during and after spreading depolarization could help patients with migraine attacks, but our knowledge of these vascular mechanisms is still incomplete. Recent findings show that control of cerebral blood flow does not only occur at the arteriole level but also at capillaries. Pericytes are vascular mural cells that can constrict or relax around capillaries, mediating local cerebral blood flow control. They participate in the constriction observed during brain ischaemia and might be involved the disruption of the microcirculation during spreading depolarization. To further understand the regulation of cerebral blood flow in spreading depolarization, we examined penetrating arterioles and capillaries with respect to vascular branching order, pericyte location and pericyte calcium responses during somatosensory stimulation and spreading depolarization. Mice expressing a red fluorescent indicator and intravenous injections of FITC-dextran were used to visualize pericytes and vessels, respectively, under two-photon microscopy. By engineering a genetically encoded calcium indicator we could record calcium changes in both pericytes around capillaries and vascular smooth muscle cells around arterioles. We show that somatosensory stimulation evoked a decrease in cytosolic calcium in pericytes located on dilating capillaries, up to the second order capillaries. Furthermore, we show that prolonged vasoconstriction following spreading depolarization is strongest in first order capillaries, with a persistent increase in pericyte calcium. We suggest that the persistence of the 'spreading cortical oligaemia' in migraine could be caused by this constriction of cortical capillaries. After spreading depolarization, somatosensory stimulation no longer evoked changes in capillary diameter and pericyte calcium. Thus, calcium changes in pericytes located on first order capillaries may be a key determinant in local blood flow control and a novel vascular mechanism in migraine. We suggest that prevention or treatment of capillary constriction in migraine with aura, which is an independent risk factor for stroke, may be clinically useful.

Dataset Information

The Role of Cell Volume in the Dynamics of Seizure, Spreading Depression, and Anoxic Depolarization.

Publications

The Role of Cell Volume in the Dynamics of Seizure, Spreading Depression, and Anoxic Depolarization.

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