The role of glial membrane ion channels in seizures and epileptogenesis

doi:10.1016/j.pharmthera.2004.05.004

Pharmacology & Therapeutics

Volume 103, Issue 2, August 2004, Pages 95-108

https://doi.org/10.1016/j.pharmthera.2004.05.004 Get rights and content

Abstract

Epilepsy is one of the most common neurological disorders, but the cellular basis of human epilepsy remains largely a mystery, and about 30% of all epilepsies remain uncontrolled. The vast bulk of epilepsy research has focused on neuronal and synaptic mechanisms, but the hypersynchronous firing that is the hallmark of epilepsy could also result from the abnormal function of glial cells by virtue of their critical role in the homeostasis of the brain's extracellular milieu. Therefore, increasing our understanding of glial pro-epileptic and epileptogenic mechanisms holds promise for the development of improved pharmacological treatments for epilepsy. Reactive astrocytes, a prominent feature of the human epileptic brain, undergo changes in their membrane properties and electrophysiology, in particular in the expression of membrane K⁺ and Na⁺ channels, which result in pro-epileptic changes in their homeostatic control of the extracellular space. Nonetheless, a causal role for reactive astrocytosis in epilepsy has been difficult to determine because glial reactivity can be induced by a wide range of central nervous system insults, including epileptic seizures themselves. A complicating factor is that different insults to the central nervous system result in reactive astrocytes with different membrane properties. Therefore, most animal models of epilepsy preselect the properties of the reactive glia studied. Finally, a causal role for reactive glia in epilepsy cannot be firmly established by examining human epileptic tissue because of its chronic and pharmacoresistant pathological condition that warranted the surgical intervention. Therefore, the development of clinically relevant models of reactive astrocytosis, and of symptomatic epileptogenesis, is needed to investigate the issue. A recently developed model of post-traumatic epileptogenesis in the rat, where chronic spontaneous recurrent seizures develop after a single event of a clinically relevant form of closed head injury, the fluid percussion injury, offers hope to help understand the role of reactive glia in seizures and epileptogenesis and lead to the development of improved therapies.

Section snippets

Why study glial cells in epilepsy?

Epilepsy is one of the most common neurological disorders affecting about 4% of individuals over their lifetimes (Browne & Holmes, 2001). Despite progress in understanding the pathogenesis of experimental seizures and epilepsy, the cellular basis of human epilepsy remains, for the large part, a mystery (McNamara, 1999). In the absence of a specific etiological understanding, drug therapy of epilepsy is directed at the control of symptoms, i.e. the suppression of seizures by chronic

Reactive gliosis in epilepsy

Virtually all insults to the central nervous system (CNS) have a feature in common: reactive gliosis. Glial reactivity—as defined by the occurrence of active cytological, immunological, morphological or functional response of glial cells to CNS insults—is thought to promote the functionally important processes of inflammation and tissue repair and participate in glial scar formation (“reactive gliosis”), which occurs after injury to the CNS Penfield, 1929, Reier, 1986. However, the role of

Potassium channels and extracellular potassium homeostasis

During neuronal activity, the extruded K⁺ accumulates in the extracellular space. Since [K⁺]_o is much smaller than its intracellular concentrations, even modest increase in [K⁺]_o results in a significant dissipation of the K⁺ gradient across cell membranes. Since neuronal excitability depends in a critical manner on the resting membrane potential and on inhibitory postsynaptic potentials, which depend on membrane K⁺ gradient, [K⁺]_o has to be finely and effectively regulated. K⁺ cannot be

Sodium channels and sodium/potassium pump

Membrane Na⁺ permeability of glial cells may play an important role in neuronal excitability and seizure precipitation because a number of glial membrane homeostatic mechanisms rely on [Na⁺]_i to function. The Na⁺/K⁺ pump, for example, is the housekeeper of ion gradients across all cell membranes since it sets the main gradients for Na⁺ and K⁺ that are then used by a variety of ion channels, cotransporters, and exchangers for their activity. The pump's activity is modulated by [Na⁺]_i and [K⁺]_o

The need for clinically relevant models of reactive glia

A variety of animal models of epilepsy have been used to study reactive gliosis and investigate its possible role in seizure precipitation and epileptogenesis. For example, kindling-induced seizures have been shown to result in astrogliosis that takes place early in the development of kindling, intensifies during the following weeks, and persists for long periods (Steward et al., 1991). In the kindling model, astrogliosis is confined to the stimulated and seizure propagating brain regions, such

Conclusions

Numerous changes in membrane ion channel expression of reactive astrocytes have been identified that can be considered pro-epileptic, but specific features of the pathophysiology of glial cells responsible for the onset of chronic seizures have not been identified. However, very little work has been done to understand which changes are the simple consequence of chronic seizures and which ones may actually be the cause. Therefore, much work still needs to be done to elucidate the basic glial

Acknowledgements

This work was supported by the NIH (grant NS 40823).

References (101)

S.R. Benbadis et al.
Epilepsy surgery, delays and referral patterns—are all your epilepsy patients controlled?
Seizure
(2003)
A. Bordey et al.
Properties of human glial cells associated with epileptic seizure foci
Epilepsy Res
(1998)
H. Brew et al.
Is the potassium channel distribution in glial cells optimal for spatial buffering of potassium?
Biophys J
(1985)
D.M. Burnard et al.
Electrophysiological properties of reactive glial cells in the kainate-lesioned hippocampal slice
Brain Res
(1990)
D.B. Clifford et al.
The functional anatomy and pathology of lithium-pilocarpine and high-dose pilocarpine seizures
Neuroscience
(1987)
M.A. Dichter et al.
Silent cells during interictal discharges and seizures in hippocampal penicillin foci. Evidence for the role of extracellular K⁺ in the transition from the interictal state to seizures
Brain Res
(1972)
F.L. Glötzner
Membrane properties of neuroglia in epileptogenic gliosis
Brain Res
(1973)
R. Jabs et al.
Qualitative analysis of membrane currents in glial cells from normal and gliotic tissue in situ: down-regulation of Na+ current and lack of P2 purinergic responses
Neuroscience
(1997)
R. Jauch et al.
Effects of barium, furosemide, ouabaine and 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) on ionophoretically-induced changes in extracellular potassium concentration in hippocampal slices from rats and from patients with epilepsy
Brain Res
(2002)
H. Köller et al.
Time course of inwardly rectifying K⁺ current reduction in glial cells surrounding ischemic brain lesions
Brain Res
(2000)

W. Löscher et al.

New horizons in the development of antiepileptic drugs

Epilepsy Res

(2002)

E. Matyja

Morphologic evidence of a primary response of glia to kainic acid administration into the rat neostriatum; studied in vivo and in vitro

Exp Neurol

(1986)

T.K. McIntosh et al.

Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model

Neuroscience

(1989)

S. Murphy et al.

Astrocytes have both M1 and M2 muscarinic receptor subtypes

Brain Res

(1986)

N. Mutsuga et al.

The contribution of local blood flow to the rapid clearance of potassium from the cortical extracellular space

Brain Res

(1976)

P.J. Reier

Gliosis following CNS injury: the anatomy of astrocytic scars and their influences on axonal elongation

G. Schneider et al.

Pathophysiological changes after traumatic brain injury: comparison of two experimental animal models by means of MRI

MAGMA

(2002)

W. Schroder et al.

AMPA receptor-mediated modulation of inward rectifier K⁺ channels in astrocytes of mouse hippocampus

Mol Cell Neurosci

(2002)

C. Steinhauser et al.

Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity

Eur J Pharmacol

(2002 Jul 5)

H. Sontheimer et al.

Channel expression correlates with differentiation stage during development of oligodendrocytes from their precursor cells in culture

Neuron

(1989)

W. Walz

Role of astrocytes in the clearance of excess extracellular potassium

Neurochem Int

(2000)

S.M. Ahmed et al.

Stretch-induced injury alters mitochondrial membrane potential and cellular ATP in cultured astrocytes and neurons

J Neurochem

(2000)

K.H. Backus et al.

Pharmacological characterization of the glutamate receptor in cultured astrocytes

J Neurosci Res

(1989)

K. Ballanyi et al.

Intracellular Na⁺ activity in cultured mouse oligodendrocytes

J Neurosci Res

(1990)

K. Ballanyi et al.

Ion activities and potassium uptake mechanisms of glial cells in guinea-pig olfactory cortex slices

J Physiol

(1987)

L.K. Bekar et al.

Intracellular chloride modulates A-type potassium currents in astrocytes

Glia

(2002)

A. Bordey et al.

Reactive astrocytes show enhanced inwardly rectifying K⁺ currents in situ

NeuroReport

(2000)

A. Bordey et al.

Electrophysiological characteristics of reactive astrocytes in experimental cortical dysplasia

J Neurophys

(2001)

C.L. Bowman et al.

Excitatory amino acids directly depolarize rat brain astrocytes in primary culture

Nature

(1984)

A. Bringmann et al.

Role of glial K⁺ channels in ontogeny and gliosis: a hypothesis based upon studies on Müller cells

Glia

(2000)

T.R. Browne et al.

Epilepsy

N Engl J Med

(2001)

J.Y. Chatton et al.

A quantitative analysis of l-glutamate-regulated Na⁺ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics

Eur J Neurosci

(2000)

Y. Chen et al.

Astrocytes and brain injury

J Cereb Blood Flow Metab

(2003)

A. Chvatal et al.

Changes in glial K⁺ currents with decreased extracellular volume in developing rat white matter

J Neurosci Res

(1997)

A. Chvatal et al.

Glial depolarization evokes a larger potassium accumulation around oligodendrocytes than around astrocytes in gray matter of rat spinal cord slices

J Neurosci Res

(1999)

R. D'Ambrosio et al.

Functional specialization and topographic segregation of hippocampal astrocytes

J Neurosci

(1998)

R. D'Ambrosio et al.

Impaired K(+) homeostasis and altered electrophysiological properties of post-traumatic hippocampal glia

J Neurosci

(1999)

R. D'Ambrosio et al.

Differential role of KIR channel and Na(+)/K(+)-pump in the regulation of extracellular K(+) in rat hippocampus

J Neurophysiol

(2002)

R. D'Ambrosio et al.

Posttraumatic epilepsy following fluid percussion injury in the rat

Brain

(2003 Nov 7)

T.E. DeCoursey et al.

Voltage-gated K⁺ channels in human T lymphocytes: a role in mitogenesis?

Nature

(1984)

I. Dietzel et al.

Relations between slow extracellular potential changes, glial potassium buffering, and electrolyte and cellular volume changes during neuronal hyperactivity in cat brain

Glia

(1989)

C.E. Dixon et al.

A fluid percussion model of experimental brain injury in the rat

J Neurosurg

(1987)

C.L. Eastman et al.

Decreased membrane permeability to potassium in frontal-parietal neocortical glia following fluid percussion injury in the rat. National Neurotrauma Society Meeting Abstract

J Neurotrauma

(2004)

E.F. Ellis et al.

A new model for rapid stretch-induced injury of cells in culture: characterization of the model using astrocytes

J Neurotrauma

(1995)

W. Feldberg et al.

Effects of calcium and potassium injected into the cerebral ventricles of the cat

J Physiol (Lond)

(1957)

C.L. Floyd et al.

Craniectomy position affects Morris water maze performance and hippocampal cell loss after parasagittal fluid percussion

J Neurotrauma

(2002)

M. Francke et al.

Loss of inwardly rectifying potassium currents by human retinal glial cells in diseases of the eye

Glia

(1997)

C.L. Garzillo et al.

Characterization of reactive astrocytes in the chronic phase of the pilocarpine model of epilepsy

Epilepsia

(2002)

M.S. Grady et al.

Neuronal and glial cell number in the hippocampus after experimental traumatic brain injury: analysis by stereological estimation

J Neurotrauma

(2003)

U. Heinemann et al.

Alterations of glial cell function in temporal lobe epilepsy

Epilepsia

(2000)

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Associate editor: M. RogawskiThe role of glial membrane ion channels in seizures and epileptogenesis

Abstract

Section snippets

Why study glial cells in epilepsy?

Reactive gliosis in epilepsy

Potassium channels and extracellular potassium homeostasis

Sodium channels and sodium/potassium pump

The need for clinically relevant models of reactive glia

Conclusions

Acknowledgements

Seizure

Epilepsy Res

Biophys J

Brain Res

Neuroscience

Brain Res

Brain Res

Neuroscience

Brain Res

Brain Res

Epilepsy Res

Exp Neurol

Neuroscience

Brain Res

Brain Res

MAGMA

Mol Cell Neurosci

Eur J Pharmacol

Neuron

Neurochem Int

Stretch-induced injury alters mitochondrial membrane potential and cellular ATP in cultured astrocytes and neurons

J Neurochem

Pharmacological characterization of the glutamate receptor in cultured astrocytes

J Neurosci Res

Intracellular Na+ activity in cultured mouse oligodendrocytes

J Neurosci Res

Ion activities and potassium uptake mechanisms of glial cells in guinea-pig olfactory cortex slices

J Physiol

Intracellular chloride modulates A-type potassium currents in astrocytes

Glia

Reactive astrocytes show enhanced inwardly rectifying K+ currents in situ

NeuroReport

Electrophysiological characteristics of reactive astrocytes in experimental cortical dysplasia

J Neurophys

Excitatory amino acids directly depolarize rat brain astrocytes in primary culture

Nature

Role of glial K+ channels in ontogeny and gliosis: a hypothesis based upon studies on Müller cells

Glia

Epilepsy

N Engl J Med

A quantitative analysis of l-glutamate-regulated Na+ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics

Eur J Neurosci

Astrocytes and brain injury

J Cereb Blood Flow Metab

Changes in glial K+ currents with decreased extracellular volume in developing rat white matter

J Neurosci Res

Glial depolarization evokes a larger potassium accumulation around oligodendrocytes than around astrocytes in gray matter of rat spinal cord slices

J Neurosci Res

Functional specialization and topographic segregation of hippocampal astrocytes

J Neurosci

Impaired K(+) homeostasis and altered electrophysiological properties of post-traumatic hippocampal glia

J Neurosci

Differential role of KIR channel and Na(+)/K(+)-pump in the regulation of extracellular K(+) in rat hippocampus

J Neurophysiol

Posttraumatic epilepsy following fluid percussion injury in the rat

Brain

Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis?

Nature

Relations between slow extracellular potential changes, glial potassium buffering, and electrolyte and cellular volume changes during neuronal hyperactivity in cat brain

Glia

A fluid percussion model of experimental brain injury in the rat

J Neurosurg

Decreased membrane permeability to potassium in frontal-parietal neocortical glia following fluid percussion injury in the rat. National Neurotrauma Society Meeting Abstract

J Neurotrauma

A new model for rapid stretch-induced injury of cells in culture: characterization of the model using astrocytes

J Neurotrauma

Effects of calcium and potassium injected into the cerebral ventricles of the cat

J Physiol (Lond)

Craniectomy position affects Morris water maze performance and hippocampal cell loss after parasagittal fluid percussion

J Neurotrauma

Associate editor: M. Rogawski
The role of glial membrane ion channels in seizures and epileptogenesis

Intracellular Na⁺ activity in cultured mouse oligodendrocytes

Reactive astrocytes show enhanced inwardly rectifying K⁺ currents in situ

Role of glial K⁺ channels in ontogeny and gliosis: a hypothesis based upon studies on Müller cells

A quantitative analysis of l-glutamate-regulated Na⁺ dynamics in mouse cortical astrocytes: implications for cellular bioenergetics

Changes in glial K⁺ currents with decreased extracellular volume in developing rat white matter

Voltage-gated K⁺ channels in human T lymphocytes: a role in mitogenesis?