Astrocytes and Epilepsy

Epilepsy, affecting about 1% of the population, comprises a group of disorders of the brain characterized by the periodic and unpredictable occurrence of seizures. It is clear that epilepsy is a major public health problem in that those affected experience the periodic and unpredictable occurrence of seizures leading to impairment of consciousness. This handicap severely impairs the performance of many tasks and secondarily the procurement and maintenance of steady employment. Elucidating the cellular and molecular mechanisms of seizure generation may lead to novel antiepileptic drug (AED) therapies.

Figure 1. Example of seizure recorded by electroencephalography (EEG).

Most current existing AEDs act on widely expressed ion channels that directly control neuronal excitability.  For example, sodium channel blockers (e.g. phenytoin) reduce the rate and/or rise of neuronal action potentials and thus inhibit high-frequency neuronal firing.  GABA receptor agonists (e.g. phenobarbital) increase the efficacy of GABAergic synapses, thus increasing inhibitory synaptic transmission.  These existing medications have at least two major drawbacks.  First, even with optimal current AED therapy, ~30% of patients have poor seizure control and become medically refractory.  Second, as these medications act as general CNS depressants and must be taken chronically for seizure suppression, they also have marked inhibitory effects on cognition and cognitive development.

Glial cells are involved in many important physiologic functions, such as sequestration and/or redistribution of K+ during neural activity, neurotransmitter cycling, and provision of energy substrates to neurons. Several recent lines of evidence strongly suggest that glial cells are potential novel targets for epilepsy. First, many studies now link glial cells to modulation of synaptic transmission. Second, functional alterations of specific glial membrane channels and receptors have been discovered in epileptic tissue. Third, direct stimulation of astrocytes has been shown to be sufficient for neuronal synchronization in epilepsy models. Fourth, pathologic specimens from patients with temporal lobe epilepsy often demonstrate marked reactive gliosis (glial cell scarring). Thus, if the cellular and molecular mechanisms by which glial cells (especially astrocytes) modulate excitability and respond to seizure activity are better understood, specific antiepileptic therapies based selectively on modulation of glial receptors and channels that are likely to have fewer deleterious side effects can be contemplated.

Figure 2. Example of reactive changes induced in astrocytes (red) 7 days after status epilepticus.

To address these questions further, our laboratory is exploring the changes that occur in astrocytes in a common animal model of epilepsy.  Interestingly, we have found dramatic alterations in AQP4 expression during the development of epilepsy.  These findings coincide with previous evidence indicating altered seizure duration, extracellular space and potassium regulation in aquaporin-4-deficient mice and altered levels of aquaporin-4 in human temporal lobe epilepsy.  However, how the cellular expression and function of aquaporin-4 is altered during the development of epilepsy remains to be more fully elucidated.  We will be examining these and related questions in well-established animal models of epilepsy. The goal of this research is to further understand astrocyte control of water and potassium metabolism in the brain, and how it goes awry in the development of epilepsy. This could directly lead to new concepts and targets for anticonvulsant drug development that may have many fewer side effects than current therapies.