Acute Breakdown of the Glial Network in Epilepsy

The scientists’ findings were detailed in the Journal of Neuroscience; Title: “ Exacerbation of epilepsy by astrocyte alkalization and gap junction uncoupling.”

Abstract:

Seizures invite seizures. At the initial stage of epilepsy, seizures intensify with each episode; however, the mechanisms underlying this exacerbation remain to be solved. Astrocytes have a strong control over neuronal excitability and the mode of information processing. This control is accomplished by adjusting the levels of various ions in the extracellular space. The network of astrocytes connected via gap junctions allows a wider or more confined distribution of these ions depending on the open probability of the gap junctions. K+ clearance relies on the K+ uptake by astrocytes and the subsequent diffusion of K+ through the astrocyte network. When astrocytes become uncoupled, K+ clearance becomes hindered. Accumulation of extracellular K+ leads to hyperexcitability of neurons. Here, using acute hippocampal slices from mice, we uncovered that brief periods of epileptiform activity result in gap junction uncoupling. In slices that experienced short-term epileptiform activity, extracellular K+ transients in response to glutamate became prolonged. Na+ imaging with a fluorescent indicator indicated that inter-cellular diffusion of small cations in the astrocytic syncytium via gap junctions became rapidly restricted after epileptiform activity. Using a transgenic mouse with astrocyte-specific expression of a pH sensor (Lck-E2GFP), we confirmed that astrocytes react to epileptiform activity with intracellular alkalization. Application of a Na+/HCO3- co-transporter blocker led to suppression of intracellular alkalization of astrocytes and to the prevention of astrocyte uncoupling and hyperactivity intensification both in vitro and in vivo. Therefore, inhibition of astrocyte alkalization could become a promising therapeutic strategy for countering epilepsy development.

Epilepsy is a disorder characterized by neuronal hyper-excitation and a progression of seizures with each episode. Anti-epileptic drugs are mostly aimed at suppressing hyperactivity, but approximately 30% of patients worldwide show drug-resistance.

Half of the brain is occupied by non-neuronal glial cells. Astrocytes are star-shaped glial cells that are connected to each other via gap junctions. Neuronal excitation leads to potassium extrusion from neurons. The excess potassium is picked up by astrocytes and diluted in the astrocyte network. Efficacy of the potassium clearance can affect neuronal signal processing.

"Astrocytes have a strong control over neuronal activity," says professor Ko Matsui of the Super-network Brain Physiology lab at Tohoku University, who led the research. "Plasticity of the neuronal network underlies learning and memory but apparently astrocyte function is also susceptible to plastic change."

A collaborative research group led by Matsui, doctoral student Mariko Onodera and researchers at Heinrich Heine University Düsseldorf, studied the plastic change of astrocytes associated with epileptogenesis in mice.

In response to hyperactivity of the surrounding neurons, Na+/HCO3- co-transporter (NBC) in astrocytes was activated. The resulting intracellular alkalization led to gap junction uncoupling and impairment of prompt potassium clearance. Pharmacological blockade of the NBC suppressed the plastic change of the astrocyte network and prevented intensification of epileptiform activity.

"Astrocytes play a crucial role in taking control of neuronal activity in healthy brains as well,” said Matsui. "Our research reveals the presence of glial plasticity and suggests a future therapeutic strategy can be aimed to control the glial function for treating disease.”