Neonatal seizures are a pernicious problem confronting child neurologists. While they are common and cause substantial morbidity, their pathophysiology is poorly understood. Most of the treatments for neonatal seizures consist of “old” anticonvulsants, such as phenobarbital and phenytoin, which, in many cases, are not very efficacious. Thus, modern understanding of neonatal seizures and therapeutics for their treatment represent a sad state of affairs.
Dr. Joseph Glykys aims to change this scenario. An Assistant Professor of Pediatrics and Neurology at the University of Iowa, Dr. Glykys investigates the pathophysiology of neonatal seizures with an eye toward developing new and better treatments.
Utilizing brain slices and forebrain explant cultures from experimental mice, Dr. Glykys and his co-workers have made numerous important discoveries. They have found that phenobarbital, which produces its anti-convulsant effects via GABA-mediated inhibition, suppresses thalamic seizure activity, but not cortical seizures, in neonatal brain tissue.
Phenobarbital produces its anticonvulsant effects by activating the GABA receptor, whose function depends on intracellular chloride concentration. Activation of the GABA receptor is inhibitory in neurons in which the intracellular chloride concentration is low, but is excitatory in cells where the chloride concentration is high. Dr. Glykys has found that intracellular chloride concentrations are low in thalamic neurons, but high in cortical neurons of neonates, thus explaining why phenobarbital effectively controls thalamic seizures, but not neocortical seizures in neonatal mice. This finding may explain the “electroclinical uncoupling” that is commonly seen in neonates, where babies have electrographic seizures that are not clinically manifest.
Dr. Glykys’ results demonstrate that an increase in extracellular osmolarity leads to the linked movement of water and chloride out of neurons and that the consequent decrease in intracellular chloride concentration renders seizures from those neurons more amenable to control with GABAergic agents.
The finding that cortical neurons have elevated intracellular chloride concentrations and are swollen during seizures, led Dr. Glykys to test the effect of mannitol, an osmotic agent commonly used to treat cerebral edema. Dr. Glykys and co-workers reasoned that if the water and chloride movement are linked in neurons, then mannitol will decrease both water and chloride content and thus decrease seizure activity. For these studies, Dr. Glykys utilized electrophysiologic techniques and two-photon imaging to evaluate neuronal cell body size and intracellular chloride concentration simultaneously.
In the brain slices of neonates, he found that mannitol decreases neuronal volume and intracellular chloride concentration, via chloride co-transporters, and decreases neocortical epileptiform activity (see figure). He further found that mannitol potentiates the effect of diazepam in reducing neocortical epileptiform activity. Dr. Glykys’ results demonstrate that an increase in extracellular osmolarity leads to the linked movement of water and chloride out of neurons and that the consequent decrease in intracellular chloride concentration renders seizures from those neurons more amenable to control with GABAergic agents.
Thus, Dr. Glykys has uncovered new and exciting facts regarding the neurophysiology of the developing brain and the basis for epileptic activity. There is great promise that these insights will lead to new treatments for the old problem of neonatal seizures.
EDITOR’S NOTE: Dr. Joseph Glykys has a great gift for clearly explaining complex subjects. Indeed, it is for this reason alone that I was able to write this article, summarizing his research. If you ever want to “get smart” about something, ask Joseph to explain it to you.