How seizures progressively lead to Epilepsy

A major mystery in epilepsy research has been why infants are more prone to seizures than adults and how those seizures progress to chronic epilepsy. Now, researchers have discovered that central to those seizures in the developing brain are neurons triggered by the neurotransmitter GABA. They say their findings could lead to new ways to treat seizures in newborns. Also, they say, their findings suggest that the use of drugs that enhance GABA action may be particularly harmful to the newborn brain.

In adults, epilepsy is caused by hyperactivation of neuronal receptors triggered by the neurotransmitter glutamate. This excess activation unleashes the storm of uncontrolled nerve cell firing that underlies epilepsy. In contrast, in adults the neurotransmitter GABA acts on its receptors to inhibit neurons. Loss of this inhibition is also involved in epilepsy.

Neurotransmitters such as glutamate and GABA are chemical signals that one neuron launches at its neighbor across connections called synapses.

Yehezkel Ben-Ari and colleagues decided to explore a possible role of GABA-controlled neural circuitry in seizures in infant animals because it was known that, while GABA excites immature neurons, it changes to an inhibitory neurotransmitter in adult neurons.

In their experiments described in the December 8, 2005, issue of Neuron, they used a preparation in which they isolated in three separate compartments the left and right hippocampi of baby rats and the nerve fibers connecting them. The researchers studied the hippocampus because it is the brain area central to epilepsy.

With this experimental arrangement, they could use drugs to block GABA receptors and/or induce electrical seizure in one hippocampus and analyze whether such manipulations influenced seizure activity in the other. Such a spreading influence is a sign that individual seizures have caused development of a chronic epileptic state.

Their experiments revealed that the GABA-triggered neurons were involved in seizures in the immature brains and also that those seizures did lead to development of an epileptic state. They found that these GABA-triggered seizures featured so-called "fast oscillations" of electrical activity that are required to transform a "naive" network of neurons into an epileptic one.

In other experiments comparing immature and adult rat hippocampi, they found that although GABA-triggered neurons were also involved in seizures in adult brains, they were not required for development of epilepsy, as they were in immature hippocampi.

The researchers concluded that their studies showed that fast oscillations involved in seizures "are also directly implicated in epileptogenesis in the immature brain and lead to the production of a persistent chronic epileptic condition."

As the neuronal network matures, however, the density of synapses triggered by glutamate increases and the contribution of GABA-triggered synapses to fast oscillations and development of epilepsy decreases, they wrote.

"This information may be important both for understanding the deleterious consequences of seizures in newborns and for developing new therapeutic treatments for seizures in young infants," wrote Ben-Ari and colleagues. "Specifically, the permissive action of excitatory GABA suggests that GABA-acting drugs may exert deleterious actions at an early developmental stage in humans."