Dodging the long-term cognitive effects of early-life seizures

Seizures seem to strengthen and "lock in" synapses too soon, leaving no room for development. (Image: Ice synapses, Joe Flintham/Flickr)

It’s well known that babies who have seizures soon after birth have roughly a 50-50 chance of developing long-term intellectual and memory deficits and cognitive disorders like autism. But until now, it wasn’t understood why these deficits occur, much less how to prevent them from happening.

In the December 14 Journal of Neuroscience, researchers at Children’s Hospital Boston, led by neurologist-neuroscientist Frances Jensen, detail in a rat model how early-life seizures affect brain development at the cellular and molecular level. But more to the point, they show that it might be possible to ward off these effects with drug treatment soon after the seizure – using a drug called NBQX or similar drugs that are already approved by the FDA.

Jenson was particularly interested in what seizures do to synapses, the connections between neurons that are rapidly developing in the infant brain.

Her previous work has shown repeatedly that newborns’ brains are different from everyone else’s.

Examining slices of brain tissue from the hippocampus, an area important in learning and memory, Jensen’s team found that after a seizure, newborn rats had a diminished pool of “silent” or inactive synapses, which should predominate soon after birth. Instead, an excessive number of synapses had been converted to an excitable form by acquiring more so-called AMPA receptors.

An excitatory brain state and strengthening of synaptic connections are normal and necessary for cognitive development. But here’s the thing: Jensen’s team found that seizures exaggerated excitation and synaptic strengthening too soon in development, to the point where synapses lost their “plasticity,” or their ability to adapt to information from the environment — what learning is all about.

Frances Jensen

“Seizures have ‘fixed’ the synapses so they have much less potential to respond to experience,” Jensen says. “Epilepsy seems to be co-opting normal synaptic plasticity mechanisms.”

As a result, the rats’ brain tissue showed diminished long-term potentiation (LTP), a widely accepted molecular proxy for learning that looks at electrical responses to stimulation of neurons as a measure of synapses’ ability to change their strength. “When we try to induce LTP in brain slices from animals that have had epilepsy, it can’t be done,” Jensen says. “There’s no more ‘flex’ in the synapses.”

All these effects were evident within 2-3 days after the seizure – but amazingly, it looks like they can be undone. When Jensen’s team gave the rats NBQX, which blocks AMPA receptors, inactive synapses and LTP were preserved, even when NBQX was given as late as 48 hours after the seizure. And the protective effects lasted into adulthood.

Since drugs similar to NBQX are already FDA-approved for other indications, Jensen believes these results might eventually lead to a clinical trial in newborns who have had seizures.

“Because we can reverse the strengthening of synapses, we might be able to modify the disease after the fact, which is one step in the right direction toward thinking about potential strategies for cures,” she says. “Epilepsy has many mechanisms and potential therapeutic targets, but this is one that may be important in undoing the cognitive effects that epilepsy may have.”