Study reveals new mechanism underlying learning deficits associated with infantile spasms

Researchers report that infantile spasms, a rare but serious seizure disorder in babies, appear to be the result of a molecular pathway gone awry. In their study of a mouse model of the disease, the researchers found that genetic mutations associated with the disease alter a pathway involved in the construction of new synapses in the hippocampus, a region of the brain essential for learning and Memory.

The results, described in the review EMBO reports, also detail the use of a potential therapeutic intervention to treat some of the developmental problems that are often associated with infantile spasms.

“We are trying to understand the reasons for learning and memory disabilities in patients with infantile spasms,” said Nien-Pei Tsai, professor of molecular and integrative physiology at the University of Illinois Urbana-Champaign who has led the study with U. of I research scientist Kwan Young Lee. Tsai is a faculty member at the Beckman Institute for Advanced Science and Technology at U. of I.

While infantile spasms often go away by age 4 or 5, long-term developmental issues affecting memory and learning persist, Tsai said.

“Learning and memory deficits last a long time and patients often need help in school,” he said. “This tells us that seizures and learning disabilities are probably caused by different problems in the brain, but no one really knows how.”

Previous research has shown that infantile spasms are often associated with mutations in a gene known as Nedd4-2, which encodes a protein called ligase that regulates the excitability of neurons, Tsai said.

“To study the role of this gene, we used mice in which Nedd4-2 is selectively removed from the brain as a model to mimic patients with altered Nedd4-2,” he said.

The researchers conducted behavioral and physiological experiments in mice with impaired Nedd4-2 ligase function and in mice with normal function. They also examined how a lack of ligase affected biochemical pathways in mouse neurons grown in cell culture.

They found that male mice lacking adequate levels of Nedd4-2 ligase in the hippocampus were impaired in their ability to learn and remember. This handicap was associated with problems in the structure of the excitatory synapses, which carry electrical signals between neurons in the hippocampus. The researchers focused on neurons in the hippocampus because this region of the brain plays a key role in converting short-term memory to long-term memory.

Their experiments showed that a lack of Nedd4-2 in the hippocampus disrupted a pathway that regulates filament growth, called actin, which supports the formation of cellular structures such as synapses. Cells lacking adequate levels of ligase suffered destruction of these filaments and had fewer excitatory synapses in the hippocampus.

Synapses need structural support to maintain their function and integrity. Actin, which is one of the critical structural components of a cell, is made up of monomers that can bind to each other to form polymers. When actin polymers are formed in synapses, synapses become stronger. This process is essential for learning and memory. “

Nien-Pei Tsai, Professor of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign

When the team exposed mice lacking adequate levels of Nedd4-2 to a drug compound that mimics ligase activity in the brain, the mice appeared to regain some of their lost hippocampal-dependent memory. The same compound restored excitatory neurons in the hippocampus in cell culture, the researchers found.

“Because we have shown that some of the learning and memory problems associated with infantile spasms can be improved by a synthetic peptide in animals, it means that one day we may be able to medically improve learning and memory. patients with mutations in this Nedd4-2 gene, ”Tsai said.