New protein could unravel the causes of epilepsy, other brain disorders

By knocking out the LRP4 gene in fruit flies, Thomas Jefferson researchers found a molecule that is involved in the formation of excitatory synapses and not of inhibitory synapses.

Neurological conditions, such as epilepsy and schizophrenia, are thought to be caused by synaptic imbalances. Thomas Jefferson University scientists have found a molecule that may shed light on how these imbalances happen and improve the understanding of these conditions.

Synapses can be excitatory or inhibitory—they either allow nerve impulses to pass from neuron to neuron, or they “dampen” the signal. An imbalance renders the brain unable to process information normally, which can lead to epilepsy and other conditions.

The Jefferson team unearthed a molecule, LRP4, that plays a role in creating excitatory synapses, according to a statement. Blocking the gene that makes LRP4 reduced the number of excitatory synapses in fruit flies by 40%. It did not affect inhibitory synapses. The results are published in eLife.

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Because fruit flies and their neurons are so tiny, the team used expansion microscopy, which physically enlarged the neurons and synapses so they could be seen more clearly. The fruit fly brains were treated with a chemical and then embedded in a gel that expanded in water.

“Most molecules involved in synapse biology are vital to both excitatory and inhibitory neurons,” said Timothy Mosca, an assistant professor at Thomas Jefferson University’s Vickie and Jack Farber Institute for Neuroscience. “The idea that we now have a molecule that appears to be specific to excitatory synapses suggests there is probably a parallel molecule that exists that helps form inhibitory ones, that we just haven’t found yet."

Gaining a better understanding of how synapses normally form and work may help researchers demystify conditions thought to be caused by synaptic dysfunction. The Jefferson scientists noted in their study that LRP4 may also play a role in the motor disorders amyotrophic lateral sclerosis (ALS) and myasthenia gravis.