Reduced protein-protein interaction implicated in epilepsy/anxiety

Reduced protein-protein interaction implicated in epilepsy/anxiety

New therapies could be on the horizon for people living with epilepsy or anxiety, thanks to a breakthrough discovery by a team of researchers studying how proteins interact to control the firing of brain cells.

The study, published in Nature Communications, provides new insight into ways to regulate a specialized "compartment" of cells in the brain that controls their signaling. If scientists and doctors can influence that compartment, they can control the firing of brain cells, which may in turn stop or prevent seizures, among other things.

"If we can better understand how the brain patterns activity, we can understand how it might go wrong in a disorder like epilepsy, where brain activity becomes uncontrolled," the lead author said. "And if we can understand what is important for this control, we can come up with better strategies for treating and improving the quality of life for people with epileptic seizures and maybe other types of disorders as well, such as anxiety or sleep disorders."

The six-year project moved one step closer to answering decades-old questions about brain wave control, by quantitatively defining how two key proteins -- the GABAA receptor a2 subunit and collybistin -- interact. To explore the biological relevance of collybistin-α2-subunit selectivity, authors generated mice with a mutation in the α2-subunit-collybistin binding region (Gabra2-1). The mutation results in loss of a distinct subset of inhibitory synapses and decreased amplitude of inhibitory synaptic currents.

Gabra2–1 mice have a striking phenotype characterized by increased susceptibility to seizures and early mortality. Surviving Gabra2-1 mice show anxiety and elevations in electroencephalogram δ power, which are ameliorated by treatment with the α2/α3-selective positive modulator, AZD7325.

"That's the piece that could potentially change textbooks: Previously, we had questions about how these pieces fit together and thought that maybe a group of three or more proteins interacted," the lead author said. "But our team's research strongly suggests that there's a very specific interaction between two of them, and this has implications for how neuroscientists might be able to regulate this area."