Epilepsy is a medical condition characterized by spontaneous seizures due to hyperexcitability of brain neurons. Assistant Professor Nien-Pei Tsai, graduate student Jiuhe Zhu and colleagues uncovered that an insufficient function or mutations of a novel epilepsy-associated gene Nedd4-2 leads to neuronal hyperexcitability caused by an uncontrolled level of a neurotransmitter receptor named AMPA receptor. These findings provide critical information to the development of therapies for epilepsy patients who carry mutations of Nedd4-2.
Human genetic studies have identified many epilepsy-associated genes, but the mechanisms by which those genes are linked to brain circuit excitability and seizures are largely unknown.
A recent study published in PLOS Genetics by Assistant Professor Nien-Pei Tsai’s lab at the Department of Molecular and Integrative Physiology uncovered how the disruption of a novel epilepsy-associated gene, named ‘neural precursor cell expressed developmentally down-regulated gene 4-like’, or Nedd4-2, leads to neuronal hyperexcitability and seizures.
Nedd4-2 encodes a ubiquitin ligase that is responsible for degrading specific substrate proteins. Dr. Tsai’s lab has previously identified a neurotransmitter receptor, named ‘AMPA receptor’, as a novel substrate of Nedd4-2.
In this current study, using a mouse model in which one of the major forms of Nedd4-2 in the brain is selectively deficient, they found that the spontaneous neuronal activity in cortical neurons is basally elevated and very sensitive to the blockage of AMPA receptor when compared with wild-type neurons.
Most importantly, the elevated seizure susceptibility in this mouse model can be normalized when the AMPA receptors are genetically reduced. When studying the Nedd4-2 that carries one of the three epilepsy-associated mutations, they found that all mutations reduce the affinity of Nedd4-2 to modulate the degradation of AMPA receptors. These findings suggest that impaired AMPA receptor degradation contributes to Nedd4-2-dependent neuronal hyperexcitability and seizures. The pharmacologically targeting of AMPA receptors has already been applied clinically for treating patients with epilepsies. This study suggests a promising therapeutic target and introduces a currently available therapy for alleviating epilepsy symptoms in patients who carry mutations of Nedd4-2.
