Angelman Symptoms Linked to Loss of Ube3a Gene in Specific Nerve Cells, Mouse Study Suggests

Loss of the maternal copy of the UBE3a gene in a specific set of nerve cells called GABAergic neurons is a key factor underlying Angelman syndrome, a mouse study suggests.

The study, “GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility,” was published in the journal Neuron.

Each gene within our DNA is located at a specific region and has two copies, one inherited from each parent. In the brain, the paternal UBE3a gene is silenced and so the maternal copy is the primary source of UBE3A levels in the brain.

Loss of the maternal UBE3a gene causes the development of Angelman syndrome and underlies the disease symptoms seen in humans and in animal models, including seizures, impaired movement, and cognitive delays.

GABA (γ-aminobutyric acid) is the main inhibitory neurotransmitter — it inhibits whichever neurons its binds to — in the adult brain. GABAergic neurons are the prime source of inhibition in the adult brain. In the cortex, they constitute 10-20% of all neurons and are a heterogeneous cell population.

Another class of neurons, called glutamatergic neurons, release glutamate, a powerful neurotransmitter whose function, unlike GABA, is to excite the nerve cells it binds to.

In animals with Angelman syndrome, the action of GABAergic neurons is markedly reduced, a feature likely causing Angelman-associated symptoms.

Researchers from the University of North Carolina at Chapel Hill investigated the impact of selectively losing the UBE3a gene in these two specific sets of cells: GABAergic or glutamatergic neurons.

Mice whose Ube3a gene was specifically deleted in their GABAergic neurons developed increased susceptibility to seizures. But the loss of the Ube3a gene in glutamatergic neurons failed to induce several Angelman syndrome symptoms, like abnormalities in brain activity — measured by electroencephalogram (EEG) — seizures and impairment in nerve cell communication.

According to these results, the UNC researchers believe that loss of the Ube3a gene specifically in GABAergic neurons could be the key factor behind the hyperexcitability of nerve cells seen in mice with the disease.

A commentary published in the journal Epilepsy Currents, by Catherine A. Christian, PhD, an assistant professor at the School of Molecular & Cellular Biology, University of Illinois, titled “Mom Genes: A Role for Loss of Maternal Ube3ain GABAergic Neurons in Angelman Syndrome,” emphasized the importance of these findings.

Christian suggested that Ube3a gene levels “in GABAergic neurons is a critical factor in the development of  [Angelman syndrome]-like seizure phenotypes in mice, and thus provide a strong rationale for focusing on GABAergic neurons in the future development of [Angelman syndrome] therapies.”