UBE3A Gene Reactivation in Inhibitory Neurons May Prevent Seizures, Angelman Mouse Study Shows

UBE3A Gene Reactivation in Inhibitory Neurons May Prevent Seizures, Angelman Mouse Study Shows

Epileptic seizures caused by disturbances in the activity of a specific type of nerve cell called an inhibitory neuron were prevented by the reactivation of the UBE3A gene in young mice with Angelman syndrome features, a study shows.

The study, “Ube3a reinstatement mitigates epileptogenesis in Angelman syndrome model mice,” was published in The Journal of Clinical Investigation.

Angelman syndrome is a genetic neurodevelopmental disorder caused by the loss or malfunction of the maternal copy of the UBE3A gene in neurons from specific regions within the brain.

The disorder is frequently associated with epileptic seizures — estimated to affect between 80% and 95% of patients — that usually fail to respond to anti-epileptic medications. However, the reason why genetic mutations in UBE3A seem to increase patients’ risk of developing epileptic seizures is not yet fully understood.

Although there is no cure for Angelman syndrome, recent studies in mouse models based on UBE3A gene replacement or reactivation in neurons hold great therapeutic potential, including for the treatment of epilepsy.

However, determining the optimal time window for gene reactivation, “and identifying the neural circuits through which UBE3A re-expression mediates its anti-epileptogenic effects, will be necessary to guide the optimal implementation of emerging UBE3A-reinstatement therapies,” according to the authors.

In the study, researchers from the University of North Carolina devised a strategy to investigate how a mouse model of Angelman syndrome, which lacked a functional maternal copy of UBE3A, develops epileptic seizures and which neural circuits are involved in the process.

To analyze the frequency and properties of epileptic seizures, investigators exposed animals to flurothyl, a volatile drug that triggers epileptic seizures, once a day, for a period of eight days and a retest after 36 days.

Interestingly, the probability of having a seizure was identical between animals lacking one copy of UBE3A and healthy control mice.

However, in the retest period, mice lacking UBE3A were more sensitive to seizures triggered by flurothyl, kainic acid (a toxin that causes neuronal overexcitation and seizures), and hyperthermia (elevated body temperature) than the control animals.

To distinguish which type of neurons — either those that promote neuronal activity (excitatory, or glutamatergic) or those that prevent neuronal activity (inhibitory or GABAergic) — were involved in epilepsy, researchers used genetically modified mice in which UBE3A was specifically deleted in each group.

Excitatory and inhibitory neural signals are the “yin and yang” of the brain. Excitatory signaling from one nerve cell to the next makes the latter cell more likely to fire an electrical signal. Inhibitory signaling makes the latter cell less likely to fire. This is the basis of communication between nerve cells in the brain.

When UBE3A was deleted in inhibitory neurons, animals were more susceptible to epileptic seizures. However, no effects were observed when UBE3A was deleted in excitatory neurons.

“These results support excitation/inhibition (E/I) imbalance [in the brain] as a potential mechanism of [epilepsy],” the investigators wrote.

Interestingly, when researchers induced the reactivation of UBE3A in juvenile mice 21 days of age, they prevented the occurrence of epileptic seizures. However, in adult animals, UBE3A reactivation failed to do so, suggesting that gene reactivation must occur before adulthood to restore normal neuronal activity.

“Our findings highlight the importance of carefully defining when UBE3A reinstatement will be efficacious in treating a range of AS phenotypes [Angelman syndrome symptoms], which can differ significantly in terms of their onset and developmental trajectory. This knowledge will be invaluable in informing the design of upcoming clinical trials leveraging UBE3A reinstatement therapies,” they concluded.

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