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Mouse Model of LGS Created Based on Mutation Found in Patient

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Mouse Model of LGS Created Based on Mutation Found in Patient
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Mice created with a single mutation found in a person with Lennox-Gastaut syndrome showed all the hallmarks of the condition, including the same seizure types, and were successfully treated with anti-epileptic medications, a study has found. 

This mouse strain represents a new model to investigate the mechanisms underlying the syndrome and may further the development of new therapies. 

The study, “GABAA receptor β3 subunit mutation D120N causes Lennox-Gastaut syndrome in knock-in mice,” was published in the journal Brain Communications

Lennox-Gastaut syndrome (LGS) can result from many different causes such as brain injury before or during birth, brain malformation, infections, or, in some cases, mutations in different genes. 

The underlying mechanisms of those with genetic mutations are not well-understood, and a lack of animal models for genetic LGS has hindered progress into the development of appropriate treatments.

One spontaneously occurring single mutation was found in a family with an affected child, but the parents were not affected. 

This mutation was in the GABRB3 gene which holds the instructions for a protein receptor called GABA-A, which in turn binds gamma-aminobutyric acid (GABA), a chemical that acts as a messenger (neurotransmitter) between brain cells

These receptors are produced in different areas of the brain and their malfunction has been implicated in several childhood epilepsies, including LGS. In cell-based tests, the mutation found in this family altered the function of the GABA-A receptor

However, exactly how this mutation causes LGS-type seizures and behavioral difficulties is unknown. 

To find out, researchers at Vanderbilt University Medical Center, in Nashville, created a special breed of mice, called Gabrb-3+/D120N knock-in mice, that carry this same mutation and conducted a series of tests to understand how it affected them. 

Multiple types of spontaneous seizures were observed in the mutant mice, such as frequent atypical absence seizures, characterized in LGS patients as vacant staring. Other types of less frequent seizures occurred, such as tonic (stiffness), myoclonic (muscle jerks), atonic (drop attacks), and generalized tonic-clonic seizures (convulsions). 

Each seizure type had characteristic patterns of electrical activity as recorded by electroencephalography (EEG) during seizures that were consistent with those found in people with LGS. 

Mutant mice had reduced early cognitive abilities and memory, which persisted throughout life, as measured by a series of maze tests in which these mice took longer to find a target hole, committed more errors to find the hole, and used a less efficient search strategy compared to normal mice (wild type). 

The mutant mice also displayed hyperactivity which worsened with age and a significant loss in overall exploratory behavior and socialization. According to the researchers, these mice “showed none of the social preferences of their wild-type littermates.”

By examining the brains of the mutant mice, the researchers found that the particular mutation did not affect the production of the receptor, but rather its function by showing changes in the electrical impulses in the nerves. These changes were predicted to increase nerve excitability, resulting in epilepsy.

In a final validation test, treating the mutant mice with the anti-epileptic therapies ethosuximide (sold under the brand name Zarontin, among others) and clobazam (sold as Onfi by Lundbeck, and Sympazan by Aquestive) significantly decreased the duration of atypical absence seizures in the hour after injection. Ethosuximide had a similar effect on the number of seizures while clobazam did not. 

Cannabidiol has been shown to be effective in treatment-resistant epilepsies such as LGS. For example, Epidiolex, a cannabidiol marketed by GW Pharmaceuticals, has been approved by the U.S. Food and Drug Administration for the treatment of seizures in LGS patients, 2 and older.

As such, mice were treated with a medicine that activated the cannabinoid receptor 1 which reduced the duration and number of atypical absence seizures.

“This [mouse model] demonstrates that a single point mutation in a single gene can cause development of multiple types of seizures and multiple behavioral abnormalities,” the researchers wrote. 

“The knock-in mouse will be useful for further investigation of the mechanisms of Lennox-Gastaut syndrome development and for development of new antiepileptic drugs and treatments,” they concluded. 

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