Single Early-Life Seizure Leads to Fragile X-Like Behaviors Later in Life, Mouse Study Finds

Single Early-Life Seizure Leads to Fragile X-Like Behaviors Later in Life, Mouse Study Finds

A single early-life seizure results in behaviors resembling fragile X syndrome (FXS) later in life, but does not exacerbate these behaviors in a fragile X mouse model, a preclinical study has found.

The study, “A single early-life seizure results in long-term behavioral changes in the adult Fmr1 knockout mouse,” was published in the journal Epilepsy Research.

Fragile X syndrome, caused by a mutation in the FMR1 gene, is the most commonly known single-gene cause of inherited intellectual disability and autism spectrum disorder (ASD).

Fragile X syndrome and ASD share several behavioral symptoms, including hyperactivity, social withdrawal, and repetitive or stereotypical behaviors. In addition to behavioral deficits, approximately 10–20% of fragile X patients have seizures.

Considerable evidence suggests that both FMR1 mutations and early-life seizures can lead to behavioral impairments, including ASD-like behaviors. However, whether these early-life seizures may exacerbate or affect behaviors associated with FMR1 mutations and fragile X syndrome remains unclear.

With this is mind, researchers evaluated long-term behavioral changes after a single early-life seizure in a mouse model of fragile X (with FMR1 deletion) and in healthy mice.

After inducing a single seizure with kainic acid — a potent neuroexcitatory molecule that is used often to induce seizures in animal models — in 10-day-old mice, they analyzed the mice’s behavior in their adulthood (90 days old) through a battery of behavioral tests.

These tests assessed repetitive behavior, activity and anxiety levels, sociability, learning and memory, and sensorimotor gating (the ability of a sensory event to suppress a motor response).

Sensorimotor gating was measured through the analysis of the startle reflex (a sudden muscular movement in response to a loud unexpected sound) and startle reduction (when a weak stimulus precedes the loud sound, lessening the startle reflex).

Fragile X mice had impaired behaviors characteristic of the disease, such as hyperactivity, increased repetitive or stereotypical behavior, enhanced startle reduction, and reduced startle responses, compared to healthy mice.

A single early-life seizure resulted in significant behavioral changes in adult healthy mice, including increased repetitive behavior (to levels comparable to those in fragile X mice), reduced sociability, and increased learning.

The team noted that enhanced learning following seizures also has been shown in humans, with early fever-associated seizures resulting in significantly better memory.

Overall, the induction of a single early-life seizure did not exacerbate fragile X-like behaviors in fragile X mice.

Opposite effects between FMR1 deletion and early-life seizures were found in exploratory and startle reduction behavioral tests.

Fragile X mice (FMR1 deletion) showed reduced time to first exploratory movement (nose poke in a hole) and enhanced startle reduction. Seizure resulted in an increased delay to first nose poke and no change in startle reduction in fragile X mice, while in healthy mice it decreased both the delay and startle reduction.

Lower startle reduction also is observed frequently in people with fragile X syndrome, the researchers stated.

Researchers hypothesize that the absence of behavior changes with early-life seizure in fragile X mice may be due to the method and time of seizure induction, since previous studies have suggested seizure-associated behavioral changes in mice with mutations in another gene known to cause ASD.

Future studies are required to confirm these findings, to evaluate whether early-life seizures affect fragile X-associated mechanisms on a molecular level in adulthood, and to explore how seizures can affect disease symptoms in other single-genetic causes of ASD.

Double-hit models like this, inducing a condition that often is found as a comorbidity (the presence of more than one disorder in the same individual) to a specific disease, “can be advantageous in understanding how comorbidities exacerbate the molecular and behavioral basis of neurodevelopmental disorders,” the researchers wrote.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.
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