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Adolescent behavioral abnormalities in a Scn1a+/- mouse model of Dravet syndrome
Dilara Bahceci1, Lyndsey Leigh Anderson1, Cassandra Veronica Occelli Hanbury Brown1
1Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, Sydney, NSW 2050, Australia; School of Medical Science and Discipline of Pharmacology, The University of Sydney, Sydney, NSW 2006, Australia.
Insights
Adolescent mice with Dravet syndrome (Scn1a+/-) show anxiety and memory deficits, modeling early developmental delays. These findings support testing early interventions for Dravet syndrome in mouse models.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Epigenetics
Background:
- Dravet syndrome is a severe pediatric epilepsy linked to SCN1A gene mutations.
- Patients experience significant developmental delays, cognitive impairments, and autistic-like behaviors.
- Existing mouse models primarily focus on adult phenotypes, not early developmental stages.
Purpose of the Study:
- To characterize the adolescent behavioral phenotype of Scn1a+/- mice, a model for Dravet syndrome.
- To identify early-onset behavioral deficits that mirror human developmental delays.
- To establish a foundation for preclinical testing of early intervention therapies.
Main Methods:
- Comparison of adolescent Scn1a+/- mice and wildtype (WT) littermates.
- Assessment of motor function, sociability, social recognition, memory, anxiety, sensorimotor gating, and compulsive behaviors.
- Utilized tests including open-field, three-chamber social tests, novel object recognition, Barnes maze, fear conditioning, elevated plus maze, and PPI.
Main Results:
- Adolescent Scn1a+/- mice showed normal locomotor activity, sociability, and sensorimotor gating.
- Significant impairments observed in social recognition memory and spatial memory.
- Increased anxiety-related behavior (thigmotaxis), atypical fear responses, and blunted startle reflexes were noted.
Conclusions:
- Adolescent Scn1a+/- mice exhibit specific behavioral impairments relevant to Dravet syndrome's early developmental impact.
- These findings highlight the utility of adolescent Scn1a+/- mice for studying early disease mechanisms.
- The study provides a crucial preclinical model for evaluating early therapeutic interventions in Dravet syndrome.
Abstract:
Dravet syndrome is an intractable pediatric epilepsy associated with SCN1A mutations. In addition to having a large seizure burden and a reduced lifespan, patients with Dravet syndrome also exhibit delays in reaching normal developmental milestones in attentional, emotional, and cognitive function. These developmental delays manifest in autistic-like social withdrawal and compulsive behavior. Additionally, cognitive impairments including deficits in sensorimotor processing and memory function are present. Several mouse models utilizing heterozygous deletion of Scn1a (Scn1a+/- mice) have been generated that recapitulate many aspects of Dravet syndrome. Studies in these mouse models of Dravet syndrome have characterized behavioral phenotypes in adult mice. In the present study, we characterized the behavioral phenotype of Scn1a+/- mice generated by targeted deletion of Scn1a exon 1 (Scn1atm1Kea) during adolescence. Identifying behavioral deficits in adolescent mice would more closely model the early onset of attentional, emotional, and cognitive delays observed in patients with Dravet syndrome. The behaviors of adolescent Scn1a+/- and wildtype (WT) mice were compared across several behavioral domains. We assessed motor function (open-field test), sociability and social recognition memory (three-chambered social preference and social interaction tests), memory function (novel object recognition, Barnes maze, fear conditioning paradigm), anxiety-related behavior (elevated plus maze and open-field thigmotaxis), startle reflex and sensorimotor gating (prepulse inhibition of startle (PPI) tests), and repetitive compulsive behavior (marble burying test). Adolescent Scn1a+/- mice exhibited normal locomotor activity, marble burying behavior, sociability, and sensorimotor gating. However, adolescent Scn1a+/- mice displayed increased anxiety-related thigmotactic behavior, atypical fear expression, blunted acoustic startle responses, and impaired social recognition and spatial memory. Our results show that Scn1a+/- mice display various behavioral impairments during adolescence, which provides a foundation for testing early intervention therapies targeting developmental delays modeled in Dravet syndrome mice.
