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Valproic Acid Exposure During the Brain Growth Spurt Leads to Autistic-Like Behaviours in Mice
Bruna Lotufo-Denucci1, Monica Cena de Sousa1, Nathan Alesi de Paula Aguiar1
1Laboratório de Neurofisiologia, Departamento de Ciências Fisiológicas, Instituto de Biologia Roberto Alcantara Gomes, Centro Biomédico, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
Insights
Valproic acid (VPA) exposure during the brain growth spurt in mice induced autism spectrum disorder (ASD)-like behaviors. This suggests the brain growth spurt is a critical period for VPA
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Behavioral Neuroscience
Background:
- Prenatal exposure to valproic acid (VPA) is linked to increased autism spectrum disorder (ASD) risk.
- Rodent studies show VPA exposure in early gestation causes autistic-like phenotypes.
- Evidence suggests VPA may pose an ASD risk beyond the first trimester.
Purpose of the Study:
- To investigate the neurobehavioral effects of VPA exposure during the brain growth spurt (third trimester equivalent) in adolescent mice.
- To determine if VPA exposure during this specific developmental window impacts social behavior, anxiety, activity, and repetitive behaviors.
Main Methods:
- Swiss mice offspring received VPA or saline injections from postnatal day 2 to 8.
- Behavioral tests included sociability, anxiety, locomotor activity, and repetitive behaviors at juvenile and adolescent stages.
- Neurotransmitter levels (serotonin, norepinephrine, dopamine) were analyzed via HPLC.
Main Results:
- Adolescent VPA-exposed mice exhibited increased anxiety-like behavior and hyperactivity.
- Reduced repetitive behavior was observed, alongside decreased sociability in one test but increased sociability in another.
- Elevated serotonin levels were found in VPA-exposed mice; other neurotransmitter levels remained unchanged.
Conclusions:
- VPA exposure during the brain growth spurt can induce specific neurobehavioral deficits in adolescent mice.
- This developmental period is critical for the manifestation of VPA-induced ASD-like behaviors.
- Findings highlight the brain growth spurt as a sensitive window for VPA's neurodevelopmental impact.
Abstract:
Prenatal exposure to valproic acid (VPA) has been associated with an increased risk of autism spectrum disorder (ASD). Studies in rodents have demonstrated that VPA exposure during the first trimester-equivalent period of gestation results in a lifelong autistic-like phenotype. A growing body of evidence suggests that VPA exposure may be a risk factor for ASD beyond the first trimester of pregnancy. Here, we investigated in adolescent Swiss mice the neurobehavioural effects of exposure to VPA during the brain growth spurt, a period that encompasses the third trimester of human gestation. Offspring received ip injections of VPA (200 mg/kg) or saline solution (NaCl 0.9%) on alternate days, from Postnatal Day 2 (PN2) to PN8. Animals were behaviourally tested either as juveniles (PN12: sociability [aggregation]) or adolescents (PN30: anxiety-like behaviour [elevated plus maze], locomotor activity [open field], repetitive behaviour [marble burying] and sociability [reciprocal social interaction and three-chamber test]). At PN33, serotonin serum levels and frontal cortical norepinephrine, dopamine and DOPAC were evaluated by HPLC. No differences were observed at PN12. Adolescent VPA mice showed increased anxiety-like behaviour, hyperactivity and reduced repetitive behaviour. Lower sociability was identified in the reciprocal social interaction. However, in the three-chamber test, social behaviour was higher in the VPA group. It also showed higher serotonin, but no other neurotransmitter level effects were observed. The results support the idea that the period of brain growth spurt may be relevant for the manifestation of neurobehavioural deficits associated with ASD induced by VPA.
