Freja Bertelsen, April 2016

Supervisors: Jørgen Scheel-Krüger, Arne Møller, Anne M. Landau

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by impaired social interaction and communication.  The aetiology of ASD is still not fully understood but research has shown a strong genetic component. In addition epigenetic and environmental factors (such as prenatal exposure to antiepileptic drugs) can cause ASD.

Today the therapeutic options are limited for patients with ASD  and unfortunately the medication available today has limited effect in many patients.

There is therefore a strong need for an animal model to establish the neurobiological pathways underlying ASD so we can hopefully prevent and treat ASD in the future.

We know from the human clinic that administration of the anti-epileptic drug Valproate (VPA) during pregnancy increases the risk of ASD in the offspring. Our group investigates the possibilities of using an animal model treated with subchronic, low doses of VPA as a model of ASD. Our goal is to investigate the consequences for the offspring when we administer low doses (20mg/kg/day and 100 mg/kg/day) to pregnant rats. This is much lower than what is reported  today in the literature; these low doses do not cause obvious physical malfunction in the offspring.

We demonstrated that the offspring from rats treated with low, subchronic doses of prenatal VPA had a significantly higher cell number in neocortex[1] (figure 1), had alteration in their GABAergic, serotonergic and oxytocin system and had behavioural deficits such as reduced play behaviour (figure 2).

We continue our work to further establish the model with microPET and behavioural analyses.

[1] Sabers A, Bertelsen FC, Scheel-Krüger J, Nyengaard JR, Møller A. 2014. Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain. A possible new animal model of autism. Neurosci Lett. 

Figur 1) : Rats exposed to 100 mg VPA/kg/day and 20 mg VPA/kg/day displayed a 12.3 % (p<0.05) and 15.8% (p<0.01) increased number of neocortical neurons, respectively. There was no statistical difference between the two VPA groups (Sabers et al. 2014). 


Figur 2) VPA significantly reduced play behaviour in the 20 mg/kg/day VPA group (p<0.05) compared to the control group. There was a non-significant decrease in play behaviour in the 100 mg/kg/day VPA group compared to the control group.