Does Prenatal Valproate Interact with a Genetic Reduction in the Serotonin Transporter? A Rat Study on Anxiety and Cognition

Abstract

There is ample evidence that prenatal exposure to valproate (or valproic acid, VPA) enhances the risk of developing Autism Spectrum Disorders (ASD). In line with this, a single injection of VPA induces a multitude of ASD-like symptoms in animals, such as rats and mice. However, there is equally strong evidence that genetic factors contribute significantly to the risk of ASD and indeed, like most other psychiatric disorders, ASD is now generally thought to results from an interaction between genetic and environmental factors. Given that VPA significantly impacts on the serotonergic system, and serotonin has strong biochemical and genetic links to ASD, we aimed to investigate the interaction between genetic reduction in the serotonin transporter and prenatal valproate administration. More specifically, we exposed both wildtype (SERT+/+) rats and rats heterozygous for the serotonin transporter deletion (SERT+/−) to a single injection of 400 mg/kg VPA at gestational day (GD) 12. The offspring, in adulthood, was assessed in four different tests: Elevated Plus Maze and Novelty Suppressed Feeding as measures for anxiety and prepulse inhibition (PPI) and latent inhibition as measures for cognition and information processing. The results show that prenatal VPA significantly increased anxiety in both paradigm, reduced PPI and reduced conditioning in the latent inhibition paradigm. However, we failed to find a significant gene–environment interaction. We propose that this may be related to the timing of the VPA injection and suggest that whereas GD12 might be optimal for affecting normal rat, rats with a genetically compromised serotonergic system may be more sensitive to VPA at earlier time points during gestation. Overall our data are the first to investigate gene * environmental interactions in a genetic rat model for ASD and suggest that timing may be of crucial importance to the long-term outcome.

Serotonin-related rodent models of early-life exposure relevant for neurodevelopmental vulnerability to psychiatric disorders

“…Furthermore, combination of stress exposure and postnatal SSRI treatment in dams alters affective susceptibility of the offspring in a SERT-dependent manner 206 . Conversely, behavioral alterations produced by in utero VPA exposure were not affected by the presence of SERT 155 . On the other hand, rats with reduced SERT expression, and a previous history of maternal separation, showed improvements in stress-coping responses 207 .…”

“…However, several studies failed to replicate some of these effects 136 , 137 , 151 . On the other hand, and related to the social deficits observed, a decreased olfactory motivation and sensorimotor capacity were found in VPA-exposed mice 134 , 139 , 142 , 145 , 155 (Table 3 ). Additionally, sex-specific aggressive and defensive strategies in social settings appeared to be affected by the VPA exposure, switching from a defensive tactic to a more aggressive one 161 .…”

“… G12.5 Wistar Han rats ↑ Entries to the same arm (Y-maze) Markram et al 142 ↓ Time in open arms (EPM) ↓ Social interaction (sniffing, touching) ↓ Sensorimotor gating (PPI) ↑ Tone and Context memories, Generalization and Extinction (Fear conditioning) = No effects (Locomotion, MWM) 500 mg/kg i.p. G12.5 Wistar rats ↑ Time in closed arms (EPM) ( in both sexes ) Edalatmanesh et al 146 ↑ Repetitive behavior and ↓ Alternation behavior (Y-maze) ( in both sexes ) ↓ Play behavior, Social exploration and contact ( in both sexes ) ↑ Spatial learning and memory (MWM) ( in both sexes ) 400 mg/kg s.c. G12.5 Wistar rats ↓ Time in open arms (EPM) Ellenbroek et al 155 ↑ Latency to feed (NSF) ↑ Sucrose consumption (Latent inhibition) ↓ Sensorimotor gating (PPI) 600 mg/kg i.p. G12.5 Wistar rats ↓ Social exploration and preference Bambini-Junior et al 143 ↑ Alternation delay (Y-maze) = No effects (MWM) 600 mg/kg i.p.…”

Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder

“…5-HT signaling facilitates several neural processes including neurogenesis, cell migration and survival, synaptogenesis, and synaptic plasticity. Interestingly, high 5-HT levels in the blood have been described for up to 45% of tested ASD subjects(Chen et al, 2015 , 2017 ; Ellenbroek et al, 2016 ). Moreover, preclinical investigations using ASD-like animal models reported that hyperserotonemia significantly reduced the motivation for social interest through inhibition of separation distress, potentially accounting for the social impairments found in ASD individuals (Ellenbroek et al, 2016 ; Nakai et al, 2017 ).…”

The Translational Umbrella - A Novel Approach to the Study of the Biological Basis of Mental Health

“…Similarly, several environmental models have been developed based on prenatal immune activation or treatment with valproate [28]. Nevertheless, the animals models that combine genetic and environmental risk factors are rare [29].…”