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Disrupted Social Hierarchy in Prenatally Valproate-Exposed Autistic-Like Rats.

ABSTRACT: Autism spectrum disorder (ASD) is characterized by impaired socio-communicational function, repetitive and restricted behaviors. Valproic acid (VPA) was reported to increase the prevalence of ASD in humans as a consequence of its use during pregnancy. VPA treatment also induces autistic-like behaviors in the offspring of rats after prenatal exposure; hence it is a preclinical disease model with high translational value. In the present study, our aim was to characterize ASD relevant behaviors of socially housed, individually identified male rats in automated home cages. The natural behavior of rats was assessed by monitoring their visits to drinking bottles in an environment without human influence aiming at reducing interventional stress. Although rodents normally tend to explore their new environment, prenatally VPA-treated rats showed a drastic impairment in initial and long-term exploratory behavior throughout their stay in the automated cage. Furthermore, VPA rats displayed psychogenic polydipsia (PPD) as well as altered circadian activity. In the competitive situation of strict water deprivation controls switched to an uneven resource sharing and only a few dominant animals had access to water. In VPA animals similar hierarchy-related changes were completely absent. While the control rats secured their chance to drink with frequent reentering visits, thereby “guarding” the water resource, VPA animals did not switch to uneven sharing and displayed no evidence of guarding behavior.

SUBMITTER: Pelsoczi P

PROVIDER: S-EPMC6974458 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo examine the behavioral functioning of children prenatally exposed to carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or valproate (VPA) monotherapy.MethodsIn collaboration with the European Registry of Antiepileptic Drugs and Pregnancy (EURAP), the Dutch EURAP & Development study was designed, a prospective observational study. Between January 2015 and March 2018, the Child Behavior Checklist and the Social Emotional Questionnaire were used to examine the nature and severity of behavioral problems. VPA-exposed children were compared to children exposed to CBZ, LTG, or LEV, taking potential confounders into account. A direct comparison was also made between LTG and LEV, as these are first-choice treatments for many women with epilepsy of childbearing potential.ResultsOf the 405 invited, 181 children were included; 26 were exposed to VPA, 37 to CBZ, 88 to LTG, and 30 to LEV. For most children, both parents completed the behavioral questionnaires. Across all four antiepileptic drug (AED) exposure groups, high percentages of children with clinically relevant behavior problems were found, with behavioral problems occurring in 32% of VPA-exposed children, 14% of CBZ, 16% of LTG, and 14% of LEV. After controlling for potential confounders, VPA-exposed children had significantly more social problems than those exposed to LTG (-2.8, 95% confidence interval [CI] = -5.2 to -0.4; P = 0.022) or LEV (-3.2, CI: -6.1 to -0.3; P = 0.028), and significantly more attention problems than LEV-exposed children (-3.7, CI: -6.7 to -0.8; P = 0.013). LTG-exposed children had significantly more attention deficit (-9.2, CI: -17.3 to 1.1; P = 0.026), but significantly less anxious behavior when compared to LEV-exposed children (9.0, CI: 0.3-17.6; P = 0.042).SignificanceCompared to population norms, a high proportion of children of mothers with epilepsy exposed prenatally to monotherapy with four common AEDs had clinical behavioral problems reported by parents. Different patterns were seen, with some but not all subscales raised for all AED exposure groups. It is important that prenatally AED-exposed children are regularly screened for behavioral problems so that appropriate help can be provided.

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Disrupted Social Hierarchy in Prenatally Valproate-Exposed Autistic-Like Rats.

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