Sensory and Motor Behaviors in Rats Treated Postnatally with Sodium Valproate

Background: Approximately 80% of children with Autism Spectrum Disorders (ASD) exhibit altered responses to normal environmental sensations. Behavioral patterns of over-responding and under-responding, specifically to touch and sounds, have been widely described. Motor coordination deficits have also been identified in this population. An animal model has been established in which two core features of autism (i.e. social deficits, repetitive behaviors) are elicited through injection of sodium valproate during sensitive periods of brain development. While this model resembles some features of autism, we do not yet know the full spectrum of behaviors these animals exhibit. Specifically, we do not know if the range of sensory responsivity seen in children with ASD is represented in this model; only patterns of over-responsiveness have been documented in the more commonly used pre-natal valproate rat model. The purpose of this study was to characterize sensory and motor patterns in the post-natal valproate rat model of autism.

Objectives: Compare auditory and tactile startle responses, sensory gating, and motor coordination in rats post-natally exposed to sodium valproate and rats with no valproate exposure.

Methods: Thirty-four Long-Evans rats were bred in our lab. Pups were randomly assigned to either the valproate or control group, with similar numbers of males (11 control, 13 valproate-treated) and females (5 control, 5 valproate-treated) per group. The teratogen valproate was delivered post-natally on days 6-12, with rats receiving a signal i.p. injection of valproate (dissolved in 0.9% saline, pH~7.3) of 150 mg/kg/day. Liter mate controls received a saline injection. All rats underwent testing for tactile and auditory responsiveness and auditory sensory gating (pre-pulse inhibition) on post-natal day (PND) 23 and day PND45. Motor testing was done on day 52 and included a video-recorded vermicelli handling task and a sunflower eating task.

Results: Valproate-treated rats exhibited significantly smaller auditory startle responses compared to responses of control rats. These differences were present in male rats on PND23 and PND45. Female rats treated with valproate showed significantly smaller responses on PND45 but not on PND23. Tactile startle response magnitude did not differ significantly between groups. Group differences in prepulse inhibition were only seen on PND45, with valproate rats inhibiting less than controls.

The Sunflower Seed Eating task and the third trial of the Vermicelli Handling task were completed significantly slower by the valproate-treated group.  During the Vermicelli Handling task, valproate-treated rats made significantly more paw adjustments and dropped the pasta significantly more often than the control rats. Valproate-treated rats were found to use a unilateral technique significantly more often than control rats and had more observed twirls, failure to contact reaches and atypical postures than the control group.

Conclusions: Findings suggest that post-natal valproate treatment elicits sensory and motor features often seen in individuals with ASD. Further, the hypo-sensitivity seen in post-natally valproate-treated rats contrasted with hyper-sensitivity previously reported in pre-natally valproate-exposed rats. This suggests that timing of teratogenic exposure during early brain development may be important to consider when investigating the neurobiological basis of sensory-motor impairments in ASD.