Gestational Valproate Alters BOLD Activation in Response to Complex Social and Primary Sensory Stimuli

Ada C Felix-Ortiz,Marcelo Febo,Manabu Sakakibara

doi:10.1371/journal.pone.0037313

Ada C Felix-Ortiz, Marcelo Febo + Show 1 more

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https://doi.org/10.1371/journal.pone.0037313

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Journal: PloS one	Publication Date: May 17, 2012
Citations: 49	License type: CC BY 4.0

Affiliation: Northeastern University, University of Florida

Abstract

Valproic acid (VPA) has been used clinically as an anticonvulsant medication during pregnancy; however, it poses a neurodevelopmental risk due to its high teratogenicity. We hypothesized that midgestational (GD) exposure to VPA will lead to lasting deficits in social behavior and the processing of social stimuli. To test this, animals were given a single IP injection of 600 mg/kg of VPA on GD 12.5. Starting on postnatal day 2 (PND2), animals were examined for physical and behavior abnormalities. Functional MRI studies were carried out after PND60. VPA and control animals were given vehicle or a central infusion of a V1a antagonist 90 minutes before imaging. During imaging sessions, rats were presented with a juvenile test male followed by a primary visual stimulus (2 Hz pulsed light) to examine the effects of prenatal VPA on neural processing. VPA rats showed greater increases in BOLD signal response to the social stimulus compared to controls in the temporal cortex, thalamus, midbrain and the hypothalamus. Blocking the V1a receptor reduced the BOLD response in VPA animals only. Neural responses to the visual stimulus, however, were lower in VPA animals. Blockade with the V1a antagonist did not revert this latter effect. Our data suggest that prenatal VPA affects the processing of social stimuli and perhaps social memory, partly through a mechanism that may involve vasopressin V1a neurotransmission.

Highlights

Autism spectrum disorders (ASD), which includes autism, Asperger’s syndrome, and pervasive developmental disorder not otherwise specified (PD-NOS), are characterized by deficits in verbal and non-verbal communication, reduced social interactions, and restricted range of interests and motor stereotypies
The behavioral data show developmental defects associated with gestational valproic acid (VPA) exposure on cognition, locomotion and social interactions that is consistent with previous work [10]
Changes in Ultrasound vocalization (USV) patterns were observed between PND5 and PND11 that were independent of the VPA treatment

Summary

Introduction

Autism spectrum disorders (ASD), which includes autism, Asperger’s syndrome, and pervasive developmental disorder not otherwise specified (PD-NOS), are characterized by deficits in verbal and non-verbal communication, reduced social interactions, and restricted range of interests and motor stereotypies. Abnormalities in size of cerebellar [17] and brainstem auditory nuclei [9] and of motor [14] and sensory cortical neuron morphology [18] have been reported in rats treated prenatally with VPA, which parallels postmortem pathological findings in autistics.

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