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Effects of Valproic Acid and Maternal Deprivation on Autism-Like Behaviours and Neurodevelopmental Outcomes in Female and Male Rats Publisher Pubmed



Sheibanitezerji S1, 2 ; Jonaidi H1 ; Sheibani V3 ; Moslemizadeh A4 ; Azizi S1 ; Dalili M5 ; Bashiri H3 ; Amiresmaili S6
Authors
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Authors Affiliations
  1. 1. Faculty of Veterinary Medicine, Shahid Bahonar University of Kerman, Kerman, Iran
  2. 2. Department of Behavioral and Molecular Neurobiology, Regensburg Center for Neuroscience, University of Regensburg, Regensburg, Germany
  3. 3. Neuroscience Research Center, Institute of Neuropharmacology, Department of Physiology and Pharmacology, Afzalipour School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
  4. 4. Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Clinical Research Development Unit, Afzalipour Hospital, Kerman University of Medical Sciences, Kerman, Iran
  6. 6. Department of Physiology, Bam University of Medical Sciences, Bam, Iran

Source: International Journal of Developmental Neuroscience Published:2025


Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by persistent social communication deficits and restricted, repetitive behaviours, with significant overlap in anxiety-related symptoms. Both genetic and environmental factors contribute to the development of ASD, with early-life stressors, such as maternal separation (MS), and exposure to neurotoxic agents, like valproic acid (VPA), being key environmental contributors. This study investigates the combined impact of maternal deprivation (MD) and postnatal VPA exposure on autism-like behaviours and neurodevelopmental outcomes in male and female rats. Rats exposed to MD from postnatal days 2 to 4 exhibited significant changes in social interaction and anxiety-like behaviours, with female rats being more sensitive to MD than males. Postnatal VPA exposure resulted in similar behavioural alterations, including increased anxiety and social impairment, aligning with previous findings of VPA-induced neurodevelopmental deficits. A combination of MD and VPA exposure exacerbated anxiety-like behaviours in females, indicating that early-life stress and environmental toxins can synergistically affect neurodevelopment. Our results further suggest that the impact of these exposures may differ between sexes, with females showing heightened sensitivity to both MD and VPA-induced stress. These findings provide valuable insights into the complex interactions between genetic, environmental and epigenetic factors in ASD pathophysiology. The study underscores the critical role of early-life stressors, such as MD, in exacerbating neurodevelopmental disorders, particularly when combined with neurotoxic environmental factors like VPA. The sex-specific differences observed in behavioural outcomes suggest the importance of considering biological sex in future ASD research and therapeutic strategies. © 2025 International Society for Developmental Neuroscience.
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