Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism
Open accessAbstract
Autism spectrum disorders (ASD) are a group of developmental disabilities characterized by impaired social interaction, communication deficit and repetitive and stereotyped behaviors. Neuroinflammation and synaptic alterations in several brain areas have been suggested to contribute to the physiopathology of ASD. Although the limbic system plays an important role in the functions found impaired in ASD, reports on these areas are scarce and results controversial. In the present study we searched in the medial prefrontal cortex (mPFC) and hippocampus of rats exposed to the valproic acid (VPA) model of ASD for early structural and molecular changes, coincident in time with the behavioral alterations. After confirming delayed growth and maturation in VPA rats, we were able to detect decreased exploratory activity and social interaction at an early time point (postnatal day 35). In mPFC, although typical cortical column organization was preserved in VPA animals, we found that interneuronal space was wider than in controls. Hippocampal CA3 (cornu ammonis 3) pyramidal layer and the granular layer of the dentate gyrus both showed a disorganized spatial arrangement in VPA animals. Neuronal alterations were accompanied with increased tomato lectin and glial fibrillary acidic protein (GFAP) immunostainings both in the mPFC and hippocampus. In the latter region, the increased GFAP immunoreactivity was CA3 specific. At the synaptic level, while mPFC from VPA animals showed increased synaptophysin (SYN) immunostaining, a SYN deficit was found in all hippocampal subfields. Additionally, both the mPFC and the hippocampus of VPA rats showed increased neuronal cell adhesion molecule (NCAM) immunostaining together with decreased levels of its polysialylated form (PSA-NCAM). Interestingly, these changes were more robust in the CA3 hippocampal subfield. Our results indicate that exploratory and social deficits correlate with region-dependent neuronal disorganization and reactive gliosis in the mPFC and hippocampus of VPA rats. While microgliosis is spread in these two limbic areas, astrogliosis, although extended in the mPFC, is circumscribed to the CA3 hippocampal subfield. Our work indicates that neuroinflammation and synaptic alterations do coexist in VPA rats, making this model suitable for studying novel aspects of neuron-glia interactions. Moreover, it suggests that the mPFC and hippocampus might behave differently in the context of the local hyperconnectivity and synaptic hypotheses of autism.
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VPA rats have increased microglia in the medial PFC and more astrocytes in the hippocampus.
“VPA rats have increased microglia in the medial PFC and more astrocytes in the hippocampus [73].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [73]
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- Authors
- Codagnone, M. G., Podestá, M. F., Uccelli, N. A., & Reinés, A.
- Affiliations
- Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
- Venue
- Developmental Neuroscience
- Publisher
- S. Karger AG
- Published
- 2015
- Volume
- 37
- Issue
- 3
- Pages
- 215-231
- ISSN
- 0378-5866 (ISSN-L)
- 1421-9859
- OpenAlex
- W1973523291
- Cited by
- 115
- References
- 76
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 12 · 2023: 12 · 2022: 13 · 2021: 8 · 2020: 8 · 2019: 12 · 2018: 11 · 2017: 8 · 2016: 6 · 2015: 2
- FWCI
- 5.40
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Developmental Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Conicet (submittedVersion, cc-by-nc-sa)
- Funders
- Consejo Nacional de Investigaciones Científicas y Técnicas (PIP 2010)
- Universidad de Buenos Aires (CONICET)
- Secretaría de Ciencia y Técnica, Universidad de Buenos Aires
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- autism spectrum disorder, neuroinflammation, medial prefrontal cortex, hippocampus, CA3, reactive gliosis, microglial activation, astrocyte activation, synaptic changes, synaptophysin, CD56, PSA-NCAM, social interaction deficits, exploratory activity, neuron-glia interactions, limbic system, glial fibrillary acidic protein
- MeSH terms
- Animals, Autistic Disorder, Behavior, Animal, Disease Models, Animal, Exploratory Behavior, Female, Hippocampus, Male, Neurons, Pregnancy, Prenatal Exposure Delayed Effects, Social Behavior, Valproic Acid, Rats, Wistar, Prefrontal Cortex, GABA Agents, Rats
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