Increased hippocampal cell density and enhanced spatial memory in the valproic acid rat model of autism

Edalatmanesh, Mohammad Amin; Nikfarjam, Haniyeh; Vafaee, Farzaneh; Moghadas, Marzieh

doi:10.1016/j.brainres.2013.06.024

Cited by 66 publications

(55 citation statements)

References 55 publications

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“…Consequently, our findings are in agreement with those described by Bailey et al [55] in autistic patients and support the notion that neuronal disorganization does exist in the hippocampus of VPA rats. On the other hand, to our knowledge there is only one previous report that studied cell organization in the hippocampal subfields of VPA rats, but an increased cell density was found [42]. The discrepancy with our results could be due to the fact that Nissl staining was used in that study, whereas we used NeuN immunostaining, which specifically labels neuron nuclei.…”

Section: Discussioncontrasting

confidence: 51%

“…However, characterization of the cytoarchitectural, glial and synaptic profiles in the mPFC is still missing. Although the hippocampus of VPA animals seems to be functionally compromised, as revealed by social and spatial deficits [31,40,41], changes in dendritic spine density [39] and cytoarchitecture in adulthood [42] are the only evidence reported on hippocampal morphology in this model. An extensive description of both areas is relevant for understanding the neurobiological basis of the VPA phenotype and learning about possible candidates for interventions in ASD.…”

Section: Introductionmentioning

confidence: 99%

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Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism

et al. 2015

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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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Section: Discussioncontrasting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism

et al. 2015

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“…Bambini-Junior et al [66] reported that rats prenatally exposed to VA presented decreased flexibility to change strategy and social impairments similar to autistic symptoms, contributing to the understanding of neurodevelopmental symptoms and oxidative imbalance associated with the autism spectrum disorder. Edalatmanesh et al [67] provided proof to support the concept that spatial memory and hippocampal cell density are increased in VA autistic like rats which involved the hippocampus abnormalities in ASD animal model. IL-6 elevation in the brain could mediate autistic-like behaviours, potentially via imbalances of neural circuitry and impairments of synaptic plasticity [55].…”

Section: Discussionmentioning

confidence: 90%

Interplay between pro-inflammatory cytokines and brain oxidative stress biomarkers: Evidence of parallels between butyl paraben intoxication and the valproic acid brain physiopathology in autism rat model

2015

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“…Cell density is increased in the hippocampus [94], but it is decreased in the cerebellum [164] and the superior olivary nuclei of the brainstem [221] following prenatal VPA exposure. VPA exposure in utero leads to fewer parvalbumin-expressing interneurons in the parietal and occipital cortex [127], fewer glutamate decarboxylase 67-immunoreactive interneurons in the dentate gyrus, in the cerebellum and in the cortex [374], and loss of motor neurons in some of the motor nerve nuclei in the brainstem [303].…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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Increased hippocampal cell density and enhanced spatial memory in the valproic acid rat model of autism

Cited by 66 publications

References 55 publications

Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism

Differential Local Connectivity and Neuroinflammation Profiles in the Medial Prefrontal Cortex and Hippocampus in the Valproic Acid Rat Model of Autism

Interplay between pro-inflammatory cytokines and brain oxidative stress biomarkers: Evidence of parallels between butyl paraben intoxication and the valproic acid brain physiopathology in autism rat model

Autism spectrum disorder: neuropathology and animal models

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