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

Codagnone, Martín Gabriel; Podestá, María Fernanda; Uccelli, Nonthué Alejandra; Reinés, Analı́a

doi:10.1159/000375489

Cited by 88 publications

(75 citation statements)

References 73 publications

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“…All of these reports demonstrate increases in density or in glial "reactivity." The prefrontal cortex (63) and the cingulate (64) have increased astroglial profiles in autism. The prefrontal cortex (63) and the cingulate (64) have increased astroglial profiles in autism.…”

Section: Discussionmentioning

confidence: 99%

Primary olfactory cortex in autism and epilepsy: increased glial cells in autism

2016

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Autism Spectrum Disorder is characterized by sensory anomalies including impaired olfactory identification. Between 5 and 46 percent of individuals with autism have a clinical diagnosis of epilepsy. Primary olfactory cortex (piriform cortex) is central to olfactory identification and is an epileptogenic structure. Cytoarchitectural changes in olfactory cortex may underlie olfactory differences seen in autism. Primary olfactory cortex was sampled from 17 post-mortem autism cases with and without epilepsy, 11 epilepsy cases without autism and 11 typically developed cases. Stereological and neuropathological methods were used to quantify glial, pyramidal and non-pyramidal cell densities in layers of the piriform as well as identify pathological differences in this area and its neighbouring region, the olfactory tubercle. We found increased layer II glial cell densities in autism with and without epilepsy, which were negatively correlated with age and positively correlated with levels of corpora amylacea in layer I. These changes were also associated with greater symptom severity and did not extend to the olfactory tubercle. Glial cell organization may follow an altered trajectory of development with age in autism. The findings are consistent with other studies implicating increased glial cells in the autism brain. Altered cytoarchitecture may contribute to sensory deficits observed in affected individuals. This study provides evidence that autism is linked to alterations in the cytoarchitectural structure that underlies primary sensory processes and is not restricted to heteromodal ("higher") cognitive centers.

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Section: Discussionmentioning

confidence: 99%

Primary olfactory cortex in autism and epilepsy: increased glial cells in autism

2016

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“…Fewer postsynaptic densities are observed in the hippocampus of VPA exposed rodents [199], whereas more and thicker postsynaptic densities are present in the medial PFC [198]. VPA rats have increased microglia in the medial PFC and more astrocytes in the hippocampus [73]. Increased glial proliferation [213] and altered astrocyte and microglial densities are observed in the hippocampus and cerebellum following VPA exposure [189].…”

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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“…Looking at the effects on postnatal development, prenatal exposure to fluoxetine induces an anxiety-like phenotype in rats [74]. Also, in rodents, valproic acid administration during pregnancy disturbs the microbiome of the offspring and results in impairment of the social behaviour of the offspring [75, 76]. Owing to the prevalence of psychotropic administration during pregnancy, it is crucial to characterize the interaction between maternal health, microbiota and offspring neurodevelopment.…”

Section: External Challenges To Maternal Microbiota Dynamicsmentioning

confidence: 99%

Microbiota and Neurodevelopmental Trajectories: Role of Maternal and Early-Life Nutrition

et al. 2019

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Pregnancy and early life are characterized by marked changes in body microbial composition. Intriguingly, these changes take place simultaneously with neurodevelopmental plasticity, suggesting a complex dialogue between the microbes that inhabit the gastrointestinal tract and the brain. The purpose of this chapter is to describe the natural trajectory of microbiota during pregnancy and early life, as well as review the literature available on its interaction with neurodevelopment. Several lines of evidence show that the gut microbiota interacts with diet, drugs and stress both prenatally and postnatally. Clinical and preclinical studies are illuminating how these disruptions result in different developmental outcomes. Understanding the role of the microbiota in neurodevelopment may lead to novel approaches to the study of the pathophysiology and treatment of neuropsychiatric disorders.

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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

Cited by 88 publications

References 73 publications

Primary olfactory cortex in autism and epilepsy: increased glial cells in autism

Primary olfactory cortex in autism and epilepsy: increased glial cells in autism

Autism spectrum disorder: neuropathology and animal models

Microbiota and Neurodevelopmental Trajectories: Role of Maternal and Early-Life Nutrition

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