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Pharmacol."],"abstract":"<jats:p>Synaptic alterations concomitant with neuroinflammation have been described in patients and experimental models of autism spectrum disorder (ASD). However, the role of microglia and astroglia in relation to synaptic changes is poorly understood. Male Wistar rats prenatally exposed to valproic acid (VPA, 450\u00a0mg\/kg, i.p.) or saline (control) at embryonic day 10.5 were used to study synapses, microglia, and astroglia in the prefrontal cortex (PFC) at postnatal days 3 and 35 (PND3 and PND35). Primary cultures of cortical neurons, microglia, and astroglia isolated from control and VPA animals were used to study each cell type individually, neuron-microglia and microglia-astroglia crosstalk. In the PFC of VPA rats, synaptic changes characterized by an increase in the number of excitatory synapses were evidenced at PND3 and persisted until PND35. At PND3, microglia and astroglia from VPA animals were morphologically similar to those of age-matched controls, whereas at PND35, reactive microgliosis and astrogliosis were observed in the PFC of VPA animals. Cortical neurons isolated from VPA rats mimicked <jats:italic>in vitro<\/jats:italic> the synaptic pattern seen <jats:italic>in vivo<\/jats:italic>. Cortical microglia and astroglia isolated from VPA animals exhibited reactive morphology, increased pro-inflammatory cytokines, and a compromised miRNA processing machinery. Microglia from VPA animals also showed resistance to a phagocytic challenge. In the presence of neurons from VPA animals, microglia isolated from VPA rats revealed a non-reactive morphology and promoted neurite outgrowth, while microglia from control animals displayed a reactive profile and promoted dendritic retraction. In microglia-astroglia co-cultures, microglia from VPA animals displayed a reactive profile and exacerbated astrocyte reactivity. Our study indicates that cortical microglia from VPA animals are insensitive or adapted to neuronal cues expressed by neurons from VPA animals. Further, long-term <jats:italic>in vivo<\/jats:italic> microgliosis could be the result of altered microglia-astroglia crosstalk in VPA animals. Thus, our study highlights cortical microglia-astroglia communication as a new mechanism implicated in neuroinflammation in ASD; consequently, we propose that this crosstalk is a potential target for interventions in this disorder.<\/jats:p>","DOI":"10.3389\/fphar.2021.707859","type":"journal-article","created":{"date-parts":[[2021,8,5]],"date-time":"2021-08-05T06:14:06Z","timestamp":1628144046000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":23,"title":["Long-Lasting Changes in Glial Cells Isolated From Rats Subjected to the Valproic Acid Model of Autism Spectrum Disorder"],"prefix":"10.3389","volume":"12","author":[{"given":"Marianela Evelyn","family":"Traetta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nonthu\u00e9 Alejandra","family":"Uccelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra Cristina","family":"Z\u00e1rate","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dante","family":"G\u00f3mez Cuautle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto Javier","family":"Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anal\u00eda","family":"Rein\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,8,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/s41420-019-0166-6","article-title":"Notch Signaling in Astrocytes Mediates Their Morphological Response to an Inflammatory Challenge","volume":"5","author":"Acaz-Fonseca","year":"2019","journal-title":"Cell Death Discov."},{"key":"B2","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1016\/j.neuron.2017.09.056","article-title":"Cell Biology of Astrocyte-Synapse Interactions","volume":"96","author":"Allen","year":"2017","journal-title":"Neuron"},{"key":"B3","first-page":"947","volume-title":"Diagnostic and Statistical Manual of Mental Disorders: DSM-5","year":"2013"},{"key":"B4","doi-asserted-by":"publisher","first-page":"4072","DOI":"10.1093\/hmg\/ddq307","article-title":"A Genome-wide Scan for Common Alleles Affecting Risk for Autism","volume":"19","author":"Anney","year":"2010","journal-title":"Hum. 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