Long-Lasting Changes in Glial Cells Isolated From Rats Subjected to the Valproic Acid Model of Autism Spectrum Disorder

UCCELLI, NONTHUÉ ALEJANDRA; RAMOS, ALBERTO JAVIER; ZÁRATE, SANDRA CRISTINA; REINÉS, ANALÍA; TRAETTA, MARIANELA EVELYN; GÓMEZ CUAUTLE, DANTE

Frontiers in Pharmacology

Frontiers

Año: 2021

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 with synaptic changes is poorly understood. Male Wistar rats prenatally exposed to valproic acid (VPA, 450 mg/kg, i.p.) or saline (control) at embryonic day 10.5 were used to study synapsestic, microglia and astroglia in the prefrontal cortex (PFC) at postnatal day (PND) 3 and 35. 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. Whereas at PND3 microglia and astroglia from VPA animals were morphologically similar to those of age-matched controls, at PND35, reactive microgliosis and astrogliosis were observed in the PFC of VPA animals. Microgliosis and astrogliosis were absent at PND3 but present at PND35 in the PFC of VPA animals. Cortical neurons isolated from VPA rats mimicked in vitro the synaptic pattern seen in vivo. 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 insensitivestunned or adapted to neuronal cues expressed by neurons from VPA animals. Further, long-term in vivo microgliosis could be the resultant 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 and consequently we propose this crosstalk as a potential target for interventions in this disorder.