Distinctive profiles of cortical and hippocampal microglia in the valproic acid rat model of autism spectrum disorder.

TRAETTA ME; UCCELLI NA; ZÁRATE S; GOMEZ MB; GOMEZ CUAUTLE D; RAMOS AJ; REINÉS A

CABA

Congreso; V IMBS Congress; 2021

facultad de Farmacia y Bioquimica, Universidad de Buenos Aires

Autism spectrum disorder (ASD) is a developmental condition characterized by social and communication deficits along with restricted and repetitive patterns of behavior. Sex differences in ASD involve higher incidence in boys and differences in the type and grade of symptoms between sexes. However, the basis of these differences is poorly understood. Microglia might play a key role since they show sex-dependent features and reactive microgliosis has been reported both in patients and animal models of ASD. The valproic acid (VPA) model of ASD mimics the main behavioral and neuroanatomical alterations found in patients with ASD. The aim of this study was to address microglia in male and female rats prenatally exposed to VPA, particularly in brain areas related to the core symptoms of ASD: the prefrontal cortex (PFC) and the hippocampus. We performed Iba1 immunostaining on tissue slices of juvenile control and VPA animals of both sexes. Regarding the PFC, both male and female VPA rats showed microgliosis characterized by a higher proportion of unramified cells. However, when analyzing the hippocampus, sex differences emerged as microgliosis was only evident in female VPA rats. To address microglia reactivity and response to different stimuli we cultured microglia cells isolated from control and VPA neonates. We performed immunoassays for Iba-1 to study microglia morphology under basal conditions and after exposure either to a pro-inflammatory stimulus (lipopolysaccharide) or a phagocytic one (synaptic terminals). While microglia from male VPA animals isolated from the cortex showed a pro-inflammatory profile and an intrinsic resistance to phagocytic stimuli, hippocampal microglia from male VPA animals matched microglia from controls under basal condition and were able to respond to pro-inflammatory and phagocytic stimuli. In the case of microglia isolated from females, both cortical and hippocampal microglia from VPA animals evidenced morphological changes under basal conditions but both were able to respond to pro-inflammatory and phagocytic stimuli. To sum up, microglia from male and female VPA rats show area- and sex-dependent changes which may underlie different behavior outcomes in female and male VPA rats.