Behavioral Alterations and Decreased Number of Parvalbumin-Positive Interneurons in Wistar Rats after Maternal Immune Activation by Lipopolysaccharide: Sex Matters

Abstract

Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.

Influence of Prenatal Drug Exposure, Maternal Inflammation, and Parental Aging on the Development of Autism Spectrum Disorder

“…Microglial infiltration in the brain may be difficult to detect. In two models that produced ASD-like behavioral deficits following MIA [i.e., mice that were exposed to two doses of poly(I:C) on E12.5 and E17.5 ( 211 ) and rats that were exposed to daily injections of LPS from E7 to delivery ( 210 )], microglial infiltration in the brain was not detected. In Chen et al, HI superimposition on MIA induced microglial infiltration in the hippocampus ( 225 ).…”

Sex Differences in Affective Dysfunction and Alterations in Parvalbumin in Rodent Models of Early Life Adversity

“…Parvalbumin (PV), a calcium-binding protein expressed within a specific subset of GABAergic neurons, is thought to be involved in affective dysregulation characteristic of anxiety (e.g., Page et al, 2019 ; Xiao et al, 2020 ) and depression (e.g., Perova et al, 2015 ; Thaweethee-Sukjai et al, 2019 ). Indeed, reduced PV levels are associated with increased anxiety-like behavior and affective dysfunction in rodent studies (Godavarthi et al, 2014 ; Lussier and Stevens, 2016 ; Xu et al, 2016 ; Todorović et al, 2019 ; Vojtechova et al, 2021 ) and indirectly in human studies looking at Tourette syndrome, which is thought to be closely related to anxiety (Kalanithi et al, 2005 ; Kataoka et al, 2009 ). A multitude of studies have also found a reduction in PV interneurons in the hippocampus (HPC), prefrontal cortex (PFC), and basolateral amygdala (BLA), all of which are thought to be important for affective regulation following ELA (Leussis et al, 2012 ; Wieck et al, 2013 ; Ganguly et al, 2015 ; Grassi-Oliveira et al, 2016 ; Gildawie et al, 2021 ).…”

6‐Shogaol improves behavior and memory in Wistar rats prenatally exposed to lipopolysaccharide

“…MIA represents a severe environmental risk factor for the development of some neuropsychiatric disorders with unclear etiology, such as ASD. In rodents, MIA can be induced by application of lipopolysaccharide (LPS) during a critical period of early development (Lee et al, 2021; Vojtechova et al, 2021). LPS is a major component of the cell wall of Gram‐negative bacteria, causing strong immune system reaction with the release of pro‐inflammatory cytokines (Smolders et al, 2018).…”