Early Development of Parvalbumin-, Somatostatin-, and Cholecystokinin-Expressing Neurons in Rat Brain following Prenatal Immune Activation and Maternal Iron Deficiency

Abstract

Prenatal maternal infection and maternal iron deficiency during pregnancy are 2 early environmental insults associated with increased risk for schizophrenia in offspring. Substantial evidence suggests that abnormalities in inhibitory γ-aminobutyric acid (GABA) interneuron function, especially in the parvalbumin subtype of GABA interneuron, both developmentally and in adulthood, may contribute mechanistically to cognitive deficits and psychotic symptoms in schizophrenia. This study used a rat model to test whether prenatal immune activation with lipopolysaccharide (LPS; at gestation days, GD, 15 and 16) or maternal iron deficiency (from GD2 to postnatal day P7) or the combination of both insults alters major subtypes of GABAergic interneurons (parvalbumin, somatostatin, cholecystokinin) in brain regions relevant to schizophrenia (medial and dorsolateral prefrontal cortex [PFC], hippocampal CA1 and dentate gyrus, ventral subiculum) in offspring at P14 or P28. Prenatal LPS treatment significantly increased the density of parvalbumin-immunoreactive neurons at P14 in the medial PFC, dorsolateral PFC, and ventral subiculum of offspring born from iron-sufficient but not iron-deficient dams. Prenatal LPS also increased cholecystokinin neuron density in the medial PFC at P28, under both iron-sufficient and iron-deficient conditions. We observed a large increase in parvalbumin neuron density from P14 to P28 in the medial PFC and subiculum across all birth groups, that was not observed in other brain regions, and significant decreases in somatostatin neuron density from P14 to P28 in all brain regions examined across all birth groups, indicating differential developmental trajectories for parvalbumin and somatostatin neurons in various brain regions during this early postnatal period. Thus, it appears that the medial PFC and ventral subiculum, brain regions involved in circuitry modulating ventral tegmental dopamine and nucleus accumbens activities, may be regions vulnerable to effects of prenatal LPS on specific subpopulations of interneurons. It is known that the timing of maturation and expansion of parvalbumin neurons in early development provides threshold levels of inhibition that trigger critical periods for cortical plasticity, leading to long-term circuit consolidation. Thus, our finding of increased parvalbumin neuron density at early developmental times might suggest a mechanism by which an acute prenatal insult like LPS exposure could produce long-term changes in prefrontal cortical or subicular function.

Effect of Immune Activation during Early Gestation or Late Gestation on Inhibitory Markers in Adult Male Rats

“…Reductions in both regions, however, are contrary to our hypothesis that postulated that the cortex is more susceptible to MIA than the striatum. Given that our previous behavioural study showed working memory impairments in GD19 polyI:C offspring, but not GD10 polyI:C offspring 50 , and multiple studies show a central role of somatostatinergic signalling in cognitive function [76][77][78][79] , our present findings suggest that the combined SSTR2 mRNA deficits in cortex and striatum (found only at GD19), in combination with the SST mRNA deficits in cortex and striatum, may contribute to the working memory deficits apparent in late gestation MIA offspring.…”

Maternal inhalation of carbon black nanoparticles induces neurodevelopmental changes in mouse offspring

“…Overall, the changes in PV interneurons bear high resemblance to the observations in established animal models of maternal inflammation [ 26 , 27 , 29 ]. As previously discussed, we were unable to detect maternal inflammation 11 and 28–29 days after exposure, but we cannot rule out that inflammation was present at earlier time points.…”

Maternal immune activation in neurodevelopmental disorders

“…This is in contrast to a recent observation that reported an increase in the number of PV immunoreactive cells in the dlPFC of adolescent male rats from LPS-treated dams (50 mg/kg i.p. on GD15/16) (Boksa et al, 2017). Other neuronal deficiencies, including in dopaminergic and serotonergic neurons, have been described in MIA models (Meyer et al, 2009b;Boksa, 2010;Vuillermot et al, 2012;Pratt et al, 2013;Smith et al, 2014;Squarzoni et al, 2014;Depino, 2015;Reisinger et al, 2015).…”

“…In contrast, MIA induction in mid-gestation (GD13-15) with Poly(I:C) results in an increase in Purkinje cell numbers in juvenile and adult mice (Aavani et al, 2015). on GD15/16) (Boksa et al, 2017). Defects in the development and function of interneurons have been implicated in a number of psychiatric disorders (Mar ın, 2012).…”