The Time of Prenatal Immune Challenge Determines the Specificity of Inflammation-Mediated Brain and Behavioral Pathology

Abstract

Disturbance to early brain development is implicated in several neuropsychiatric disorders including autism, schizophrenia, and mental retardation. Epidemiological studies have indicated that the risk of developing these disorders is enhanced by prenatal maternal infection, presumably as a result of neurodevelopmental defects triggered by cytokine-related inflammatory events. Here, we demonstrate that the effects of maternal immune challenge between middle and late gestation periods in mice are dissociable in terms of fetal brain cytokine responses to maternal inflammation and the pathological consequences in brain and behavior. Specifically, the relative expression of pro-and anti-inflammatory cytokines in the fetal brains in response to maternal immune challenge may be an important determinant among other developmental factors for the precise pathological profile emerging in later life. Thus, the middle and late gestation periods correspond to two windows with differing vulnerability to adult behavioral dysfunction, brain neuropathology in early adolescence, and of the acute cytokine responses in the fetal brain.

Adult behavioral and pharmacological dysfunctions following disruption of the fetal brain balance between pro-inflammatory and IL-10-mediated anti-inflammatory signaling

“…Here, we focused on adult spatial exploration, sensorimotor gating and selective associative learning, because previous reports in rodents have repeatedly demonstrated that prenatal PolyI:C exposure leads to functional abnormalities in these neuropsychological domains when the animals reach adult age. [14][15][16][17][18][19] First, spatial exploration was studied in an open field by focusing on the time the animals spent in the central area of the field during a 30-min test period. This test is widely applied to assess explorative behavior in rodents.…”

“…Fetal brains were extracted under visual guidance using a dissecting microscope (Stemi 2000-C; Zeiss, Oberkochen, Germany), as described previously. 16,17 Each fetal brain sample was weighed, placed in 1-ml Eppendorf (Hamburg, Germany) tubes, and stored at À801C until further processing (see below). To assess the long-term cytokine effects of prenatal PolyI:C exposure, pregnant macIL-10tg and wt dams were administered with PolyI:C or vehicle on GD 9 as described above, and the animals were allowed to give birth.…”

“…12 They may also be critically involved in the precipitation of the long-term behavioral, cognitive and pharmacological consequences of prenatal immune challenge as shown in vivo. [13][14][15][16][17][18][19][20] In contrast, very little is known about the putative roles of anti-inflammatory cytokines in the association between prenatal inflammation and the emergence of brain and behavioral abnormalities. One of the best characterized anti-inflammatory cytokine is IL-10.…”

“…26,27 Maternal immune activation by PolyI:C exposure in rodents is known to precipitate a wide spectrum of behavioral, cognitive and pharmacological abnormalities in the adult offspring. [14][15][16][17][18][19] Hence, the combination of the prenatal PolyI:C model with a mouse model of genetically driven IL-10 overexpression by macrophages allows us to explore the effects of pro-and anti-inflammatory cytokine signaling on brain and behavioral development following prenatal inflammatory conditions and innate immune imbalances. Here, we focused on the impact of the genetically and environmentally induced immunological manipulations on behavioral functions and pharmacological responses known to be disrupted by prenatal immune challenge, including sensorimotor gating, selective associative learning, spontaneous exploratory behavior and sensitivity to the psychomotor-stimulant effects of dopaminergic and glutamatergic drug challenge.…”

“…Here, we focused on the impact of the genetically and environmentally induced immunological manipulations on behavioral functions and pharmacological responses known to be disrupted by prenatal immune challenge, including sensorimotor gating, selective associative learning, spontaneous exploratory behavior and sensitivity to the psychomotor-stimulant effects of dopaminergic and glutamatergic drug challenge. [14][15][16][17][18][19] …”