Myriel Nyffeler

The time of prenatal immune challenge determines the specificity of inflammation-mediated brain and behavioral pathology.

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 brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice.

Maternal infection during pregnancy increases the risk for neurodevelopmental disorders such as schizophrenia and autism in the offspring. This association appears to be critically dependent on the precise prenatal timing. However, the extent to which distinct adult psychopathological and neuropathological traits may be sensitive to the precise times of prenatal immune activation remains to be further characterized. Here, we evaluated in a mouse model of prenatal immune challenge by the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyIC), whether prenatal immune activation in early/middle and late gestation may influence the susceptibility to some of the critical cognitive, pharmacological, and neuroanatomical dysfunctions implicated in schizophrenia and autism. We revealed that PolyIC-induced prenatal immune challenge on gestation day (GD) 9 but not GD17 significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation specifically in late gestation impaired working memory, potentiated the locomotor reaction to the NMDA-receptor antagonist dizocilpine, and reduced hippocampal NMDA-receptor subunit 1 expression. On the other hand, potentiation of the locomotor reaction to the dopamine-receptor agonist amphetamine and reduction in Reelin- and Parvalbumin-expressing prefrontal neurons emerged independently of the precise times of prenatal immune challenge. Our findings thus highlight that prenatal immune challenge during early/middle and late fetal development in mice leads to distinct brain and behavioral pathological symptom clusters in adulthood. Further examination and evaluation of in utero immune challenge at different times of gestation may provide important new insight into the neuroimmunological and neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders such as schizophrenia and autism.

Relative Prenatal and Postnatal Maternal Contributions to Schizophrenia-Related Neurochemical Dysfunction after In Utero Immune Challenge

Prenatal exposure to infections represents a risk factor for the emergence of neuropsychiatric disorders in later life, including schizophrenia and autism. However, it remains essentially unknown whether this association is primarily attributable to prenatal and/or postnatal maternal effects on the offspring. Here, we addressed this issue by dissecting the relative contributions of prenatal inflammatory events and postnatal maternal factors in an animal model of prenatal viral-like infection. Pregnant mice were exposed to the inflammatory agent polyriboinosinic-polyribocytidilic acid (PolyI:C; 5 mg/kg, i.v.) or vehicle treatment on gestation day 9, and offspring born to PolyI:C- and vehicle-treated dams were cross fostered to surrogate rearing mothers that had either experienced inflammatory or sham treatment during pregnancy. We demonstrate that a variety of dopamine- and glutamate-related pharmacological and neuroanatomical disturbances emerge after prenatal immune challenge regardless of whether neonates were raised by vehicle- or PolyI:C-exposed surrogate mothers. However, the adoption of prenatal control animals to immune-challenged surrogate mothers was also sufficient to induce specific pharmacological and neuroanatomical abnormalities in the fostered offspring. Multiple schizophrenia-related dysfunctions emerging after prenatal immune challenge are thus mediated by prenatal but not postnatal maternal effects on the offspring, but immunological stress during pregnancy may affect postpartum maternal factors in such a way that being reared by an immune-challenged surrogate mother can confer risk for distinct forms of psychopathology in adult life.

Maternal immune activation during pregnancy increases limbic GABAA receptor immunoreactivity in the adult offspring: Implications for schizophrenia

Prenatal exposures to a variety of infections have been associated with an increased incidence of schizophrenia. We have reported that a single injection of the synthetic cytokine releaser PolyI:C to pregnant mice produced offspring that exhibited multiple schizophrenia-related behavioral deficits in adulthood. Here, we characterized the effect of maternal inflammation during fetal brain development on adult limbic morphology and expression of GABAA-receptors. The PolyI:C treatment did not induce morphological abnormalities but resulted in a significant increase in GABAA receptor subunit alpha2 immunoreactivity (IR) in the ventral dentate gyrus and basolateral amygdala in adult treated compared to control subjects. Correlative analyses between the a2 subunit IR in the ventral dentate gyrus and the performance in the prepulse inhibition paradigm revealed a significant correlation in controls that was however absent in the pathological condition. These results suggest that prenatal immune activation-induced disturbances of early brain development result in profound alterations in the limbic expression of GABAA receptors that may underlie the schizophrenia-related behavioral deficits in the adult mice.

Age-related accumulation of Reelin in amyloid-like deposits

Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimers disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Abeta species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD.

Differential expression of PSD proteins in age-related spatial learning impairments

Deficits in hippocampus-dependent spatial learning that are typical for a subpopulation of aged rats are not associated with loss of neurons or excitatory synapses but accompanied by significant reduction of postsynaptic density (PSD) area in perforated synapses. Here, we examined whether structural alterations in aged learning-impaired rats correlate with altered content of PSD proteins which are critically involved in normal synaptic function. Spatial memory tasks were used to separate male rats into young, aged learning-unimpaired and impaired groups. Semi-quantitative immunohistochemistry revealed significant alterations in the content of the AMPA receptor GluR1 subunit, PSD-95 and synGAP in the hippocampal formation of aged-learning impaired compared to aged-unimpaired and young rats. While synGAP expression was reduced, GluR1 and PSD95 levels were selectively increased in aged-learning-impaired subjects. These findings suggest that age-induced changes of the PSD protein expression levels are more pronounced in learning-impaired rats compared to unimpaired subjects and that the alterations in synaptic protein content may result in reduced synaptic function, potentially underlying the individual differences in mnemonic functions during aging.

Abnormal differentiation of newborn granule cells in age-related working memory impairments

Age-related declines in spatial memory have been linked to abnormal functional properties and connectivity of newborn granule cells. However, the relationship between adult neurogenesis, aging, and cognitive performance seems more complex than previously anticipated, likely due to the difficulty of disentangling alterations related to training as such and those associated with cognitive performance. Here, we investigated how different aspects of adult neurogenesis might be related to training, age and cognitive performance amongst aged subjects by comparing behaviourally naïve and tested rats of 3, 6, 24mo of age. We separated aged rats into learning-impaired and -unimpaired groups based on their performance in the Morris water maze to investigate neurogenesis-related morphological and neurochemical changes. We report an age-related decline in cell proliferation and maturation independent of cognitive performance and testing. We confirm an age-related altered differentiation of newborn neurons which was particularly prominent in learning-impaired rats. This was associated with an abnormally prolonged expression of the early progenitor marker Nestin, potentially also affecting maturation, survival/integration of newborn neurons into existing neuronal networks, which might underlie the individual differences in cognitive performance during aging.