Abstract Epidemiological studies with human populations indicate associations between maternal infection during pregnancy and increased risk in offspring for central nervous system (CNS) disorders ...including schizophrenia, autism and cerebral palsy. Since 2000, a large number of studies have used rodent models of systemic prenatal infection or prenatal immune activation to characterize changes in brain function and behavior caused by the prenatal insult. This review provides a comprehensive summary of these findings, and examines consistencies and trends across studies in an effort to provide a perspective on our current state of understanding from this body of work. Results from these animal modeling studies clearly indicate that prenatal immune activation can cause both acute and lasting changes in behavior and CNS structure and function in offspring. Across laboratories, studies vary with respect to the type, dose and timing of immunogen administration during gestation, species used, postnatal age examined and specific outcome measure quantified. This makes comparison across studies and assessment of replicability difficult. With regard to mechanisms, evidence for roles for several acute mediators of effects of prenatal immune activation has emerged, including circulating interleukin-6, increased placental cytokines and oxidative stress in the fetal brain. However, information required to describe the complete mechanistic pathway responsible for acute effects of prenatal immune activation on fetal brain is lacking, and no studies have yet addressed the issue of how acute prenatal exposure to an immunogen is transduced into a long-term CNS change in the postnatal animal. Directions for further research are discussed.
...it has been suggested that smoking may contribute to the development and maintenance of anxiety disorders through nicotine's modulation of fear memory and emotion processing.13 Effects of smoking ...on monoaminergic and glutamatergic systems, oxidative stress, and inflammatory and neurotrophic processes have also been hypothesized to contribute to the neuropathological mechanisms involved in the progression of bipolar disorder.14 Smoking causes brain changes on its own that may affect psychiatric symptoms With regards to neuropsychological function, short-term administration of nicotine has positive effects on aspects of cognition, including learning, memory and attention in healthy individuals,15-17 as well as in patients with schizophrenia, Alzheimer disease or ADHD.15,16 In contrast, chronic tobacco smoking has been shown to be associated with deficits in cognitive function, prominently verbal memory and processing speed, in middle-aged to elderly adults.16,17 Structural neuroimaging studies indicate that chronic tobacco smoking is associated with cortical thinning and size decreases in various brain structures.
While some candidate biomarkers can be shown to be highly associated with a psychiatric disorder (i.e., high sensitivity), the specificity of the biomarkers for the disorder may also be particularly ...problematic in the case of psychiatric disorders. In general, there is large overlap in pathophysiological findings among psychiatric disorders, and a biomarker must not only differentiate disorder A from healthy control conditions, but must also differentiate disorder A from disorders B-Z.
Other proteins, which have been shown to be reduced in the postmortem brains of persons with schizophrenia, may also plausibly interact with mechanisms regulating synaptic stability and elimination.
Epidemiological evidence suggests that maternal infection during pregnancy may be a risk factor for schizophrenia and autism. Altered expression of glutamic acid decarboxylase (GAD67) and reelin in ...the hippocampus has been reported in post-mortem studies of people with schizophrenia or autism. We used two mouse models of maternal inflammation, featuring either the viral RNA mimic, poly (I:C), or the bacterial endotoxin, lipopolysaccharide (LPS), to compare effects of maternal inflammation on GAD67 and reelin expression in the hippocampal stratum oriens of juvenile mice. Pregnant Swiss-Webster mice were treated with poly (I:C) or LPS on gestational day 9. At postnatal days (PD) 14 and 28, brains from male and female offspring were processed immunohistochemically, and NeuN-, GAD67- and reelin-positive cells estimated using unbiased stereological cell counting methods. In offspring at PD14, GAD67 and reelin expression were unaffected by prenatal poly (I:C) or prenatal LPS treatment, although prenatal LPS mice showed increased neuronal (NeuN) density at this age. However, at PD28, mice prenatally treated with poly (I:C) displayed a decreased number of reelin-positive cells in dorsal stratum oriens. Interestingly, at PD28, we also found increased GAD67 expression in the ventral stratum oriens in male mice prenatally treated with LPS, and in female mice prenatally treated with poly (I:C). Our findings describe sex-, age-, and immunogen-specific alterations in regional hippocampal GAD67 and reelin expression as a result of early maternal inflammation. These neurodevelopmental changes could have significant effects on GABAergic neurotransmission and synaptic plasticity.
► We compare LPS or poly (I:C) administration on gestational day 9 in mice. ► We examine alterations in reelin and GAD67 expression in stratum oriens of offspring. ► At postnatal day 28 there are treatment and sex specific changes in reelin and GAD67. ► Reelin and GAD67 changes as a result of maternal inflammation are immunogen-specific.
Abstract Both iron deficiency (ID) and infection are common during pregnancy and studies have described altered brain development in offspring as a result of these individual maternal exposures. ...Given their high global incidence, these two insults may occur simultaneously during pregnancy. We recently described a rat model which pairs dietary ID during pregnancy and prenatal immune activation. Pregnant rats were placed on iron sufficient (IS) or ID diets from embryonic day 2 (E2) until postnatal day 7, and administered the bacterial endotoxin, lipopolysaccharide (LPS) or saline on E15/16. In this model, LPS administration on E15 caused greater induction of the pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor-α, in ID dams compared to IS dams. This suggested that the combination of prenatal immune activation on a background of maternal ID might have more adverse neurodevelopmental consequences for the offspring than exposure to either insult alone. In this study we used this model to determine whether combined exposure to maternal ID and prenatal immune activation interact to affect juvenile and adult behaviors in the offspring. We assessed behaviors relevant to deficits in humans or animals that have been associated with exposure to either maternal ID or prenatal immune activation alone. Adult offspring from ID dams displayed significant deficits in pre-pulse inhibition of acoustic startle and in passive avoidance learning, together with increases in cytochrome oxidase immunohistochemistry, a marker of metabolic activity, in the ventral hippocampus immediately after passive avoidance testing. Offspring from LPS treated dams showed a significant increase in social behavior with unfamiliar rats, and subtle locomotor changes during exploration in an open field and in response to amphetamine. Surprisingly, there was no interaction between effects of the two insults on the behaviors assessed, and few observed alterations in juvenile behavior. Our findings show that long-term effects of maternal ID and prenatal LPS were additive, such that offspring exposed to both insults displayed more adult behavioral abnormalities than offspring exposed to one alone.
More recently, some laboratories have attempted to confirm maternal infection more precisely by analyzing antibodies for viral infection in maternal serum that had been stored from 30 to 40 years ...until offspring had grown and developed schizophrenia. As can be appreciated, these are very challenging studies with limits in the sample size due to limited availability of stored serum, questions about storage and stability of samples, etc.
As outlined earlier, publication of negative findings is essential to interpreting the overall significance of a field of research. However, papers with negative findings are less likely to be highly ...cited than papers with positive findings and less likely overall to be noticed in the scientific commun - ity.
With the presentation in Ottawa this spring of the report from the Truth and Reconciliation Commission (TRC) of Canada on Indian residential schools, the well-being of Canada's Aboriginal peoples ...took centre stage for a few days in the media and minds of the Canadian public. The TRC documented key historical issues that have contributed to major mental health disparities in Canada's indigenous population and pointed the way toward a larger process of national reconciliation. Because JPN is the official journal of the Canadian College of Neuropsychopharmacology, a Canadian society devoted to understanding mental health and disease, the authors are taking the opportunity with this editorial to keep the discussion going forward by highlighting the mental wellness of Aboriginal peoples in Canada. They present a brief historical background of some of the factors recognized as contributing to current mental health challenges faced by the Aboriginal population and end with some suggestions on how mental health professionals might contribute to the reconciliation process.
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