Microglia are the primary innate immune cells of the central nervous system and extensively contribute to brain homeostasis. Dysfunctional or excessive activity of microglia may be associated with several neuropsychiatric disorders, including schizophrenia. Therefore, we examined whether aripiprazole and risperidone could influence the expression of the Cd200-Cd200r and Cx3cl1-Cx3cr1 axes, which are crucial for the regulation of microglial activity and interactions of these cells with neurons. Additionally, we evaluated the impact of these drugs on microglial pro- and anti-inflammatory markers (Cd40, Il-1β, Il-6, Cebpb, Cd206, Arg1, Il-10 and Tgf-β) and cytokine release (IL-6, IL-10). The research was executed in organotypic cortical cultures (OCCs) prepared from the offspring of control rats (control OCCs) or those exposed to maternal immune activation (MIA OCCs), which allows for the exploration of schizophrenia-like disturbances in animals. All experiments were performed under basal conditions and after additional stimulation with lipopolysaccharide (LPS), following the \"two-hit\" hypothesis of schizophrenia. We found that MIA diminished the mRNA level of Cd200r and affected the OCCs\' response to additional LPS exposure in terms of this parameter. LPS downregulated the Cx3cr1 expression and profoundly changed the mRNA levels of pro- and anti-inflammatory microglial markers in both types of OCCs. Risperidone increased Cd200 expression in MIA OCCs, while aripiprazole treatment elevated the gene levels of the Cx3cl1-Cx3cr1 dyad in control OCCs. The antipsychotics limited the LPS-generated increase in the expression of proinflammatory factors (Il-1β and Il-6) and enhanced the mRNA levels of anti-inflammatory components (Cd206 and Tgf-β) of microglial polarization, mostly in the absence of the MIA procedure. Finally, we observed a more pronounced modulating impact of aripiprazole on the expression of pro- and anti-inflammatory cytokines when compared to risperidone in MIA OCCs. In conclusion, our data suggest that MIA might influence microglial activation and crosstalk of microglial cells with neurons, whereas aripiprazole and risperidone could beneficially affect these changes in OCCs.

BACKGROUND: A large body of work has reported a link between prenatal exposure to infection and increased psychiatric risk in offspring. However, studies to date have focused primarily on exposure to severe prenatal infections and/or individual psychiatric diagnoses in clinical samples, typically measured at single time points, and without accounting for important genetic and environmental confounders. In this study, we investigated whether exposure to common infections during pregnancy is prospectively associated with repeatedly assessed child psychiatric symptoms in a large population-based study.
METHODS: Our study was embedded in a prospective pregnancy cohort (Generation R; n = 3,598 mother-child dyads). We constructed a comprehensive prenatal infection score comprising common infections for each trimester of pregnancy. Child total, internalizing, and externalizing problems were assessed repeatedly using the parent-rated Child Behavioral Checklist (average age: 1.5, 3, 6, 10, and 14 years). Linear mixed-effects models were run adjusting for a range of confounders, including child polygenic scores for psychopathology, maternal chronic illness, birth complications, and infections during childhood. We also investigated trimester-specific effects and child sex as a potential moderator.
RESULTS: Prenatal exposure to infections was associated with higher child total, internalizing, and externalizing problems, showing temporally persistent effects, even after adjusting for important genetic and environmental confounders. We found no evidence that prenatal infections were associated with changes in child psychiatric symptoms over time. Moreover, in our trimester-specific analysis, we did not find evidence of significant timing effects of prenatal infection on child psychiatric symptoms. No interactions with child sex were identified.
CONCLUSIONS: Our research adds to evidence that common prenatal infections may be a risk factor for psychiatric symptoms in children. We also extend previous findings by showing that these associations are present early on, and that rather than changing over time, they persist into adolescence. However, unmeasured confounding may still explain in part these associations. In the future, employing more advanced causal inference designs will be crucial to establishing the degree to which these effects are causal.

Second generation antipsychotic drugs including aripiprazole, olanzapine and risperidone are prescribed increasingly (mostly off-label) to treat various mental disorders in children and adolescents. Early treatment with antipsychotics during this period may have long-lasting behavioural impacts, but to date there have been only limited investigations. Maternal infection could be implicated in the aetiology of various mental disorders including schizophrenia. Exposure of pregnant rodents to polyriboinosinic-polyribocytidylic acid (Poly I:C) causes schizophrenia-like behavioural abnormalities and neurodevelopmental conditions such as autism spectrum disorders in offspring. This study, using a Poly I:C rat model, investigated the long-lasting effects of early aripiprazole, olanzapine and risperidone treatment in the childhood/adolescent period (postnatal day 22-50) on adult behaviours of male rats. The study showed that early treatment with three antipsychotics had different effects on long-term behavioural changes in adults. Prenatal Poly I:C exposure (5 mg/kg) at gestation day 15 caused deficits in pre-pulse inhibition and social interaction, as well as cognitive impairments, that could be partially improved by early antipsychotic treatment in the juvenile period. Early antipsychotic treatment during the childhood-adolescent period resulted in similar long-lasting effects on pre-pulse inhibition, anxiety- and depressive-related behaviours in both Poly I:C and healthy (control) male rats. Overall, these results suggest that both prenatal Poly I:C exposure and early antipsychotic treatment in the childhood/adolescent period had long-lasting effects on adult behaviours of male rats, while early antipsychotic treatment could partly prevent the onset of behavioural abnormalities resulting from prenatal insult.

Attention-deficit/hyperactivity disorder (ADHD) has been associated with several autoimmune diseases (AD), both within individuals and across relatives, implying common underlying genetic or environmental factors in line with studies indicating that immunological mechanisms are key to brain development. To further elucidate the relationship between ADHD and autoimmunity we performed a population-wide familial co-aggregation study.
We linked Swedish national registries, defined a birth cohort with their biological relatives and identified individuals diagnosed with ADHD and/or 13 ADs. The cohort included 5 178 225 individuals born between 1960 and 2010, of whom 118 927 (2.30%) had been diagnosed with ADHD. We then investigated the associations between ADHD and ADs within individuals and across relatives, with logistic regression and structural equation modelling.
Within individuals, ADHD was associated with a diagnosis of any of the 13 investigated ADs (adjusted odds ratio (OR) =1.34, 95% confidence interval (CI) = 1.30-1.38) as well as several specific ADs. Familial co-aggregation was observed. For example, ADHD was associated with any of the 13 ADs in mothers (OR = 1.29, 95% CI = 1.26-1.32), fathers (OR = 1.14, 95% CI = 1.11-1.18), full siblings (OR = 1.19, 95% CI = 1.15-1.22), aunts (OR = 1.12, 95% CI = 1.10-1.15), uncles (OR = 1.07, 95% CI = 1.05-1.10) and cousins (OR = 1.04, 95% CI = 1.03-1.06). Still, the absolute risks of AD among those with ADHD were low. The genetic correlation between ADHD and a diagnosis of any of the investigated ADs was 0.13 (95% CI = 0.09-0.17) and the environmental correlation was 0.02 (95% CI = -0.03-0.06).
We found that ADHD and ADs co-aggregate among biological relatives, indicating that the relationship between ADHD and autoimmune diseases may in part be explained by shared genetic risk factors. The patterns of familial co-aggregation of ADHD and ADs do not readily support a role of maternal immune activation in the aetiology of ADHD. The findings have implications for aetiological models of ADHD. However, screening for autoimmunity among individuals with ADHD is not warranted.

Infection, particularly prenatal infection, leads to an enhanced risk of schizophrenia in the offspring. Interestingly, few data exist on the pathway(s) such as TLR and inflammasome, primarily involved in sensing the microorganisms and inducing downstream inflammatory responses, apoptosis and neuroprogressive changes that drive prenatal infection-induced risk of schizophrenia. Herein, we aimed to discern whether prenatal infection-induced maternal immune activation (MIA) causes schizophrenia-like behaviours through activation of TLR and inflammasome pathways in the brain of offspring. Sprague Dawley rats (n=15/group) were injected either with poly (I:C) or LPS or saline at gestational day (GD)-12. Significantly elevated plasma levels of IL-6, TNF-α and IL-17A assessed after 24 hours were observed in both the poly (I:C) and LPS-treated rats, while IL-1β was only elevated in LPS-treated rats, indicating MIA. The offspring of poly (I:C)-and LPS-treated dams displayed increased anxiety-like behaviours, deficits in social behaviours and prepulse inhibition. The hippocampus of offspring rats showed increased expression of Tlr3, Tlr4, Nlrp3, Il1b, and Il18 of poly (I:C) and Tlr4, Nlrp3, Cas1, Il1b, and Il18 of LPS-treated dams. Furthermore, Tlr and inflammasome genes were associated with social deficits and impaired prepulse inhibition in offspring rats. The results suggest that MIA due to prenatal infection can trigger TLR and inflammasome pathways and enhances the risk of schizophrenia-like behaviours in the later stages of life of the offspring.

Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental disorders later in life. The impact of the gestational timing of MIA exposure on downstream development remains unclear.
We characterized neurodevelopmental trajectories of mice exposed to the viral mimetic poly I:C (polyinosinic:polycytidylic acid) either on gestational day 9 (early) or on day 17 (late) using longitudinal structural magnetic resonance imaging from weaning to adulthood. Using multivariate methods, we related neuroimaging and behavioral variables for the time of greatest alteration (adolescence/early adulthood) and identified regions for further investigation using RNA sequencing.
Early MIA exposure was associated with accelerated brain volume increases in adolescence/early adulthood that normalized in later adulthood in the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety-like, stereotypic, and sensorimotor gating behaviors observed in adolescence normalized in adulthood. MIA exposure in late gestation had less impact on anatomical and behavioral profiles. Multivariate maps associated anxiety-like, social, and sensorimotor gating deficits with volume of the dorsal and ventral hippocampus and anterior cingulate cortex, among others. The most transcriptional changes were observed in the dorsal hippocampus, with genes enriched for fibroblast growth factor regulation, autistic behaviors, inflammatory pathways, and microRNA regulation.
Leveraging an integrated hypothesis- and data-driven approach linking brain-behavior alterations to the transcriptome, we found that MIA timing differentially affects offspring development. Exposure in late gestation leads to subthreshold deficits, whereas exposure in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders.

Multiple lines of evidence support the pathogenic role of maternal immune activation (MIA) in the occurrence of the schizophrenia-like disturbances in offspring. While in the brain the homeostatic role of neuron-microglia protein systems is well documented, the participation of the CX3CL1-CX3CR1 and CD200-CD200R dyads in the adverse impact of MIA often goes under-recognized. Therefore, in the present study, we examined the effect of MIA induced by polyinosinic:polycytidylic acid (Poly I:C) on the CX3CL1-CX3CR1 and CD200-CD200R axes, microglial trajectory (MhcII, Cd40, iNos, Il-1β, Tnf-α, Il-6, Arg1, Igf-1, Tgf-β and Il-4), and schizophrenia-like behaviour in adult male offspring of Sprague-Dawley rats. Additionally, according to the \"two-hit\" hypothesis of schizophrenia, we evaluated the influence of acute challenge with Poly I:C in adult prenatally MIA-exposed animals on the above parameters. In the present study, MIA evoked by Poly I:C injection in the late period of gestation led to the appearance of schizophrenia-like disturbances in adult offspring. Our results revealed the deficits manifested as a diminished number of aggressive interactions, presence of depressive-like episodes, and increase of exploratory activity, as well as a dichotomy in the sensorimotor gating in the prepulse inhibition (PPI) test expressed as two behavioural phenotypes (MIAPPI-low and MIAPPI-high). Furthermore, in the offspring rats subjected to a prenatal challenge (i.e., MIA) we noticed the lack of modulation of behavioural changes after the additional acute immune stimulus (Poly I:C) in adulthood. The important finding reported in this article is that MIA affects the expression and levels of the neuron-microglia proteins in the frontal cortex and hippocampus of adult offspring. We found that the changes in the CX3CL1-CX3CR1 axis could affect microglial trajectory, including decreased hippocampal mRNA level of MhcII and elevated cortical expression of Igf-1 in the MIAPPI-high animals and/or could cause the up-regulation of an inflammatory response (Il-6, Tnf-α, iNos) after the \"second hit\" in both examined brain regions and, at least in part, might differentiate behavioural disturbances in adult offspring. Consequently, the future effort to identify the biological background of these interactions in the Poly I:C-induced MIA model in Sprague-Dawley rats is desirable to unequivocally clarify this issue.

Genetic and environmental risk factors for psychiatric disorders are suggested to disrupt the trajectory of brain maturation during adolescence, leading to the development of psychopathology in adulthood. Rodent models are powerful tools to dissect the specific effects of such risk factors on brain maturational profiles, particularly when combined with Magnetic Resonance Imaging (MRI; clinically comparable technology). We therefore investigated the effect of maternal immune activation (MIA), an epidemiological risk factor for adult-onset psychiatric disorders, on rat brain maturation using atlas and tensor-based morphometry analysis of longitudinal in vivo MR images. Exposure to MIA resulted in decreases in the volume of several cortical regions, the hippocampus, amygdala, striatum, nucleus accumbens and unexpectedly, the lateral ventricles, relative to controls. In contrast, the volumes of the thalamus, ventral mesencephalon, brain stem and major white matter tracts were larger, relative to controls. These volumetric changes were maximal between post-natal day 50 and 100 with no differences between the groups thereafter. These data are consistent with and extend prior studies of brain structure in MIA-exposed rodents. Apart from the ventricular findings, these data have robust face validity to clinical imaging findings reported in studies of individuals at high clinical risk for a psychiatric disorder. Further work is now required to address the relationship of these MRI changes to behavioral dysfunction and to establish thier cellular correlates.

Evidence suggests that there is a link between the endocannabinoid system (ECS) and neuropsychiatric illnesses, including schizophrenia. Whilst the ECS has been shown to be involved in immune system regulation in various ways, it is known that infections during pregnancy can modulate the immune system of the mother and increase the risk for schizophrenia in offspring. In animal studies, maternal immune activation following administration of viral or bacterial mimics has been shown to reproduce many key structural, behavioural, and pharmacological abnormalities in offspring that resemble schizophrenia. In the present study, we used Positron Emission Tomography (PET) and [(18)F]MK-9470, a selective high-affinity inverse agonist radioligand for cannabinoid type 1 receptors (CB1R), to longitudinally assess CB1R expression in the progeny of female rats exposed to the viral mimic polyriboinosinic-polyribocytidilic acid (poly I:C) (4mg/kg i.v.) or vehicle at gestational day 15 (GD 15). PET scans were performed in offspring at postnatal days (PND) 32-42 (adolescence) and in the same animals again at PNDs 75-79 (adulthood). Sixteen regions of interest were assessed, encompassing the whole rat brain. At adolescence, offspring exposed prenatally to poly I:C had significantly lower CB1R relative Standard Uptake Values (rSUV) compared to controls in the globus pallidus (p=0.046). In adulthood, however, poly I:C exposed offspring had higher levels of CB1R rSUV in sensory cortex (p=0.034) and hypothalamus (p=0.032) compared to controls. Our results suggest that prenatal poly I:C leads to long term alterations in the integrity of the ECS that are age and region-specific. The increased CB1R expression in adulthood following poly I:C mirrors the increased CB1R observed in patients with schizophrenia in post-mortem and in vivo PET studies.