Abstract
BackgroundPrenatal exposure to the viral mimic poly-I:C via the pregnant dam has been shown to lead to a broad spectrum of neuro-psycho-pathological features phenotypic of schizophrenia, recapitulating the well established link between maternal infection in pregnancy and increased schizophrenia risk in the offspring. We previously showed using longitudinal imaging that prenatal poly-I:C leads postnatally to volumetric brain abnormalities that precede the emergence of behavioral abnormalities (selective attention deficits and excessive response to amphetamine) in adulthood, and that an ultra-low dose of risperidone (RIS) given prior to “symptom” emergence, prevents the emergence of behavioral as well as structural brain deficits. Here we aimed at showing that the efficacy of RIS (assessed at adulthood) is a function of time of administration, with earlier but not later being effective.MethodsOn gestation day 15, pregnant Wistar rats were injected IV with polyI:C (4 mg/kg/ml) or saline. Offspring received daily injections of RIS (0.045 mg/kg) at 4 different time windows (TW): PNDs 34–47 (TW1), PNDs 48–61 (TW2), PNDs 62–75 (TW3) or PNDs 106–120 (TW4), and underwent structural imaging (scanned on a 7.0 T/30 cm; Bruker, Rheinstetten, Germany) and behavioral assessment of amphetamine-induced activity (AIA) and latent inhibition (LI). Excessive AIA is considered to mimic the exacerbation of psychotic symptoms in response to amphetamine in schizophrenia patients. LI reflects the normal attentional capacity to ignore stimuli that were experienced as irrelevant in the past; disrupted LI is considered to reflect a failure to ignore irrelevant stimuli and is seen in amphetamine-treated rodents and humans, in schizotypal persons, and in acutely psychotic schizophrenia patients. Testing was conducted on PNDs >90 (for TWs 1–3) and PNDs 106 and 150 (for TW4).ResultsPoly-I:C offspring had larger lateral ventricles (LV) and smaller prefrontal cortex (PFC), striatal (STR) and hippocampal (HIP) volumes, as well as disrupted LI and enhanced AIA compared to their controls. The effects of RIS on these abnormalities was a function of the administration window. RIS was fully effective when given in TW1 (significant prenatal treatment x drug treatment interaction for each of the brain regions as well as for both behavioral indices, and significant differences between poly-IC-vehicle but not between poly-I:C-RIS and the control groups). In TW2, RIS prevented all abnormalities with the exception of HIP volume reduction (statistics as above except for HIP region). In contrast, in both TW 3 and 4, RIS failed to prevent both structural and behavioral abnormalities (only main effect of prenatal treatment for volumetric and AIA measures and only prenatal treatment x preexposure interaction for LI).DiscussionThese results provide the first demonstration that intervention must indeed be provided early in order to be effective, with efficacy declining as the animal matures. Furthermore, they provide strong support for structure-function relationship because there is no prevention of behavioral abnormalities without prevention of structural abnormalities. Finally, since at the 0.045mg/kg dose RIS is a selective 5HT2A/2C antagonist, our results suggest that such antagonism is a promising route for prevention in high risk individuals.
Highlights
Positron emission tomography (PET) using radiolabeled ligands selective for the 18 kDa translocator protein (TSPO) is the most widely used technique to assess putative neuroimmune abnormalities in vivo
A 2-way ANOVA revealed a significant interaction between treatment and brain region for amoeboid but not resting microglia
These data confirm and extend our prior findings demonstrating that microglial activation is present already after 28 days of exposure to haloperidol and this effect is most prominent in the STR
Summary
S191 starting an AP or patients newly switching to CLZ. Groups A and B will be assessed at a single time point (week 0) whereas Group C will be assessed prospectively at weeks 0, 3, and 12 with the same measures collected. The difference between analytical groups (i.e. groups A, B, and C) at different time points (i.e. baseline, week 3 and 6) for variables such as BMI and metabolic parameters marker change are analyzed using two-way repeated measures ANCOVA, including significant covariates. Analysis of the Operational Taxonomic Unit network generated using QIIME will be further analyzed using linear discriminant analysis (LDA) effect size (LEfSe) method. This method uses LDA scores to estimate the effect size of differentially abundant taxa (at phyla, class or other levels) and ranks the relative difference of microbial taxa that discriminate groups with biological consistency and statistical significance. Marie Cotel*,1, Ewelina Lenartowicz, Sridhar Natesan, Maria Dadabhoy, Anthony Vernon1 1Institute of Psychiatry, Psychology & Neuroscience, King’s College London; 2Research Center for Molecular Medicine of the Austrian Academy of Sciences
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have