S188. The Phosphodiesterase-9 Inhibitor BI 409306 Attenuates Social Interaction and Dopaminergic Deficits in Adult Offspring of poly(I:C)-Based Maternal Immune Activation Neurodevelopmental Mouse Model

AbstractMaternal immune activation (MIA) plays a role in the etiology of schizophrenia. MIA by prenatal exposure of polyinosinic:polycytidylic acid [poly(I:C)] in rodents caused behavioral and neurobiological changes relevant to schizophrenia in adult offspring. We investigated whether the novel antidepressant (R)-ketamine could prevent the development of psychosis-like phenotypes in adult offspring after MIA. We examined the effects of (R)-ketamine (10 mg/kg/day, twice weekly for 4 weeks) during juvenile and adolescent stages (P28–P56) on the development of cognitive deficits, loss of parvalbumin (PV)-immunoreactivity in the medial prefrontal cortex (mPFC), and decreased dendritic spine density in the mPFC and hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, we examined the role of TrkB in the prophylactic effects of (R)-ketamine. Repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages significantly blocked the development of cognitive deficits, reduced PV-immunoreactivity in the prelimbic (PrL) of mPFC, and decreased dendritic spine density in the PrL of mPFC, CA3 and dentate gyrus of the hippocampus from adult offspring after prenatal poly(I:C) exposure. Furthermore, pretreatment with ANA-12 (TrkB antagonist: twice weekly for 4 weeks) significantly blocked the beneficial effects of (R)-ketamine on cognitive deficits of adult offspring after prenatal poly(I:C) exposure. These data suggest that repeated intermittent administration of (R)-ketamine during juvenile and adolescent stages could prevent the development of psychosis in adult offspring after MIA. Therefore, (R)-ketamine would be a potential prophylactic drug for young subjects with high-risk for psychosis.

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M180. SUSCEPTIBILITY AND RESILIENCE IN A MOUSE MODEL OF MATERNAL IMMUNE ACTIVATION

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa030.492 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S204-S205

Author(s):

Flavia Müller ◽

Joseph Scarborough ◽

Juliet Richetto ◽

Sina Schalbetter ◽

Ulrike Weber-Stadlbauer ◽

...

Keyword(s):

Mouse Model ◽

Immune Activation ◽

Psychotic Disorders ◽

Sensorimotor Gating ◽

Epidemiological Studies ◽

Poly I:C ◽

Behavioral Testing ◽

Experimental Conditions ◽

Maternal Immune Activation ◽

Mitochondrial Functions

Abstract Background Epidemiological studies over the past decades have repeatedly implicated maternal immune activation (MIA) in the etiology of psychiatric illnesses, including schizophrenia and related psychotic disorders. Not all offspring exposed to MIA, however, develop overt pathologies, suggesting that some are susceptible while others are resilient to MIA. To elucidate susceptibility and resilience in MIA, we used a mouse model that is based on prenatal exposure to the viral mimic poly(I:C). Methods Poly(I:C)-based MIA was induced in C57BL6/N mice on gestation day 12. Control dams received vehicle solution only. Offspring of poly(I:C)- or vehicle-exposed dams were subjected to a comprehensive behavioral testing battery when they reached adulthood (12 weeks of age onwards). Next-generation mRNA sequencing and gene pathway analyses were conducted after behavioral testing to explore the molecular correlates of resilience and susceptibility to MIA. Results Behavioral characterization coupled with unbiased TwoStep cluster analysis of a large number offspring (N >150) revealed that offspring exposed to MIA could be stratified into susceptible and resilient subgroups. While the former was characterized by deficits in social interaction, sensorimotor gating, and working memory, the behavioral profile of the latter was indistinguishable from control offspring. Susceptible and resilient MIA offspring were also dissociable by the presence of distinct molecular profiles in cortical and subcortical brain areas. In the medial prefrontal cortex, susceptible MIA offspring displayed a more profound deregulation of genes relevant for oxidative phosphorylation and mitochondrial functions than resilient MIA offspring. In the amygdala, the susceptible and resilient offspring differed in gene transcription pertinent to opioid signaling, DARPP-32 signaling, and G protein-coupled receptor signaling. Discussion Our data show that MIA can result in substantial phenotypic and transcriptomic variability even in the context of genetic homogeneity and under identical experimental conditions. If extended further, our model system may help to explain why only a subgroup of offspring exposed to MIA develops overt neurodevelopmental sequelae.

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Role of Polyinosinic:Polycytidylic Acid-Induced Maternal Immune Activation and Subsequent Immune Challenge in the Behaviour and Microglial Cell Trajectory in Adult Offspring: A Study of the Neurodevelopmental Model of Schizophrenia

International Journal of Molecular Sciences ◽

10.3390/ijms22041558 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1558

Author(s):

Katarzyna Chamera ◽

Ewa Trojan ◽

Katarzyna Kotarska ◽

Magdalena Szuster-Głuszczak ◽

Natalia Bryniarska ◽

...

Keyword(s):

Immune Activation ◽

Mrna Level ◽

Poly I:C ◽

Adult Offspring ◽

Sprague Dawley ◽

Maternal Immune Activation ◽

Polyinosinic:Polycytidylic Acid ◽

Sprague Dawley Rats ◽

Tnf Α

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.

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Maternal immune activation in rats attenuates the excitability of monoamine-secreting neurons in adult offspring in a sex-specific way

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2020.12.002 ◽

2020 ◽

Author(s):

Kristina Csatlosova ◽

Eszter Bogi ◽

Barbora Durisova ◽

Daniil Grinchii ◽

Ruslan Paliokha ◽

...

Keyword(s):

Immune Activation ◽

Adult Offspring ◽

Maternal Immune Activation

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The Effect of Maternal Immune Activation on Social Play-Induced Ultrasonic Vocalization in Rats

Brain Sciences ◽

10.3390/brainsci11030344 ◽

2021 ◽

Vol 11 (3) ◽

pp. 344

Author(s):

Kinga Gzielo ◽

Agnieszka Potasiewicz ◽

Ewa Litwa ◽

Diana Piotrowska ◽

Piotr Popik ◽

...

Keyword(s):

Immune Activation ◽

Social Play ◽

Autism Spectrum ◽

Repetitive Behaviors ◽

Male Rats ◽

Poly I:C ◽

Maternal Immune Activation ◽

Increased Risk ◽

Adolescent Rats ◽

The Impact

Prenatal maternal infection is associated with an increased risk of various neurodevelopmental disorders, including autism spectrum disorders (ASD). Maternal immune activation (MIA) can be experimentally induced by prenatal administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic viral-like double-stranded RNA. Although this MIA model is adopted in many studies, social and communicative deficits, included in the first diagnostic criterion of ASD, are poorly described in the offspring of poly(I:C)-exposed dams. This study aimed to characterize the impact of prenatal poly(I:C) exposure on socio-communicative behaviors in adolescent rats. For this purpose, social play behavior was assessed in both males and females. We also analyzed quantitative and structural changes in ultrasonic vocalizations (USVs) emitted by rats during the play test. Deficits of social play behaviors were evident only in male rats. Males also emitted a significantly decreased number of USVs during social encounters. Prenatal poly(I:C) exposure also affected acoustic call parameters, as reflected by the increased peak frequencies. Additionally, repetitive behaviors were demonstrated in autistic-like animals regardless of sex. This study demonstrates that prenatal poly(I:C) exposure impairs socio-communicative functioning in adolescent rats. USVs may be a useful tool for identifying early autistic-like abnormalities.

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