Adolescent environmental enrichment prevents the emergence of schizophrenia-like abnormalities in a neurodevelopmental model of schizophrenia

Bator, Ewelina; Latusz, Joachim; Wędzony, K; Maćkowiak, Marzena

doi:10.1016/j.euroneuro.2017.11.013

Cited by 42 publications

(30 citation statements)

References 58 publications

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“…This finding contrasts with the data obtained for Wistar rats, described previously by our team [ 40 ] and by Kirsten et al [ 75 ], suggesting that social interactions strongly depend on an interaction between the genetic background and experimental design [ 53 , 76 ]. In the present study, we applied a different protocol [ 48 ] than the procedure based on the assessment of social interaction in the resident–intruder paradigm which was used previously [ 40 ].…”

Section: Discussionmentioning

confidence: 99%

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Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200–CD200R and CX3CL1–CX3CR1 Systems

Chamera

Szuster-Głuszczak

Trojan

et al. 2020

Cells

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Early life challenges resulting from maternal immune activation (MIA) may exert persistent effects on the offspring, including the development of psychiatric disorders, such as schizophrenia. Recent evidence has suggested that the adverse effects of MIA may be mediated by neuron–microglia crosstalk, particularly CX3CL1–CX3CR1 and CD200–CD200R dyads. Therefore, the present study assessed the behavioural parameters resembling schizophrenia-like symptoms in the adult male offspring of Sprague-Dawley rats that were exposed to MIA and to an additional acute lipopolysaccharide (LPS) challenge in adulthood, according to the “two-hit” hypothesis of schizophrenia. Simultaneously, we aimed to clarify the role of the CX3CL1–CX3CR1 and CD200–CD200R axes and microglial reactivity in the brains of adult offspring subjected to MIA and the “second hit” wit LPS. In the present study, MIA generated a range of behavioural changes in the adult male offspring, including increased exploratory activity and anxiety-like behaviours. The most intriguing finding was observed in the prepulse inhibition (PPI) test, where the deficit in the sensorimotor gating was age-dependent and present only in part of the rats. We were able to distinguish the occurrence of two groups: responsive and non-responsive (without the deficit). Concurrently, based on the results of the biochemical studies, MIA disrupted mainly the CD200–CD200R system, while the changes of the CX3CL1–CX3CR1 axis were less evident in the frontal cortex of adult non-responsive offspring. MIA markedly affected the immune regulators of the CD200–CD200R pathway as we observed an increase in cortical IL-6 release in the responsive group and IL-4 in the non-responsive offspring. Importantly, the “second hit” generated disturbances at the behavioural and biochemical levels mostly in the non-responsive adult animals. Those offspring were characterized both by disturbed PPI and “priming” microglia. Altogether, the exposure to MIA altered the immunomodulatory mechanisms, including the CD200–CD200R axis, in the brain and sensitized animals to subsequent immunological challenges, leading to the manifestation of schizophrenia-like alterations.

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Section: Discussionmentioning

confidence: 99%

“…The tests investigating social interactions of the animals were performed using the protocol described by Bator et al [ 48 ]. The experiments were conducted in an open field arena (60 × 60 × 30 cm) made of black Plexiglas and dimly illuminated (18 lx) with indirect light.…”

Section: Methodsmentioning

confidence: 99%

Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200–CD200R and CX3CL1–CX3CR1 Systems

Chamera

Szuster-Głuszczak

Trojan

et al. 2020

Cells

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“…The experiments investigating social interactions of the animals ( n = 6 in each group) were conducted based on a protocol described by Bator et al [ 43 ] in an open field space (60 × 60 × 30 cm) made of black Plexiglas and dimly illuminated (18 lx) with indirect light. The day before the test, male offspring (PND91) were transferred to the experimental room and were allowed to individually adapt to the open field arena for 7 min.…”

Section: Methodsmentioning

confidence: 99%

The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Chamera

Kotarska

Szuster-Głuszczak

et al. 2020

J Neuroinflammation

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Background The bidirectional communication between neurons and microglia is fundamental for the homeostasis and biological function of the central nervous system. Maternal immune activation (MIA) is considered to be one of the factors affecting these interactions. Accordingly, MIA has been suggested to be involved in several neuropsychiatric diseases, including schizophrenia. The crucial regulatory systems for neuron-microglia crosstalk are the CX3CL1-CX3CR1 and CD200-CD200R axes. Methods We aimed to clarify the impact of MIA on CX3CL1-CX3CR1 and CD200-CD200R signalling pathways in the brains of male Wistar rats in early and adult life by employing two neurodevelopmental models of schizophrenia based on the prenatal challenge with lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (Poly I:C). We also examined the effect of MIA on the expression of microglial markers and the profile of cytokines released in the brains of young offspring, as well as the behaviour of adult animals. Moreover, we visualized the localization of ligand-receptor systems in the hippocampal regions (CA1, CA3 and DG) and the frontal cortex of young rats exposed to MIA. The differences between groups were analysed using Student’s t test. Results We observed that MIA altered developmental trajectories in neuron-microglia communication in the brains of young offspring, as evidenced by the disruption of CX3CL1-CX3CR1 and/or CD200-CD200R axes. Our data demonstrated the presence of abnormalities after LPS-induced MIA in levels of Cd40 , Il-1β , Tnf-α , Arg1 , Tgf-β and Il-10 , as well as IBA1, IL-1β and IL-4, while after Poly I:C-generated MIA in levels of Cd40 , iNos , Il-6 , Tgf-β , Il-10 , and IBA1, IL-1β, TNF-α, IL-6, TGF-β and IL-4 early in the life of male animals. In adult male rats that experienced prenatal exposure to MIA, we observed behavioural changes resembling a schizophrenia-like phenotype. Conclusions Our study provides evidence that altered CX3CL1-CX3CR1 and/or CD200-CD200R pathways, emerging after prenatal immune challenge with LPS and Poly I:C, might be involved in the aetiology of schizophrenia.

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“…The extracted chromatin was sheared to 100-1000 bp using a Sonic Dismembrator Vibra-Cell VCX-130 (Sonics, USA). Each sample was sonicated five times on ice for 10 s each time at 20% of maximum power (Bator et al 2018). Chromatin was immunoprecipitated using the antibody anti-myocyte enhancer factor 2D (MEF2D, Santa Cruz Biotechnology, USA) and EZ-Magna ChIP according to the manufacturer's instructions.…”

Section: Chromatin Immunoprecipitationmentioning

confidence: 99%

“…The mPFC was dissected from coronal sections, frozen with liquid nitrogen and stored at − 20°C (Bator et al 2018, Mackowiak et al 2014. Cytosolic and nuclear extracts of the isolated brain region were obtained using a ProteoExtract Subcellular Proteome Extraction Kit as recommended by the manufacturer (Calbiochem, Germany).…”

Section: Western Blottingmentioning

confidence: 99%

Early-life blockade of NMDA receptors induces epigenetic abnormalities in the adult medial prefrontal cortex: possible involvement in memory impairment in trace fear conditioning

Latusz

Maćkowiak

2019

Psychopharmacology

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Rationale Several findings indicate that early-life dysfunction of N-methyl-D-aspartate (NMDA) receptors might cause schizophrenia-like abnormalities in adulthood that might be induced by impairments in epigenetic regulation. Objectives In the present study, we investigated whether postnatal blockade of NMDA receptors (within the first 3 weeks of life) by the competitive antagonist CGP 37849 (CGP) might affect some epigenetic markers in the adult medial prefrontal cortex (mPFC). Methods Histone H3 phosphorylation at serine 10 (H3S10ph), histone H3 acetylation at lysine 9 or 14 (H3K9ac or H3K14ac, respectively), or expression of histone deacetylase (HDAC) 2, HDAC5, myocyte enhancer factor (MEF) 2D and activity-regulated cytoskeleton-associated protein (Arc) were analysed. Moreover, we also evaluated whether the deacetylase inhibitor sodium butyrate (SB; 1.2 mg/kg, ip) could prevent behavioural and neurochemical changes in the mPFC induced by CGP during memory retrieval in the trace fear conditioning paradigm. Results The results showed that CGP administration increased the number of H3S10ph nuclei but did not affect H3K9ac and H3K14ac or HDAC2 protein levels. However, CGP administration altered the HDAC5 mRNA and protein levels and increased the mRNA and protein levels of MEF2D. CGP also increased Arc mRNA, which was correlated with an increase in the amount of Arc DNA bound to MEF2D. SB given 2 h after training prevented impairment of the freezing response and disruption of epigenetic markers (H3S10ph, HDAC5, MEF2D) and Arc expression during memory retrieval induced by CGP administration. Conclusions The early-life blockade of NMDA receptors impairs some epigenetic regulatory processes in the mPFC that are involved in fear memory formation.

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Adolescent environmental enrichment prevents the emergence of schizophrenia-like abnormalities in a neurodevelopmental model of schizophrenia

Cited by 42 publications

References 58 publications

Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200–CD200R and CX3CL1–CX3CR1 Systems

Maternal Immune Activation Sensitizes Male Offspring Rats to Lipopolysaccharide-Induced Microglial Deficits Involving the Dysfunction of CD200–CD200R and CX3CL1–CX3CR1 Systems

The prenatal challenge with lipopolysaccharide and polyinosinic:polycytidylic acid disrupts CX3CL1-CX3CR1 and CD200-CD200R signalling in the brains of male rat offspring: a link to schizophrenia-like behaviours

Early-life blockade of NMDA receptors induces epigenetic abnormalities in the adult medial prefrontal cortex: possible involvement in memory impairment in trace fear conditioning

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