Modulation of schizophrenia-related genes in the forebrain of adolescent and adult rats exposed to maternal immune activation.

Maternal immune activation (MIA) is an environmental risk factor for schizophrenia, and may contribute to other developmental disorders including autism and epilepsy. Activation of pro-inflammatory cytokine systems by injection of the synthetic double-stranded RNA polyriboinosinic-polyribocytidilic acid (Poly I:C) mediates important neurochemical and behavioral corollaries of MIA, which have relevance to deficits observed in schizophrenia. We examined the consequences of MIA on forebrain expression of neuregulin-1 (NRG-1), brain-derived neurotrophic factor (BDNF) and their receptors, ErbB4 and trkB, respectively, genes associated with schizophrenia. On gestational day 14, pregnant rats were injected with Poly I:C or vehicle. Utilizing in situ hybridization, expression of NRG-1, ErbB4, BDNF, and trkB was examined in male rat offspring at postnatal day (P) 14, P30 and P60. ErbB4 mRNA expression was significantly increased at P30 in the anterior cingulate (AC Ctx), frontal, and parietal cortices, with increases in AC Ctx expression continuing through P60. ErbB4 expression was also elevated in the prefrontal cortex (PFC) at P14. In contrast, NRG-1 mRNA was decreased in the PFC at P60. Expression of BDNF mRNA was significantly upregulated in the PFC at P60 and decreased in the AC Ctx at P14. Expression of trkB was increased in two regions, the piriform cortex at P14 and the striatum at P60. These findings demonstrate developmentally and regionally selective alterations in the expression of schizophrenia-related genes as a consequence of MIA. Further study is needed to determine contributions of these effects to the development of alterations of relevance to neuropsychiatric diseases.

Hemmerle AM ，Ahlbrand R ，Bronson SL ，Lundgren KH ，Richtand NM ，Seroogy KB ... -  《-》

Maternal immune activation alters glutamic acid decarboxylase-67 expression in the brains of adult rat offspring.

Activation of the maternal innate immune system, termed "maternal immune activation" (MIA), represents a common environmental risk factor for schizophrenia. Whereas evidence suggests dysregulation of GABA systems may underlie the pathophysiology of schizophrenia, a role for MIA in alteration of GABAergic systems is less clear. Here, pregnant rats received either the viral mimetic polyriboinosinic-polyribocytidilic acid or vehicle injection on gestational day 14. Glutamic acid decarboxylase-67 (GAD67) mRNA expression was examined in male offspring at postnatal day (P)14, P30 and P60. At P60, GAD67 mRNA was elevated in hippocampus and thalamus and decreased in prefrontal cortex of MIA offspring. MIA-induced alterations in GAD expression could contribute to the pathophysiology of schizophrenia.

Cassella SN ，Hemmerle AM ，Lundgren KH ，Kyser TL ，Ahlbrand R ，Bronson SL ，Richtand NM ，Seroogy KB ... -  《-》

The influence of immune activation at early vs late gestation on fetal NRG1-ErbB4 expression and behavior in juvenile and adult mice offspring.

Maternal inflammation during pregnancy is associated with a higher incidence of mental disorders (e.g. schizophrenia and autism) in the offspring. In our study, we investigate the involvement of the NRG-ErbB signaling pathway in rodent fetal brains four hours following maternal immune activation (MIA) insult at two different gestational days (i.e. early vs late). Furthermore, we test the long-term behavioral alteration of the exposed MIA mice at juvenile and adulthood. We demonstrate that MIA at late, but not at early gestation day, altered the expression of NRG1, its receptor ErbB4, and the dopamine D2 receptor four hours post injection of viral or bacterial mimic material in fetal brain. At the behavioral levels, adult late-MIA-exposed female offspring, but not juvenile, display lack preference to a novel object. While working memory alteration observed only in adult male MIA-exposed offspring at late gestation day. In addition, we found that adult females MIA-exposed mice spent more time in the center of the open field than female-saline groups. On the other hand, juvenile male offspring exposed to MIA at early, but not late, gestation day displayed a significant alteration in social interaction. Our results suggest that MIA during late gestation immediately influences the expression levels of the NRG1 and ErbB4 genes, and affects long-term behavioral changes at adulthood. These behavioral changes are time related and sex-specific. Thus, immune activation at late stages of the embryonic brain development initiates the activation of the NRG1-ErbB4 pathway and this disturbance might result in cognitive dysfunction in adulthood.

Dabbah-Assadi F ，Alon D ，Golani I ，Doron R ，Kremer I ，Beloosesky R ，Shamir A ... -  《-》

Prenatal Cocaine Exposure Alters BDNF-TrkB Signaling in the Embryonic and Adult Brain.

Prenatal cocaine exposure remains a major public health concern because of its adverse effects on cognitive function. Although the molecular mechanisms underlying the cognitive impairment are not fully understood, brain-derived neurotrophic factor (BDNF) signaling via its receptor tyrosine kinase B (TrkB) is emerging as a potential candidate. We used a mouse model to examine the impact of ongoing cocaine exposure on BDNF expression in the dorsal forebrain on embryonic day 15 (E15) as well as the long-term effects of prenatal cocaine exposure on BDNF-TrkB signaling in the frontal cortex in early postnatal (postnatal day 16; P16) and adult (P60) male and female mice. We found that ongoing cocaine exposure decreased BDNF expression in the E15 dorsal forebrain, prenatal cocaine exposure did not alter BDNF or TrkB (total or phosphorylated) expression in the frontal cortex at P16, and that the prenatal cocaine exposure produced significant increases in BDNF, the activated (phosphorylated) form of TrkB, as well as Bdnf mRNA in the frontal cortex at P60. The increase in BDNF protein and mRNA expression at P60 was concurrent with hyperacetylation of histone H3 at the Bdnf promoter in the frontal cortex. The increase in frontal cortical BDNF and activated TrkB at P60 occurred in male but not female mice. Thus, our data demonstrate that ongoing cocaine exposure produces a decrease in BDNF expression in the embryonic brain, and that prenatal cocaine exposure produces a sex-specific increase in frontal cortical BDNF-TrkB signaling at P60 only in male mice. Lastly, hyperacetylation of histone H3 at the Bdnf promoter is one epigenetic mechanism mediating the effects of prenatal cocaine exposure on Bdnf expression at P60 in male mice.

McCarthy DM ，Mueller KA ，Cannon EN ，Huizenga MN ，Darnell SB ，Bhide PG ，Sadri-Vakili G ... -  《-》

Investigating 7,8-Dihydroxyflavone to combat maternal immune activation effects on offspring gene expression and behaviour.

Infection during pregnancy is a substantial risk factor for the unborn child to develop autism or schizophrenia later in life, and is thought to be driven by maternal immune activation (MIA). MIA can be modelled by exposing pregnant mice to Polyinosinic: polycytidylic acid (Poly-I:C), a viral mimetic that induces an immune response and recapitulates in the offspring many neurochemical features of ASD and schizophrenia, including altered BDNF-TrkB signalling and disruptions to excitatory/inhibitory balance. Therefore, we hypothesised that a BDNF mimetic, 7,8-Dihydroxyflavone (7,8-DHF), administered prophylactically to the dam may prevent the neurobehavioural sequelae of disruptions induced by MIA. Dams were treated with 7,8-DHF in the drinking water (0.08 mg/ML) from gestational day (GD) 9-20 and were exposed to Poly-I:C at GD17 (20 mg/kg, i.p.). Foetal brains were collected 6 h post Poly-I:C exposure for RT-qPCR analysis of BDNF, cytokine, GABAergic and glutamatergic gene targets. A second adult cohort were tested in a battery of behavioural tests relevant to schizophrenia and the prefrontal cortex and ventral hippocampus dissected for RT-qPCR analysis. Foetal brains exposed to Poly-I:C showed increased IL-6, but reduced expression of Ntrk2 and multiple GABAergic and glutamatergic markers. Anxiety-like behaviour was observed in adult offspring prenatally exposed to poly-I:C, which was accompanied by altered expression of Gria2 in the prefrontal cortex and Gria4 in the ventral hippocampus. While 7-8 DHF normalised the expression of some glutamatergic (Grm5) and GABAergic (Gabra1) genes in Poly-I:C exposed offspring, it also led to substantial alterations in offspring not exposed to Poly-I:C. Furthermore, mice exposed to 7,8-DHF prenatally showed increased pre-pulse inhibition and reduced working memory in adulthood. These data advance understanding of how 7,8-DHF and MIA prenatal exposure impacts genes critical to excitatory/inhibitory pathways and related behaviour.

Gillespie B ，Dunn A ，Sundram S ，Hill RA ... -  《-》