Effects of prenatal Poly I:C exposure on global histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activity in the mouse brain.

The aim of our study was to investigate the brain-specific epigenetic effects on global enzymatic histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activity after prenatal exposure to maternal immune challenge by polyinosinic:polycytidylic acid (Poly I:C) at gestational day (GD) 17 in C57BL/6JRccHsd mouse offspring. Pregnant mice were randomly divided into 2 groups, receiving either 5 mg/kg Poly I:C or phosphate buffered saline (PBS) intravenously at GD 17. Subsequently, the effects on whole brain enzymatic HDAC and DNMT activity and the protein levels of various HDAC isoforms were assessed in the offspring. Overall, a significant sex × treatment interaction effect was observed after prenatal exposure to maternal immune challenge by Poly I:C, indicative of increased global HDAC activity particularly in female offspring from mothers injected with Poly I:C when compared to controls. Results on the levels of specific HDAC isoforms suggested that neither differences in the levels of HDAC1, HDAC2, HDAC3, HDAC4 or HDAC6 could explain the increased global HDAC activity observed in female Poly I:C offspring. In conclusion, we show that Poly I:C administration to pregnant mice alters global brain HDAC, but not DNMT activity in adult offspring, whereas it is still unclear which specific HDAC(s) mediate(s) this effect. These results indicate the necessity for further research on the epigenetic effects of Poly I:C.

Quinolinic acid-immunoreactivity in the naïve mouse brain.

Quinolinic acid (QUIN) has been suggested to be involved in infections, inflammatory neurological disorders and in the development of psychiatric disorders. In this view, several studies have been performed to investigate QUIN localization in the brain and its neurotoxic effects. However, evidence is lacking regarding QUIN in healthy, control conditions. The aim of this study was to investigate the region-specific distribution and pattern of QUIN expression in the naïve mouse brain. In addition, possible sex differences in QUIN-immunoreactivity and its link with affect-related behavioural observations were assessed. For this purpose, naïve mice were subjected to the forced swim test (FST) and 20 min open field (OF) testing to measure affect-related behaviour. Afterwards, brains were assessed for QUIN-immunoreactivity. QUIN-immunoreactivity was particularly observed in the cingulate cortex (CC), highlighting clearly delineated cells, and the thalamic reticular nucleus (TRN), showing a more diffuse staining pattern. Subsequently, QUIN-positive cells in the CC were counted, while QUIN-immunoreactivity in the TRN was examined using gray value measurements. No significant differences between sexes were observed for the number of QUIN-positive cells in the CC, neither in levels of QUIN-immunoreactivity in the TRN. A direct correlation was found between QUIN-positive cells in the CC and QUIN-immunoreactivity in the TRN. Moreover, in male mice, a very strong correlation (rsp=.943; p<.01) between QUIN-immunoreactivity at the level of the TRN and motor activity in the OF was observed. Thus, our results suggest that QUIN - detected in the CC and the TRN - may play a role in regulating motor activity in normal conditions.

Effects of subcutaneous LPS injection on gestational length and intrauterine and neonatal mortality in mice.

BACKGROUND: Infection during pregnancy can predispose offspring to develop various psychiatric disorders such as depression in later life. In order to investigate the potential mechanisms underlying these associations, animal models of maternal infection have been employed. As such, lipopolysaccharide (LPS) has been commonly used to mimic a bacterial infection in pregnant mice. OBJECTIVE: The original aim of our study was to investigate the effects of different doses of subcutaneous LPS administration on affective behavior in adult mouse offspring. In the present paper, however, we report that subcutaneous LPS administration has a profound impact on gestational length, litter size, and perinatal mortality in the offspring, even at a relatively low dose. METHODS: Pregnant mice were randomly divided into 3 groups, receiving either a high (2 mg/kg) or a low (0.5 mg/kg) dose of LPS or phosphate-buffered saline by means of subcutaneous injection. Subsequently, the effects on gestational length, litter size, and perinatal mortality in the offspring were assessed. RESULTS: After subcutaneous injection with a high dose of LPS, we observed a significant decrease in gestational length and an increase in neonatal mortality. When the low dose was administered, a tendency towards a reduced litter size was observed, most likely reflecting increased intrauterine mortality in response to prenatal maternal LPS exposure. CONCLUSIONS: We showed that subcutaneous administration of 2 mg/kg LPS to pregnant mice in the last phase of gestation should be avoided because of high offspring mortality rates, whereas subcutaneous injection of 0.5 mg/kg LPS seems to result in reabsorption of the fetuses.

Kynurenines: from the perspective of major psychiatric disorders.

Psychiatric disorders are documented to be associated with a mild pro-inflammatory state. Pro-inflammatory mediators could activate the tryptophan breakdown and kynurenine pathway with a shift toward the neurotoxic arm where excitotoxic N-methyl-D-aspartate receptor agonist quinolinic acid is formed. An unbalanced metabolism in terms of neuroprotective and neurotoxic effects, such as reduced kynurenic acid to kynurenine ratio, has been demonstrated in the major psychiatric disorders such as unipolar depression, bipolar manic-depressive disorder and schizophrenia, and in drug-induced neuropsychiatric side effects such as interferon-α treated patients. The changes in serum or plasma are shown to be associated with central changes such as in the cerebrospinal fluid and certain brain areas. While currently available antidepressants and mood stabilizers could not efficiently improve these neurochemical changes within the same period that could induce clinical improvement, some antipsychotic treatments could reverse certain metabolic imbalances. Some of these changes were tested also in animal models. In this review the role of this unbalanced kynurenine metabolism through interactions with other neurochemicals is discussed as a major contributing pathophysiological mechanism in psychiatric disorders. Moreover, the biomarker role of kynurenine metabolites and future therapeutic opportunities are also discussed.