Interplay between inflammation and neural plasticity: Both immune activation and suppression impair LTP and BDNF expression.

An increasing number of studies show that both inflammation and neural plasticity act as key players in the vulnerability and recovery from psychiatric disorders and neurodegenerative diseases. However, the interplay between these two players has been limitedly explored. In fact, while a few studies reported an immune activation, others conveyed an immune suppression, associated with an impairment in neural plasticity. Therefore, we hypothesized that deviations in inflammatory levels in both directions may impair neural plasticity. We tested this hypothesis experimentally, by acute treatment of C57BL/6 adult male mice with different doses of two inflammatory modulators: lipopolysaccharide (LPS), an endotoxin, and ibuprofen (IBU), a nonselective cyclooxygenase inhibitor, which are respectively a pro- and an anti-inflammatory agent. The results showed that LPS and IBU have different effects on behavior and inflammatory response. LPS treatment induced a reduction of body temperature, a decrease of body weight and a reduced food and liquid intake. In addition, it led to increased levels of inflammatory markers expression, both in the total hippocampus and in isolated microglia cells, including Interleukin (IL)-1ß, and enhanced the concentration of prostaglandin E2 (PGE2). On the other hand, IBU increased the level of anti-inflammatory markers, decreased tryptophan 2,3-dioxygenase (TDO2), the first step in the kynurenine pathway known to be activated during inflammatory conditions, and PGE2 levels. Though LPS and IBU administration differently affected mediators related with pro- or anti-inflammatory responses, they produced overlapping effects on neural plasticity. Indeed, higher doses of both LPS and IBU induced a statistically significant decrease in the amplitude of long-term potentiation (LTP), in Brain-Derived Neurotrophic Factor (BDNF) expression levels and in the phosphorylation of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunit GluR1, compared to the control group. Such effect appears to be dose-dependent since only the higher, but not the lower, dose of both compounds led to a plasticity impairment. Overall, the present findings indicate that acute treatment with pro- and anti-inflammatory agents impair neural plasticity in a dose dependent manner.

Prenatal Immune Challenge in Mice Leads to Partly Sex-Dependent Behavioral, Microglial, and Molecular Abnormalities Associated with Schizophrenia.

Epidemiological studies revealed that environmental factors comprising prenatal infection are strongly linked to risk for later development of neuropsychiatric disorders such as schizophrenia. Considering strong sex differences in schizophrenia and its increased prevalence in males, we designed a methodological approach to investigate possible sex differences in pathophysiological mechanisms. Prenatal immune challenge was modeled by systemic administration of the viral mimic polyinosinic-polycytidylic acid (Poly I:C) to C57BL/6 mice at embryonic day 9.5. The consequences on behavior, gene expression, and microglia-brain immune cells that are critical for normal development-were characterized in male vs. female offspring at adulthood. The cerebral cortex, hippocampus, and cerebellum, regions where structural and functional alterations were mainly described in schizophrenia patients, were selected for cellular and molecular analyses. Confocal and electron microscopy revealed most pronounced differences in microglial distribution, arborization, cellular stress, and synaptic interactions in the hippocampus of male vs. female offspring exposed to Poly I:C. Sex differences in microglia were also measured under both steady-state and Poly I:C conditions. These microglial alterations were accompanied by behavioral impairment, affecting for instance sensorimotor gating, in males. Consistent with these results, increased expression of genes related to inflammation was measured in cerebral cortex and hippocampus of males challenged with Poly I:C. Overall, these findings suggest that schizophrenia's higher incidence in males might be associated, among other mechanisms, with an increased microglial reactivity to prenatal immune challenges, hence determining disease outcomes into adulthood.