Interleukin-4 is a participant in the regulation of depressive-like behavior.

Inflammatory immune activation has been frequently associated with the development of major depression. Microglia might serve as an important interface in this immune system-to-brain communication. Interleukin-4, the major Th2 type cytokine, might be protective against depression due to its ability to counter-regulate inflammation and to inhibit serotonin transporter activity. By using an Interferon-α mouse model, we show that a decreased IL-4 responsiveness of microglia was specifically related to the development of depressive-like behavior. IL-4 deficient mice in a BALB/cJ background showed a considerable increase of depressive-like behavior in the forced swim (FST) and tail suspension test (TST) and reduced avoidance behavior in an active avoidance task. Prior conditioning with unescapable foot shocks further decreased avoidance behavior (learned helplessness) but to a similar level as in the wild type strain. IFN-α treatment was not able to further enhance the already increased level of depressive-like behavior in the FST and TST. Thus, IL-4 seems to be a critical participant in the regulation of depressive-like behavior in an untreated baseline condition. Increase of depressive-like behavior during inflammation in wild-type mice might be mediated to some extent by a reduction of IL-4 signaling.

Schizophrenia associated sensory gating deficits develop after adolescent microglia activation.

Maternal infection during pregnancy is a well-established risk factor for schizophrenia in the adult offspring. Consistently, prenatal Poly(I:C) treatment in mice has been validated to model behavioral and neurodevelopmental abnormalities associated with schizophrenia. By using the Poly(I:C) BALB/c mouse model, we investigated the functional profile of microglia by flow cytometry in relation to progressive behavioral changes from adolescence to adulthood. Prenatal Poly(I:C) treatment induced the expected sensory gating deficits (pre-pulse inhibition (PPI) of the acoustic startle response) in 100day-old adult offspring, but only in female not in male descendants. No PPI-deficits were present in 30day-old adolescent mice. Sensory gating deficits in adult females were preceded by a strong M1-type microglia polarization pattern during puberty as determined by flow cytometric analysis of multiple pro- and anti-inflammatory surface markers. Microglia activation in females did not persist until adulthood and was absent in behaviorally unaffected male descendants. Further, the specific activation pattern of microglia was not mirrored by a similar activation of peripheral immune cells. We conclude that prenatal Poly(I:C) treatment induces post pubertal deficits in sensory gating which are specifically preceded by a pro-inflammatory activation pattern of microglia during puberty.

Flow cytometric characterization of microglia in the offspring of PolyI:C treated mice.

The neuropathology of schizophrenia has been reported to be closely associated with microglial activation. In a previous study, using the prenatal PolyI:C schizophrenia animal model, we showed an increase in cell numbers and a reduction in microglial branching in 30-day-old PolyI:C descendants, which suggests that there is microglial activation during adolescence. To provide more information about the activation state, we aimed to examine the expression levels of Iba1, which was reported to be up-regulated in activated microglia. We used a flow cytometric approach and investigated CD11b and CD45, two additional markers for the identification of microglial cells. We demonstrated that intracellular staining against Iba1 can be used as a reliable flow cytometric method for identification of microglial cells. Prenatal PolyI:C treatment had long-term effects on CD11b and CD45 expression. It also resulted in a trend towards increased Iba1 expression. Imbalance in CD11b, CD45, and Iba1 expression might contribute to impaired synaptic surveillance and enhanced activation/inflammatory activity of microglia in adult offspring.

Microglia activation is associated with IFN-α induced depressive-like behavior.

Inflammatory immune activation has been frequently associated with the development of major depression. This association was confirmed in patients receiving long-term treatment with pro-inflammatory interferon-α (IFN-α). Microglia, the resident immune cells in the brain, might serve as an important interface in this immune system-to-brain communication. The aim of the present study was to investigate the role of microglia in an IFN-α mouse model of immune-mediated depression. Male BALB/c mice were treated with daily injections of IFN-α for two weeks. Depressive-like behavior was analyzed in the forced swim and tail suspension test. Activation of microglia was measured by flow cytometry. Pro-inflammatory M1 type (MHC-II, CD40, CD54, CD80, CD86, CCR7), anti-inflammatory M2 type (CD206, CD200R), and maturation markers (CD11c, CCR7) were tested, as well as the chemokine receptor CCR2. IFN-α led to a significant increase in depressive-like behavior and expression of the pro-inflammatory surface markers MHC-II, CD86, and CD54, indicating M1 polarization. Because IFN-α-treated mice showed great individual variance in the behavioral response to IFN-α, they were further divided into vulnerable and non-vulnerable subgroups. Only IFN-α vulnerable mice (characterized by their development of depressive-like behavior in response to IFN-α) showed an increased expression of MHC-II and CD86, while CD54 was similarly enhanced in both subgroups. Thus, IFN-α-induced activation of microglia was specifically associated with depressive-like behavior.