Impaired plasticity of intrinsic excitability in the dentate gyrus alters spike transfer in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline related to deficits in synaptic transmission and plasticity. We report in APP/PS1 mice, a double transgenic mouse model of AD, that females displayed an early burden of Aβ plaques load in the stratum moleculare of the dentate gyrus (DG) together with prominent neuroinflammatory activation of astrocytes and microglia. Robust deficits in hippocampus-dependent memory tasks were observed in APP/PS1 female mice as early as 3 months of age.

PGE-EP3 signaling pathway impairs hippocampal presynaptic long-term plasticity in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by early cognitive deficits linked to synaptic dysfunction and loss. Considerable evidence suggests that neuroinflammation contributes to AD. Prostaglandin E (PGE), a key neuroinflammatory molecule, modulates hippocampal synaptic transmission and plasticity.

Synaptic plasticity and spatial working memory are impaired in the CD mouse model of Williams-Beuren syndrome.

Mice heterozygous for a complete deletion (CD) equivalent to the most common deletion found in individuals with Williams-Beuren syndrome (WBS) recapitulate relevant features of the neurocognitive phenotype, such as hypersociability, along with some neuroanatomical alterations in specific brain areas. However, the pathophysiological mechanisms underlying these phenotypes still remain largely unknown. We have studied the synaptic function and cognition in CD mice using hippocampal slices and a behavioral test sensitive to hippocampal function.

Microglia-derived purines modulate mossy fibre synaptic transmission and plasticity through P2X4 and A1 receptors.

Recent data have provided evidence that microglia, the brain-resident macrophage-like cells, modulate neuronal activity in both physiological and pathophysiological conditions, and microglia are therefore now recognized as synaptic partners. Among different neuromodulators, purines, which are produced and released by microglia, have emerged as promising candidates to mediate interactions between microglia and synapses. The cellular effects of purines are mediated through a large family of receptors for adenosine and for ATP (P2 receptors).

Impaired interleukin-1beta and c-Fos expression in the hippocampus is associated with a spatial memory deficit in P2X(7) receptor-deficient mice.

Recent evidence suggests that interleukin-1beta (IL-1beta), which was originally identified as a proinflammatory cytokine, is also required in the brain for memory processes. We have previously shown that IL-1beta synthesis in the hippocampus is dependent on P2X(7) receptor (P2X(7)R), which is an ionotropic receptor of ATP. To substantiate the role of P2X(7)R in both brain IL-1beta expression and memory processes, we examined the induction of IL-1beta mRNA expression in the hippocampus of wild-type (WT) and homozygous P2X(7) receptor knockout mice (P2X(7)R(-/-)) following a spatial memory task.

Dual modulation of synaptic transmission in the nucleus tractus solitarius by prostaglandin E2 synthesized downstream of IL-1beta.

The activation of the innate immune system induces the production of blood-borne proinflammatory cytokines like interleukin-1beta (IL-1beta), which in turn triggers brain-mediated adaptative responses referred to as sickness behaviour. These responses involve the modulation of neural networks in key regions of the brain. The nucleus tractus solitarius (NTS) of the brainstem is a key nucleus for immune-to-brain signalling.

In vitro and in vivo evidence for a role of the P2X7 receptor in the release of IL-1 beta in the murine brain.

The P2X(7) receptor (P2X(7)R) is a purinoceptor expressed predominantly by cells of immune origin, including microglial cells. P2X(7)R has a role in the release of biologically active proinflammatory cytokines such as IL-1 beta, IL-6 and TNFalpha. Here we demonstrate that when incubated with lipopolysaccharide (LPS), glial cells cultured from brain of P2X(7)R(-/-) mice produce less IL-1 beta compared to glial cells from brains of wild-type mice.

NFkappaB activates in vivo the synthesis of inducible Cox-2 in the brain.

Interleukin-1beta (IL-1beta) induces cyclooxygenase-2 (Cox-2) expression in many of its cellular targets resulting in production and release of prostaglandins. Although IL-1beta-induced Cox-2 expression most likely requires activation of nuclear transcription factor kappa B (NFkappaB) pathway, this has never been formally demonstrated in vivo. We tested this using a specific inhibitor of NFkappaB activation, the NEMO binding domain (NBD) peptide, that has been shown previously to be effective in various in vivo models of acute inflammation.

ATP binding cassette transporter ABC1 is required for the release of interleukin-1beta by P2X7-stimulated and lipopolysaccharide-primed mouse Schwann cells.

Schwann cells are best known as myelinating glial cells of the peripheral nervous system, but they also participate actively in the sphere of immunity by producing pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta). In a previous study, we demonstrated that posttranslational processing of IL-1beta by immune-challenged Schwann cells required the P2X7 receptor. Remarkably, the release of IL-1beta was not associated with cell death, indicating the involvement of an active mechanism.

Nuclear factor kappaB nuclear translocation as a crucial marker of brain response to interleukin-1. A study in rat and interleukin-1 type I deficient mouse.

The signalling pathways that mediate early central effects of interleukin-1 (IL-1) during the acute phase reaction have been poorly elucidated. Interaction of IL-1beta to its specific receptor interleukin-1 receptor type I (IL-1RI) leads to nuclear factor kappa B (NuFkappaB) nuclear translocation and a robust transcriptional activation of inhibitor of kappa B alpha (IkappaBalpha) within the rat brain. Indeed, we demonstrated that IL-1RI expressed in blood brain barrier (BBB) cells and in circumventricular organs (CVOs) is crucial for p65-NFkappaB translocation induced by peripheral injection of IL-1beta.

[The immune status of Schwann cells: what is the role of the P2X7 receptor?].

The peripheral nervous system (PNS) displays structural barriers and a lack of lymphatic drainage which strongly limit the access of molecules and cells from the immune system. In addition, the PNS has the ability to set up some specific mechanisms of immune protection to limit the pathogenicity of inflammation processes following insults by pathogens or inflammatory autoimmune diseases like the Guillain-Barré syndrome. Schwann cells are among the most prominent cells which can display immune capabilities in the PNS.

Maturation and release of interleukin-1beta by lipopolysaccharide-primed mouse Schwann cells require the stimulation of P2X7 receptors.

The P2X7 receptor, mainly expressed by immune cells, is a ionotropic receptor activated by high concentration of extracellular ATP. It is involved in several processes relevant to immunomodulation and inflammation. Among these processes, the production of extracellular interleukin-1beta (IL-1beta), a pro-inflammatory cytokine, plays a major role in the activation of the cytokine network.