Inhibition of IL-1β signaling normalizes NMDA-dependent neurotransmission and reduces seizure susceptibility in a mouse model of Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disorder caused by prion protein (PrP) misfolding, clinically recognized by cognitive and motor deficits, electroencephalographic abnormalities, and seizures. Its neurophysiological bases are not known. To assess the potential involvement of NMDA receptor (NMDAR) dysfunction, we analyzed NMDA-dependent synaptic plasticity in hippocampal slices from Tg(CJD) mice, which model a genetic form of CJD. Because PrP depletion may result in functional upregulation of NMDARs, we also analyzed PrP knock-out (KO) mice. Long-term potentiation (LTP) at the Schaffer collateral-commissural synapses in the CA1 area of ∼100-d-old Tg(CJD) mice was comparable to that of wild-type (WT) controls, but there was an inversion of metaplasticity, with increased GluN2B phosphorylation, which is indicative of enhanced NMDAR activation. Similar but less marked changes were seen in PrP KO mice. At ∼300 d of age, the magnitude of LTP increased in Tg(CJD) mice but decreased in PrP KO mice, indicating divergent changes in hippocampal synaptic responsiveness. Tg(CJD) but not PrP KO mice were intrinsically more susceptible than WT controls to focal hippocampal seizures induced by kainic acid. IL-1β-positive astrocytes increased in the Tg(CJD) hippocampus, and blocking IL-1 receptor signaling restored normal synaptic responses and reduced seizure susceptibility. These results indicate that alterations in NMDA-dependent glutamatergic transmission in Tg(CJD) mice do not depend solely on PrP functional loss. Moreover, astrocytic IL-1β plays a role in the enhanced synaptic responsiveness and seizure susceptibility, suggesting that targeting IL-1β signaling may offer a novel symptomatic treatment for CJD.SIGNIFICANCE STATEMENT Dementia and myoclonic jerks develop in individuals with Creutzfeldt-Jakob disease (CJD), an incurable brain disorder caused by alterations in prion protein structure. These individuals are prone to seizures and have high brain levels of the inflammatory cytokine IL-1β. Here we show that blocking IL-1β receptors with anakinra, the human recombinant form of the endogenous IL-1 receptor antagonist used to treat rheumatoid arthritis, normalizes hippocampal neurotransmission and reduces seizure susceptibility in a CJD mouse model. These results link neuroinflammation to defective neurotransmission and the enhanced susceptibility to seizures in CJD and raise the possibility that targeting IL-1β with clinically available drugs may be beneficial for symptomatic treatment of the disease

Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures

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The role of IL-1 receptor/toll-like receptor signaling in seizures

Epilepsie is een van de meest voorkomende neurologische aandoeningen; het komt voor bij ongeveer één procent van de wereldbevolking. Ongeveer dertig procent van alle epilepsiepatiënten reageert niet op de beschikbare medicijnen. De belangrijkste uitdaging is het ontwikkelen van nieuwe anti-epileptica voor de therapieresistente vormen van epilepsie. Mattia Maroso onderzocht de moleculaire mechanismen die betrokken zijn bij onbehandelbare epilepsie en suggereert dat ontstekingsprocessen in de hersenen, optredend bij aanvallen, een belangrijke rol spelen bij de aandoening

Age-dependent vascular changes induced by status epilepticus in rat forebrain: Implications for epileptogenesis

International audienceBrain inflammation, angiogenesis and increased blood-brain barrier (BBB) permeability occur in adult rodent and human epileptogenic brain tissue. We addressed the role of these events in epileptogenesis using a developmental approach since the propensity to develop spontaneous seizures, therefore the induction of epileptogenesis, is age-dependent and increases with brain maturation. Inflammation, angiogenesis and BBB permeability were studied in postnatal day (PN)9 and PN21 rats, 1 week and 4 months after pilocarpineinduced status epilepticus. Brain inflammation was evaluated by interleukin(IL)-1β immunohistochemistry; angiogenesis was quantified by measuring the density of microvessels identified by an anti-laminin antibody or by the intraluminal signal of FITC-albumin; BBB integrity was assessed by extravascular IgG immunostaining or detection of parenchymal extravasation of FITC-albumin. Neither inflammation nor angiogenesis or changes in BBB permeability were detected in PN9 rats after status epilepticus, and these rats did not develop spontaneous seizures in adulthood as assessed by video-EEG monitoring. Differently, status epilepticus in PN21 rats induced chronic inflammation, angiogenesis and BBB leakage in the hippocampus in 62% of rats, while in the remaining rats only transient inflammation in forebrain was observed. Epilepsy developed in about 62% of PN21 rats exposed to SE and these epileptic rats showed the three phenomena concomitantly in the hippocampus. PN21 rats that did not develop epilepsy 4 months after status epilepticus, as assessed by video-EEG monitoring, they did not show inflammation, angiogenesis or BBB damage in forebrain at this time. Our data show that age-dependent vascular changes and brain inflammation induced by status epilepticus are associated with epileptogenesis, suggesting that these phenomena are implicated in the mechanisms underlying the occurrence of spontaneous seizures

Receptor for Advanced Glycation Endproducts is upregulated in temporal lobe epilepsy and contributes to experimental seizures

Toll-like receptor 4 (TLR4) activation in neuron and astrocytes by High Mobility Group Box 1 (HMGB1) protein is a key mechanism of seizure generation. HMGB1 also activates the Receptor for Advanced Glycation Endproducts (RAGE), but it was unknown whether RAGE activation contributes to seizures or to HMGB1 proictogenic effects. We found that acute EEG seizures induced by 7ng intrahippocampal kainic acid (KA) were significantly reduced in Rage-/- mice relative to wild type (Wt) mice. The proictogenic effect of HMGB1 was decreased in Rage-/- mice, but less so, than in Tlr4-/- mice. In a mouse mesial temporal lobe epilepsy (mTLE) model, status epilepticus induced by 200ng intrahippocampal KA and the onset of the spontaneous epileptic activity were similar in Rage-/-, Tlr4-/- and Wt mice. However, the number of hippocampal paroxysmal episodes and their duration were both decreased in epileptic Rage-/- and Tlr4-/- mice vs Wt mice. All strains of epileptic mice displayed similar cognitive deficits in the novel object recognition test vs the corresponding control mice. CA1 neuronal cell loss was increased in epileptic Rage-/- vs epileptic Wt mice, while granule cell dispersion and doublecortin (DCX)-positive neurons were similarly affected. Notably, DCX neurons were preserved in epileptic Tlr4-/- mice. We did not find compensatory changes in HMGB1-related inflammatory signaling nor in glutamate receptor subunits in Rage-/- and Tlr4-/- naïve mice, except for ~20% NR2B subunit reduction in Rage-/- mice. RAGE was induced in neurons, astrocytes and microvessels in human and experimental mTLE hippocampi. We conclude that RAGE contributes to hyperexcitability underlying acute and chronic seizures, as well as to the proictogenic effects of HMGB1. RAGE and TLR4 play different roles in the neuropathologic sequelae developing after status epilepticus. These findings reveal new molecular mechanisms underlying seizures, cell loss and neurogenesis which involve inflammatory pathways upregulated in human epileps

Neural stem cell lineage-specific cannabinoid type-1 receptor regulates neurogenesis and plasticity in the adult mouse hippocampus.

Neural stem cells (NSCs) in the adult mouse hippocampus occur in a specific neurogenic niche, where a multitude of extracellular signaling molecules converges to regulate NSC proliferation as well as fate and functional integration. However, the underlying mechanisms how NSCs react to extrinsic signals and convert them to intracellular responses still remains elusive. NSCs contain a functional endocannabinoid system, including the cannabinoid type-1 receptor (CB1). To decipher whether CB1 regulates adult neurogenesis directly or indirectly in vivo, we performed NSC-specific conditional inactivation of CB1 by using triple-transgenic mice. Here, we show that lack of CB1 in NSCs is sufficient to decrease proliferation of the stem cell pool, which consequently leads to a reduction in the number of newborn neurons. Furthermore, neuronal differentiation was compromised at the level of dendritic maturation pointing towards a postsynaptic role of CB1 in vivo. Deteriorated neurogenesis in NSC-specific CB1 knock-outs additionally resulted in reduced long-term potentiation in the hippocampal formation. The observed cellular and physiological alterations led to decreased short-term spatial memory and increased depression-like behavior. These results demonstrate that CB1 expressed in NSCs and their progeny controls neurogenesis in adult mice to regulate the NSC stem cell pool, dendritic morphology, activity-dependent plasticity, and behavior