30 research outputs found
Complement system as glutamate modulator and synaptic organizer in EAE animal model.
No full textIn recent years, there has been a growing interest in the interaction between the central nervous system (CNS) and the immune system. This has led to the finding that the CNS is an immune-privileged environment. A principal component of the innate immune system is the complement system, which is essential for the primary defense of the human body against pathogens.
The complement system is frequently described as a "double-edged sword" in the context of the CNS. On one hand, it facilitates the physiological maturation of neural networks and plays a crucial role in promoting synaptic pruning during brain development. On the other hand, a dysregulation of this system can lead to excessive synaptic loss, which could contribute to the progression of neurodegenerative diseases. Additionally, research conducted over the past two decades has revealed a "non-canonical" role for the complement system in modulating neurotransmission at chemical synapses.
This thesis aims to examine the function of the complement system in pathological conditions, in both aberrant synaptic elimination and glutamate modulation, as promoter of neurodegenerative processes. In particular, the study employed an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS).
To evaluate the first aim regarding the role of the complement system as a synaptic modulator of neurotransmission, three specific objectives were pursued: first, to assess complement-induced glutamate release from both synapses and astrocytes in healthy mice, second to evaluate complement system alterations and glutamate release in EAE mice at various disease stages, and third to explore the role of excitatory amino acid transporters in these processes.
To elucidate the second aim regarding the involvement of excessive synaptic pruning in neurodegeneration, I focused on developing appropriate methods to highlight microglial phagocytosis of cortical nerve terminals (synaptosomes). Next, the objective was to quantify pruning differences between EAE and healthy mice, and to explore the impact of complement proteins (C3) on synaptic vulnerability.
In the initial phase of the study, an investigation was conducted into structural synapse impairments within the cortex and hippocampus of EAE mice. It was observed that while inflammatory markers GFAP and CD11b were elevated, only the cortical region exhibited changes in the postsynaptic marker PSD95, that resulted overexpressed. This may be a compensatory mechanism for reduced glutamate release efficiency. In addition to astrocytosis and microgliosis an overexpression in the protein density of C1q and C3 complement components was detected in EAE mice.
Building on these findings, I analysed the role of the complement system in modulating glutamate transmission. The results showed that complement-induced glutamate release varies depending on the particle type, specifically whether it is synaptosomes or gliosomes. Astrocytic gliosomes exhibit higher release activity, which is mediated by glutamate transporters working in reverse mode. In EAE mice, this modulation becomes imbalanced, with reduced release in synaptosomes and increased release in gliosomes. This imbalance, supported by proteomic changes in glutamate transporters EAAT1 and EAAT2, suggests that complement activity can be involved in a maladaptation of the astrocyte-neuron communication, indicating a potential excitotoxic imbalance.
The second phase of the study examines complement-mediated synaptic pruning, employing new techniques to measure microglial phagocytosis of synaptosomes. The results demonstrate that EAE synaptosomes have an increase susceptibility to pruning, which may be driven by the interaction between C3 and its receptor, resulting in the phagocytosis of synapses by microglia.
These findings collectively highlight the complex role of the complement system in synaptic dysfunction, providing insights into potential therapeutic targets for MS and other neurodegenerative diseases
Spatial and temporal mush heterogeneity during eruptions recorded in clinopyroxene from the 2021 paroxysms at Mt. Etna, Italy
No full textTextural and compositional zoning of volcanic minerals archives pre-eruptive magma processes. Crystals erupted simultaneously may be sampled from different regions of the plumbing system and hence record variable histories due to complex magma dynamics. In addition, crystals erupted throughout the course of an eruption may record temporal variations in the plumbing system. To resolve mush variability on both spatial and temporal scales, we investigate clinopyroxene erupted during a series of paroxysmal episodes between February–April 2021 at Mt. Etna, Italy. Using a combination of high-resolution geochemical techniques, we observe that Cr enrichments in clinopyroxene mantle zones, grown upon eruption-triggering mafic rejuvenation, exhibit both temporal and spatial (sample-scale) variability. Temporal variability correlates with changes in glass compositions, attesting to the ability of clinopyroxene to track magma maficity throughout an eruption. Spatial variability, indicated by the scatter of Cr concentrations, is greatest for the first event and lowest for the final paroxysm. In conjunction with core textures, degree of sector enrichment and thermobarometry, our data suggest that the onset of the paroxysms was preceded by the remobilisation of a mid-crustal clinopyroxene mush (534±46 MPa) by hot, mafic magma causing variable resorption of mush-derived crystal cores. Towards the end of the eruption, waning magma supply led to less efficient mush remobolisation and mixing, resulting in homogenous crystal populations. Our results highlight that clinopyroxene Cr contents and sector enrichment can be used to track mafic rejuvenation and magma evolution throughout eruptions, while also reflecting spatial heterogeneities within the plumbing system
Non-canonical Roles of Complement in the CNS: From Synaptic Organizer to Presynaptic Modulator of Glutamate Transmission
No full textThe central nervous system (CNS) is not an immune-privileged compartment, but it is intimately intertwined with the immune system. Among the components shared by the two compartments is the complement, a main constituent of innate immunity, which is also produced centrally and controls the development and organization of synaptic connections. Complement is considered a doubled-faced system that, besides controlling the physiological development of the central network, also subserves synaptic engulfment pivotal to the progression of neurodegenerative diseases. Quite interestingly, besides these “canonical” roles, evidence in the last two decades highlighted other “non-canonical” role(s), thereby complementing modulates chemical transmission at central synapsis. It emerged that glutamate is the preferential target of these “non-canonical” complement-induced effects, which include i) the control of the release of glutamate from neurons and astrocytes and ii) the control of the number and the functions of central glutamatergic receptor subtypes (i.e., the NMDA receptors, the AMPA/kainate receptors, and the metabotropic glutamate receptors) in plasma membranes. This review summarizes some of the available results supporting the role of complement as a “modulator” of central glutamate transmission, paying particular attention to those events that occur presynaptically. Taking into consideration the enormous progress in complement pharmacology and the increasing number of therapeutics in clinical trials, deepening our knowledge of these” non-canonical” role(s) could pave the road to new therapeutic approaches for the management of central neurological diseases
Complement regulates glutamate release and participates to synaptic deficiencies, in a multiple sclerosis mouse model
No full textRole of complement in regulating glutamate transmission in an experimental model of multiple sclerosis.
No full textA rare case of hypomelanosis of Ito presenting with generalized alopecia
No full textA rare case of hypomelanosis of Ito presenting with generalized alopeci
Complement modulates glutamate release and contributes to synaptic impairments in a mouse model of multiple sclerosis
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Exploring the role of complement in regulating glutamate transmission at cortical synapses in mice suffering from Experimental Autoimmune Encephalomyelitis.
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