Person: Chelini, Gabriele
Loading...
Email Address
AA Acceptance Date
Birth Date
Research Projects
Organizational Units
Job Title
Last Name
Chelini
First Name
Gabriele
Name
Chelini, Gabriele
Search Results
Now showing 1 - 3 of 3
Publication 10.3 GLIA-EXTRACELLULAR MATRIX INTERACTIONS IN THE PATHOPHYSIOLOGY OF SCHIZOPHRENIA AND BIPOLAR DISORDER(Oxford University Press, 2018) Berretta, Sabina; Chelini, Gabriele; Pantazopoulos, CharalamposAbstract Background: Growing evidence from our group and others indicates that key neural functions, including regulation of synaptic plasticity and axonal guidance and connectivity, arise from interactions between glial cells, neurons, and the extracellular matrix. Several distinct populations of glial cells critically contribute to the composition of main components of the extracellular matrix (ECM), synthesizing them and secreting them into the extracellular space, where they become incorporated in organized ECM structures. The brain ECM, and chondroitin sulfate proteoglycans (CSPGs) in particular, play a key role in brain development and adult life, in turn regulating glial functions as well as synaptic plasticity and neural connectivity. We have previously shown that glial cells expressing CSPGs are altered in the amygdala and entorhinal cortex of people with schizophrenia (SZ) and bipolar disorder (BD). These changes are accompanied by marked decreases of perineuronal nets (PNNs), organized ECM structures unsheathing distinct neuronal populations. Recent and ongoing studies are focused on novel CSPG-enriched ECM structures, related to synaptic complexes and myelinated axons, their relationship to glial populations and their involvement in the pathophysiology of SZ and BD. Methods: Postmortem tissue samples from the amygdala, entorhinal cortex and thalamus from a well characterized cohort of healthy control, SZ and BD subjects were included in these studies. Multiplex immunofluorescence combined with quantitative microscopy was used to quantify glial cells and CSPGs, while electron microscopy on human and mouse tissue were used to investigate ultrastructural morphology. Step-wise ANOVA analyses included several potential confounds such as exposure to pharmacological agents and substance abuse. Results: Our results show that at least two novel ECM structures are present in the human brain. The first, enriched in CSPGs bearing chondroitin sulfation in position 6 (CS-6), and named here ‘CS-6 clusters’ was found to be markedly decreased in the amygdala of people with SZ and BD. Electron microscopy studies show that CS-6 clusters are composed of astrocytes synthesizing and secreting CS-6 CSPGs in the vicinity of adjacent groups of dendrites, where it is incorporated into postsynaptic densities of dendritic spines. The second CSPG-enriched ECM structure, i.e. axonal coats, has been observed in the human thalamus to envelope distinct populations of axons, interweaving with myelin sheets. Its main CSPG components appear to be synthesized and secreted by oligodendrocytes precursor cells located in the vicinity of axon bundles. Preliminary results show abnormalities affecting both oligodendrocyte precursors and axonal coats in SZ. Discussion In summary, our results show complex interactions between glial cells, neurons and ECM, potentially affecting synaptic functions and axonal conductance. Results in SZ and BD point to a profound disruption of these interactions in several brain regions.Publication The tetrapartite synapse: a key concept in the pathophysiology of schizophrenia(2018) Chelini, Gabriele; Pantazopoulos, Charalampos; Durning, Peter; Berretta, SabinaGrowing evidence points to synaptic pathology as a core component of the pathophysiology of schizophrenia (SZ). Significant reductions of dendritic spine density and altered expression of their structural and molecular components have been reported in several brain regions, suggesting a deficit of synaptic plasticity. Regulation of synaptic plasticity is a complex process, one that requires not only interactions between pre- and post-synaptic terminals, but also glial cells and the extracellular matrix (ECM). Together, these elements are referred to as the ‘tetrapartite synapse’, an emerging concept supported by accumulating evidence for a role of glial cells and the extracellular matrix in regulating structural and functional aspects of synaptic plasticity. In particular, chondroitin sulfate proteoglycans (CSPGs), one of the main components of the ECM, have been shown to be synthesized predominantly by glial cells, to form organized perisynaptic aggregates known as perineuronal nets (PNNs), and to modulate synaptic signaling and plasticity during postnatal development and adulthood. Notably, recent findings from our group and others have shown marked CSPG abnormalities in several brain regions of people with SZ. These abnormalities were found to affect specialized ECM structures, including PNNs, as well as glial cells expressing the corresponding CSPGs. The purpose of this review is to bring forth the hypothesis that synaptic pathology in SZ arises from a disruption of the interactions between elements of the tetrapartite synapse.Publication F42. CHONDROTIN-6 SULFATE CLUSTERS: ASSOCIATION OF SYNAPTIC DOMAINS AND REGULATION OF SYNAPTIC PLASTICITY DURING FEAR LEARNING(Oxford University Press, 2018) Chelini, Gabriele; Berciu, Cristina; Pilobello, Kanoelani; Peter, Durning; Rachel, Jenkins; Kahn, Moazzzam; Ramikie, Teniel; Subramanian, Siva; Ressler, Kerry; Pantazopoulos, Charalampos; Berretta, SabinaAbstract Background: Emerging evidence from our group and others has brought the brain extracellular matrix (ECM) to the forefront of investigations on brain disorders. Our group has shown that organized perisynaptic ECM aggregates, i.e. perineuronal nets (PNNs) are decreased in several brain regions in people with schizophrenia (SZ) and bipolar disorder (BD). PNNs were detected by their expression of specific chondroitin sulfate proteoglycans (CSPGs), main components of the ECM, thought to play a key role in synaptic regulation during development and adulthood. Our studies have also shown that glial cells expressing CSPGs are altered in these disorders, suggesting a link between glial cell and PNN abnormalities. Finally, we have recently shown that novel CSPG structures, bearing a distinct CS-6 sulfation pattern and named CS-6 glial clusters, are decreased in the amygdala of people with SZ and BD. The morphology and function of CS-6 glial clusters is not currently known, but evidence from rodents and on the role of CSPGs in regulating synaptic functions strongly suggest that they may affect synaptic plasticity. We tested this hypothesis using a combination of human postmortem and rodent brain studies. Methods: High Resolution electron microscopy was used to investigate the ultrastructural organization of CS-6 glia clusters. A transgenic mouse model expressing green fluorescent protein in a subset of excitatory pyramidal neurons was used to investigate dendritic spines association with CS-6 glia clusters. Mice were exposed to a single session of auditory fear conditioning for a total of 15 minutes. Animals were euthanized 4 hours after behavioral test. Multiplex immunocytochemistry was used to visualize CS-6 clusters. Results: In human tissue, we show that CS-6 glia clusters are widespread in several brain regions, including the amygdala, entorhinal cortex, thalamus and hippocampus. Ultrastructural results show that CS-6 glia clusters are formed by CS-6 accumulations surrounding several dendrites. CS-6 expression was dected in astrocytes surrounding the dendrites, particularly in astrocytic endfeet enveloping dendritic spines, and within spines postsynaptic densities. Following auditory fear conditioning, marked changes of CS-6 glia clusters were observed in hippocampus regions dentate gyrus (g>1.5) and CA2 (g>1.5) and basolateral amygdala (g>1). Discussion These findings suggest that CS-6 glia clusters may represent segregated microdomains, dynamically regulated during learning and contributing to the modulation of synaptic regulation machinery. Specifically, we postulate that astrocytes synthesize CS-6 CSPG and secrete it through their endfeet around dendrites, modulating structural plasticity of dendritic spines. These results suggest a relationship between the abnormalities in CSPGs expression and alteration in dendritic spines, two pathological landmarks observed in postmortem brains of people with SZ and BD.