Dr Paola Bezzi, MER, Group Leader
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Cellular Biology and Morphology Rue du Bugnon 9 |
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Research activities :
- The role of astrocytes in the pathophysiology of neuropsychiatric diseases: focus on schizophrenia and 22q11 deletion syndrome.
Research key words :
- Astrocytes, schizophrenia, cellular imaging, TIRF microscopy, confocal and two photon microscopy, EM
The role of astrocytes in the pathophysiology of neuropsychiatric diseases: focus on schizophrenia and 22q11 deletion syndrome
The present interdisciplinary project is a collaboration between P. Bezzi’s lab (DBCM, UNIL), expert in the dynamics of brain communication, P. Magistretti (EPFL) expert in neuropsychiatric diseases and in the role of glial cells in coupling synaptic activity and energy metabolism, S. Eliez (UNIGE), expert in behavioral psychiatry & neuroimaging, who study the identification of longitudinal structural brain changes and cognitive biases in genetically homogeneous subgroups at risk for psychosis (22q11.2 deletion syndrome) and R. Gruetter (EPFL) expert in functional brain neuroimaging.
22q11 microdeletion represents the first unequivocal association between a well-defined genetic lesion and schizophrenia at the population level, accounting for about 1%–2% of the disease in Caucasian samples. 22q11 deletion syndrome (DS) is caused by deletion of about 32 contiguous genes on human chromosome 22, and presumably results from diminished dosage of one or all of these genes, particularly during development. Individuals with the 22q11 microdeletions show dopaminergic and glutamatergic alterations and a spectrum of deficits in cognitive tasks linked to activity in prefrontal cortex (PFC) and hippocampus. Approximatively 30% of them develop typical schizophrenia or psychosis in adolescence or early adulthood. Most of the 27 known genes located within the deleted 22q11 region are expressed in the brain in a relatively wide pattern; thus, it is likely that more than one gene contributes to the marked risk associated with this locus. Interestingly, two of the candidate risk genes for behaviour phenotype of 22q11, the one encoding for proline dehydrogenase (PRODH) and the one encoding for catechol-O-methyltransferase (COMT), are highly expressed in astrocytes. In particular PRODH appears to be one of the top 40 cell-type-specific genes expressed by astrocytes.
Our aim is to combine our complementary scientific, medical and methodological expertise to provide a new view of brain cell communication and its alteration in animal models of 22q11 DS. In particular we are interested in defining whether morphological and functional properties of astrocytes located in PFC are altered in neuropsychiatric diseases. By combining the use of imaging technologies such as electron microscopy, total internal reflection fluorescence (TIRF), confocal, in vivo two-photon microscopy and of animal models of 22q11 DS, we will setup a strategy to study whether (a) structural rearrangements and/or functional modifications occur in astroglial cells located the prefrontal cortex of juvenile and adult 22q11 mice model and whether (b) neuron-astrocytes metabolic coupling is somehow perturbed in the early and late phase of the pathology. S. Eliez will provide the 22q11 deletion animal model and give the opportunity to test the role of astrocytic-derived dopamine in patients with 22q11 syndrome or early psychosis. Finally, in collaboration with G. Gruetter we will use neuroimaging techniques to provide indirect indices of dopamine synthesis and release and putative astrocytic/synaptic dopamine levels both in animal models and in patients.
Representative publications :
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Marchaland J, Calì C, Voglmaier SM, Li H, Regazzi R, Edwards RH, Bezzi P. Fast subplasma membrane Ca2+ transients control exo-endocytosis of synaptic-like microvesicles in astrocytes. J of Neurosci, 28(37):9122-32, 2008.
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Calì C, Marchaland J, Regazzi R, Bezzi P. SDF 1-alpha (CXCL12) triggers glutamate exocytosis from astrocytes on a millisecond time scale: imaging analysis at the single-vesicle level with TIRF microscopy. J of Neuroimm, 198(1-2):82-91, 2008.
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P. Bezzi, V. Gundersen, J.L. Galbete, G. Seifert, C. Steinhauser, E. Pilati and A. Volterra, Astrocytes contain a vesicular compartment competent for regulated exocytosis of glutamate, Nature Neuroscience, (7): 623-620 (2004).
