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Andrea Volterra

Session:
Seminar Session II

Institute:
Research Group of Andrea Volterra, Department of Fundamental Neuroscience, University of Lausanne, Lausanne, Switzerland

 
Website:
https://wwwfbm.unil.ch/dnf/group/glia-an-active-synaptic-partner/member/volterra-andrea-volterra

ResearchGate:
https://www.researchgate.net/scientific-contributions/38335319_Andrea_Volterra
Biography:

Professor Volterra received his PhD in Pharmacology at the University of Miland and subsequently performed his postdoctoral research at the Columbia University in the labs of S. Siegelbaum and the Nobel Prize winner, E. Kandel. Later, he pursued his independent career in the Department of Pharmacology at the University of Milan, and then he moved to the DNF which he directed from 2004 to 2012. roughout his career, he won several prizes, and only last year, 2017, his work was rewarded with eodore Ott Prize for Neurosciences. He has signi cantly contributed to the seminal work of the astrocyte-neuron communication eld in the last twenty years.

Abstract:

Towards decoding the language of astrocyte-neuron-vascular communication via 1D-to-3D Ca2+ imaging

Astrocytes sense neuronal inputs and in turn can modulate synapses and blood vessels via intracellular Ca2+ signaling. Despite their importance, the properties of astrocytic Ca2+ signals are not well understood and led in the last decade to controversial observations and a hot debate as to the real role of astrocytes in synaptic and vascular functions. One of the key problems is that astrocytic Ca2+ dynamics so far have been studied with conventional 2D imaging, which we find monitors at maximum ~5% of an astrocyte volume and ~10% of its activity. To overcome this problem, we developed 3D Ca2+ imaging of entire individual astrocytes in adult hippocampal slices and in vivo in awake mice using the genetically-encoded Ca2+ indicator GCaMP6f (Bindocci et al., Science, 2017). We were able to routinely acquire two full z-stacks of ∼60 focal planes/sec, comprising the whole volume of an individual astrocyte, and captured all Ca2+ events lasting ≥1.5 sec (FWHM). We also visualized faster events in 10Hz acquisitions on smaller volumes (8 planes/sec). Concerning distribution, 80% of an astrocyte Ca2+ activity was localized in the optically sub-resolved part of the cell (the so-called gliapil), where most of the intermingling with synapses is present, with the remaining 20% being present in the structural core (soma, stem processes, end-feet). Core activity was mostly in processes and end-feet, whereas somatic activity was infrequent and not representative of the astrocyte Ca2+ dynamics. This is an important observation because the astrocyte role in synaptic and vascular functions has been classically interpreted based on recordings of just somatic Ca2+ activity. Moreover, 10Hz acquisitions showed that activity in processes is mainly fast (FWHM:~0.7 sec) and local (~40 um3, ~12% of the process volume), resembling in size the events produced by minimal axonal stimulations (~60 um3), therefore possibly containing a large component generated by synaptic inputs. Likewise, Ca2+ activity in end-feet is mostly confined to the end-foot domain itself, is fast (FWHM: 0.75 sec) and often occurs asynchronously in different end-feet of an individual astrocyte, even when they cover contiguous segments of the same vessel. These data imply that astrocytes possess distinct signaling domains and that local signaling is a primary component of their processing, with most of the activity remaining highly compartmentalized under normal conditions. Further, combining fast 1-to-3D imaging and several synthetic and genetically encoded Ca2+ indicators, we developed imaging conditions allowing us to consistently visualize and study the population of fast and local Ca2+ “events” in astrocytic processes. We found that these small and fast events represent the vast majority of all Ca2+ transients detected in a 3D astrocyte. In IP3R2ko mice, originally described as fully devoid of astrocytic Ca2+ events, the fast astrocytic Ca2+ activity was reduced (in both number and amplitude) but not at all abolished, in line with the more recent view that Ca2+ dynamics in astrocytes depend on multiple and mutually interactive Ca2+ sources. This observation is important in view of the “negative” data in IP3R2ko concerning synaptic, vascular and behavioral relevance of astrocytic Ca2+activity. Therefore, all the past IP3R2ko data need revision in light of the new findings. Overall, our work provides a novel state-ofthe-artfor correctly studying the biology of astrocytes and their communications with neurons and the vascular cells in physiology and disease.

Supported by grants: ERC Advanced "Astromnesis" and SNSF 31003A-173124 to AV.