Détails de la réservation
- Le : 4 October 2018
- De : 11 h 00
- à : 13 h 30
- Salle : Amphi Centre Broca Nouvelle - Aquitaine
Détails de l'évènement
Michel Baudry
Dean, Graduate College of Biomedical Sciences Western University of Health
Sciences Pomona, CA USA
"Opposite functions of calpain-1 and calpain-2 in the brain"
Résumsé
Since the discovery of calpain in the central nervous system over 40 years ago, many studies have shown that calpains participate in both synaptic plasticity and neuronal degeneration. However, very few studies have examined the specific roles of the two major calpain isoforms in the brain, calpain-1 and calpain-2. We recently found that calpain-1 and calpain-2 play opposite roles in both synaptic plasticity and neurodegeneration. Calpain-1 activation is required for the induction of long-term potentiation (LTP) and is neuroprotective, while calpain-2 activation during the consolidation period limits the extent of LTP and is neurodegenerative. Following theta-burst stimulation (TBS) used to induce LTP, calpain-1 is rapidly activated and triggers ERK phosphorylation/activation and LTP induction, while calpain-2 activation within minutes after TBS inhibits ERK and terminates LTP induction; thus, this mechanism represents a molecular brake for LTP. We analyzed the functions of calpain-1 and calpain-2 in several neurodegeneration models, including acute glaucoma and traumatic brain injury. In every case, calpain-1 and calpain-2 have different time courses of activation and exhibit opposite functions in neuronal survival. This duality of functions is determined by their association with different scaffolding proteins, resulting in differential subcellular localization and signaling pathway regulation. Specifically, calpain-1 and calpain-2 are preferentially coupled to synaptic and extrasynaptic NMDARs, respectively. We have identified a selective calpain-2 inhibitor (C2I), which both enhances learning and is neuroprotective. C2I is neuroprotective at low doses (0.3 mg/kg, ip) in a mouse controlled cortical impact model of TBI and a mouse model of acute glaucoma, as a result of calpain-2 inhibition. These findings underscore the importance of considering specific calpain isoforms as potential clinical targets for the treatment of cognitive and neurodegenerative diseases.
Invitant : Daniel Choquet, Team Leader: Dynamic organization & Function of synapses / Directeur de l'IINS
Responsable
- Nom : Choquet Daniel