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Séminaire impromptu - Michel BaudryOpposite functions of calpain-1 and calpain-2 in the brain

Abstract :

 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.

Selected publications

Calpain inhibition reduces NMDA receptor rundown in rat substantia nigra dopamine neurons.Zhao J, Baudry M, Jones S. Neuropharmacology. 2018 Jul 15;137:221-229. doi: 10.1016/j.neuropharm.2018.05.003. Epub 2018 May 4. PMID: 29772491

 Calpain-2 as a therapeutic target for acute neuronal injury. Wang Y, Bi X, Baudry M. Expert Opin Ther Targets. 2018 Jan;22(1):19-29. doi: 10.1080/14728222.2018.1409723. Epub 2017 Nov 28. Review. PMID: 29168923

The tyrosine phosphatase PTPN13/FAP-1 links calpain-2, TBI and tau tyrosine phosphorylation. Wang Y, Hall RA, Lee M, Kamgar-Parsi A, Bi X, Baudry M. Sci Rep. 2017 Sep 18;7(1):11771. doi: 10.1038/s41598-017-12236-3.

Calpain-1 deletion impairs mGluR-dependent LTD and fear memory extinction. Zhu G, Briz V, Seinfeld J, Liu Y, Bi X, Baudry M. Sci Rep. 2017 Feb 16;7:42788. doi: 10.1038/srep42788.

Scientific focus :

Dr. Baudry is an internationally known neuroscientist, and is one of the 100 ISI Highly Cited neuroscientists in the world. After graduating from the prestigious Ecole Polytechnique in Paris in 1971, Dr. Baudry obtained a PhD in biochemistry at the University of Paris VII in 1977, under the direction of professors J.C. Schwartz and J.P. Changeux, two of France’s most distinguished neurobiologists. He moved to the United States in 1978 for a postdoctoral period with Professor Gary Lynch at the University of California, Irvine, and remained at UCI as an associate professor until 1989, when he joined USC.  He was the Professor of Departments of Biological Sciences, Neurology and Biomedical Engineering  at the University of Southern California (USC) till 2012 before joining Western University. Michel Baudry is currently the dean of the Graduate College of Biomedical Sciences at Western University of Health Sciences. In collaboration with Lynch, Dr. Baudry developed a biochemical theory for learning and memory that remains one of the most widely accepted theories in the field. His research is directed at understanding the molecular mechanisms of learning and memory, as well as those involved in neurodegenerative processes underlying numerous brain diseases. He is member of American Neuroscience Society, International Society of Neurochemistry, Fellow of the World Innovation Foundation. He has published more than 350 manuscripts in peer-reviewed journals and is reviewing manuscripts for a wide range of journals.