title: Calpain-1 deletion impairs mGluR-dependent LTD and fear memory extinction.
abstract: Recent studies indicate that calpain-1 is required for the induction of long-term potentiation (LTP) elicited by theta-burst stimulation in field CA1 of hippocampus. Here we determined the contribution of calpain-1 in another type of synaptic plasticity, the long-term depression (LTD) elicited by activation of type-I metabotropic glutamate receptors (mGluR-LTD). mGluR-LTD was associated with calpain-1 activation following T-type calcium channel opening, and resulted in the truncation of a regulatory subunit of PP2A, B56α. This signaling pathway was required for both the early and late phase of Arc translation during mGluR-LTD, through a mechanism involving mTOR and ribosomal protein S6 activation. In contrast, in hippocampal slices from calpain-1 knock-out (KO) mice, application of the mGluR agonist, DHPG, did not result in B56α truncation, increased Arc synthesis and reduced levels of membrane GluA1-containing AMPA receptors. Consistently, mGluR-LTD was impaired in calpain-1 KO mice, and the impairment could be rescued by phosphatase inhibitors, which also restored Arc translation in response to DHPG. Furthermore, calpain-1 KO mice exhibited impairment in fear memory extinction to tone presentation. These results indicate that calpain-1 plays a critical role in mGluR-LTD and is involved in many forms of synaptic plasticity and learning and memory.
authors.affiliation: Graduate College of Biomedical Sciences, Pomona, CA 91766, USA.|Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei 230038, China.
authors.forename: Guoqi
authors.initials: G
authors.lastname: Zhu
authors.affiliation: Graduate College of Biomedical Sciences, Pomona, CA 91766, USA.|VIB Center for the Biology of Disease, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Victor
authors.initials: V
authors.lastname: Briz
authors.affiliation: Graduate College of Biomedical Sciences, Pomona, CA 91766, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Seinfeld
authors.affiliation: Graduate College of Biomedical Sciences, Pomona, CA 91766, USA.|College of Osteopathic Medicine of the Pacific Western University of Health Sciences Pomona, CA 91766, CA 91766, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: College of Osteopathic Medicine of the Pacific Western University of Health Sciences Pomona, CA 91766, CA 91766, USA.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Bi
authors.affiliation: Graduate College of Biomedical Sciences, Pomona, CA 91766, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Baudry
mesh_terms: D000818:Animals; D020747:Calcium Channels, T-Type / Q000378:metabolism; D002154:Calpain / Q000235:genetics*; D005108:Extinction, Psychological; D005239:Fear; D017353:Gene Deletion; D036881:Long-Term Synaptic Depression; D008297:Male; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D054648:Protein Phosphatase 2 / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*
chemical_list: D020747:Calcium Channels, T-Type; D018091:Receptors, AMPA; D018094:Receptors, Metabotropic Glutamate; D054648:Protein Phosphatase 2; D002154:Calpain; C112682:Capn1 protein, mouse