RVG-mediated calpain2 gene silencing in the brain impairs learning and memory.
In the central nervous system, two calpain isoforms are highly expressed: calpain1 and calpain2. Here, we show for the first time that activation of the calpain isoform, calpain2, is a necessary event in hippocampal synaptic plasticity and in learning and memory. We developed a fluorescence resonance energy transfer-based animal model to monitor in vivo calpain activation in single cells and in real time. Additionally, utilizing a novel rabies virus glycoprotein-chimeric peptide, which enabled the transvascular delivery of small interfering RNA to the brain against calpain2, we down-regulated the calpain2 isoform in vivo. Calpain2 gene silencing eliminated long-term potentiation and impaired learning and memory. Our results not only identify the calpain2 isoform as a critical mediator in learning and memory but also highlight an innovative, highly efficient calpain2-targeting peptide capable of isoform-specific gene silencing in the brain. We anticipate these innovative technologies and our better understanding of the calpain machinery, particularly of the calpain2 isoform, will have substantial influence on future translational studies, attracting considerable interest in the use of calpain models and calpain-specific inhibitors in the development of therapeutics.
Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA. szadran@mednet.ucla.edu
Sohila
S
Zadran
Garnik
G
Akopian
Homera
H
Zadran
John
J
Walsh
Michel
M
Baudry
D000595:Amino Acid Sequence; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002154:Calpain / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D003216:Conditioning, Operant; D004151:Dipeptides / Q000494:pharmacology; D016503:Drug Delivery Systems; D004597:Electroshock; D005106:Exploratory Behavior / Q000502:physiology; D005239:Fear; D005260:Female; D031541:Fluorescence Resonance Energy Transfer; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D006023:Glycoproteins / Q000008:administration & dosage / Q000235:genetics*; D007859:Learning Disabilities / Q000235:genetics*; D008297:Male; D008569:Memory Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics*; D010455:Peptides / Q000008:administration & dosage / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D011950:Receptors, Cholinergic / Q000378:metabolism; D016037:Single-Blind Method; D019789:Tetraethylammonium / Q000494:pharmacology; D014764:Viral Proteins / Q000008:administration & dosage / Q000235:genetics*
D019208:Brain-Derived Neurotrophic Factor; D004151:Dipeptides; D006023:Glycoproteins; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D010455:Peptides; D034741:RNA, Small Interfering; D011950:Receptors, Cholinergic; D014764:Viral Proteins; C583075:rabies virus glycoprotein peptide; C015462:polyarginine; D019789:Tetraethylammonium; D002154:Calpain; C570925:Capn2 protein, mouse; C058076:calpain inhibitor III