title: Cdk5 is a New Rapid Synaptic Homeostasis Regulator Capable of Initiating the Early Alzheimer-Like Pathology.
abstract: Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase implicated in synaptic plasticity, behavior, and cognition, yet its synaptic function remains poorly understood. Here, we report that physiological Cdk5 signaling in rat hippocampal CA1 neurons regulates homeostatic synaptic transmission using an unexpectedly rapid mechanism that is different from all known slow homeostatic regulators, such as beta amyloid (Aβ) and activity-regulated cytoskeleton-associated protein (Arc, aka Arg3.1). Interestingly, overproduction of the potent Cdk5 activator p25 reduces synapse density, and dynamically regulates synaptic size by suppressing or enhancing Aβ/Arc production. Moreover, chronic overproduction of p25, seen in Alzheimer's patients, induces initially concurrent reduction in synapse density and increase in synaptic size characteristic of the early Alzheimer-like pathology, and later persistent synapse elimination in intact brains. These results identify Cdk5 as the regulator of a novel rapid form of homeostasis at central synapses and p25 as the first molecule capable of initiating the early Alzheimer's synaptic pathology.
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA Undergraduate Class of 2011, Yuanpei Honors College, Peking University, Beijing 100871, China Current address: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yanghui
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Picower Institute for Learning and Memory and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Su
authors.affiliation: Picower Institute for Learning and Memory and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Li-Huei
authors.initials: LH
authors.lastname: Tsai
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: J
authors.initials: J
authors.lastname: Julius Zhu
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000201:enzymology* / Q000473:pathology*; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D008854:Microscopy, Electron; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology; D018408:Patch-Clamp Techniques; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D013569:Synapses / Q000201:enzymology* / Q000473:pathology*; D046509:Tissue Culture Techniques
chemical_list: D016229:Amyloid beta-Peptides; C492235:Cdk5r1 protein, rat; D003598:Cytoskeletal Proteins; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat
keywords: Cdk5; cortex; hippocampus; neurodegenerative diseases; synaptic depression; synaptic homeostasis