title: PKC activation during training restores mushroom spine synapses and memory in the aged rat.
abstract: Protein kinase C (PKC) ε and α activation has been implicated in synaptogenesis. We used aged rats to test whether the PKCε/α activator bryostatin and PKCε-specific activator DCP-LA combined with spatial memory training could restore mushroom dendritic spinogenesis and synaptogenesis. Compared with young rats, aged, learning-impaired rats had lower memory retention; lower densities of mushroom spines and synapses in the apical dendrites of CA1 pyramidal neurons; fewer PKCε-containing presynaptic axonal boutons; and lower activation and expression of two PKCε/α substrates, the mRNA-stabilizing protein HuD and brain-derived neurotrophic factor (BDNF). PKC activator treatment combined with spatial memory training restored mushroom spines and mushroom spine synapses; rescued PKCε/α expression and PKC/HuD/BDNF signaling; and normalized memory to the levels seen in young rats. These effects were produced by treatment with either bryostatin or the PKCε-specific activator, DCP-LA. Bryostatin also reversed alterations in GABAergic inhibitory postsynaptic currents (IPSPs) in aged, learning-impaired rats. Thus, our results support the therapeutic potential of PKC activators when added to cognitive rehabilitation for inducing mushroom spine synaptogenesis and reversing memory decline associated with aging.
authors.affiliation: Blanchette Rockefeller Neurosciences Institute at West Virginia University, Morgantown, WV 26505, USA. jhongpaisan@brni.org
authors.forename: Jarin
authors.initials: J
authors.lastname: Hongpaisan
authors.forename: Changqing
authors.initials: C
authors.lastname: Xu
authors.forename: Abhik
authors.initials: A
authors.lastname: Sen
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Nelson
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Alkon
mesh_terms: D000375:Aging; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D054713:Bryostatins / Q000494:pharmacology; D002210:Caprylates / Q000494:pharmacology; D003712:Dendrites / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism; D000067779:ELAV-Like Protein 4; D004558:Electric Stimulation; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000378:metabolism*; D017966:Pyramidal Cells / Q000166:cytology / Q000187:drug effects; D051381:Rats; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
chemical_list: C506022:8-(2-(2-pentyl-cyclopropylmethyl)cyclopropyl)octanoic acid; D000779:Anesthetics, Local; D019208:Brain-Derived Neurotrophic Factor; D054713:Bryostatins; D002210:Caprylates; D051959:ELAV Proteins; D000067779:ELAV-Like Protein 4; C000594136:Elavl4 protein, rat; D004791:Enzyme Inhibitors; C012647:QX-314; D008012:Lidocaine; D011493:Protein Kinase C