Proteasome inhibition enhances the induction and impairs the maintenance of late-phase long-term potentiation.
Protein degradation by the ubiquitin-proteasome pathway plays important roles in synaptic plasticity, but the molecular mechanisms by which proteolysis regulates synaptic strength are not well understood. We investigated the role of the proteasome in hippocampal late-phase long-term potentiation (L-LTP), a model for enduring synaptic plasticity. We show here that inhibition of the proteasome enhances the induction of L-LTP, but inhibits its maintenance. Proteasome inhibitor-mediated enhancement of the early part of L-LTP requires activation of NMDA receptors and the cAMP-dependent protein kinase. Augmentation of L-LTP induction by proteasome inhibition is blocked by a protein synthesis inhibitor anisomycin and is sensitive to the drug rapamycin. Our findings indicate that proteasome inhibition increases the induction of L-LTP by stabilizing locally translated proteins in dendrites. In addition, our data show that inhibition of the proteasome blocks transcription of brain-derived neurotrophic factor (BDNF), which is a cAMP-responsive element-binding protein (CREB)-inducible gene. Furthermore, our results demonstrate that the proteasome inhibitors block degradation of ATF4, a CREB repressor. Thus, proteasome inhibition appears to hinder CREB-mediated transcription. Our results indicate that blockade of proteasome activity obstructs the maintenance of L-LTP by interfering with transcription as well as translation required to sustain L-LTP. Thus, proteasome-mediated proteolysis has different roles during the induction and the maintenance of L-LTP.
Dong
Chenghai
C
Department of Neurobiology and Anatomy, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA.
Upadhya
Sudarshan C
SC
Ding
Lan
L
Smith
Thuy K
TK
Hegde
Ashok N
AN
D000818:Animals; D000841:Anisomycin / Q000008:administration & dosage / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects; D017774:Long-Term Potentiation / Q000187:drug effects*; D051379:Mice; D009473:Neuronal Plasticity / Q000187:drug effects; D010447:Peptide Hydrolases / Q000494:pharmacology; D061988:Proteasome Inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D013569:Synapses / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D025801:Ubiquitin / Q000187:drug effects*
D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D061988:Proteasome Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D025801:Ubiquitin; D000841:Anisomycin; D017868:Cyclic AMP-Dependent Protein Kinases; D010447:Peptide Hydrolases