An essential postsynaptic role for the ubiquitin proteasome system in slow homeostatic synaptic plasticity in cultured hippocampal neurons.
Chronic increases or decreases in neuronal activity initiates compensatory changes in synaptic strength that emerge slowly over a 12-24 h period, but the mechanisms underlying this slow homeostatic response remain poorly understood. Here, we show an essential role for the ubiquitin proteasome system (UPS) in slow homeostatic plasticity induced by chronic changes in network activity. In cultured hippocampal neurons, UPS inhibitors drive a slow increase in miniature excitatory postsynaptic current (mEPSC) amplitude and synaptic AMPA receptor subunit GluA1 and GluA2 expression that both mirrors and occludes the changes produced by chronic suppression of network activity with tetrodotoxin (TTX). These non-additive effects were similarly observed under conditions of chronic hyperactivation of network activity with bicuculline--the increase in mEPSC amplitude and GluA1/2 expression with chronic UPS inhibition persists during network hyperactivation, which scales synaptic strength and AMPA receptor expression in the opposite direction when UPS activity is intact. Finally, cell-autonomous UPS inhibition (via expression of the ubiquitin chain elongation mutant, UbK48R) enhances mEPSC amplitude in a manner that mimics and occludes changes in network activity, demonstrating a postsynaptic role for the UPS in slow homeostatic plasticity. Taken together, our results suggest that the UPS acts as an integration point for translating sustained changes in network activity into appropriate incremental compensatory changes at synapses.
Jakawich
S K
SK
Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI 48109, USA.
Neely
R M
RM
Djakovic
S N
SN
Patrick
G N
GN
Sutton
M A
MA
D000818:Animals; D000831:Animals, Newborn; D001640:Bicuculline / Q000494:pharmacology; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000166:cytology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*
D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D004791:Enzyme Inhibitors; D058787:GABA-A Receptor Antagonists; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D018091:Receptors, AMPA; D026941:Sodium Channel Blockers; D025801:Ubiquitin; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin; D046988:Proteasome Endopeptidase Complex; D001640:Bicuculline