Abstract
CaMKII and PSD-95 are the two most abundant postsynaptic proteins in the postsynaptic density (PSD). Overexpression of either can dramatically increase synaptic strength and saturate long-term potentiation (LTP). To do so, CaMKII must be activated, but the same is not true for PSD-95; expressing wild-type PSD-95 is sufficient. This raises the question of whether PSD-95's effects are simply an equilibrium process [increasing the number of AMPA receptor (AMPAR) slots] or whether activity is somehow involved. To examine this question, we blocked activity in cultured hippocampal slices with TTX and found that the effects of PSD-95 overexpression were greatly reduced. We next studied the type of receptors involved. The effects of PSD-95 were prevented by antagonists of group I metabotropic glutamate receptors (mGluRs) but not by antagonists of ionotropic glutamate receptors. The inhibition of PSD-95-induced strengthening was not simply a result of inhibition of PSD-95 synthesis. To understand the mechanisms involved, we tested the role of CaMKII. Overexpression of a CaMKII inhibitor, CN19, greatly reduced the effect of PSD-95. We conclude that PSD-95 cannot itself increase synaptic strength simply by increasing the number of AMPAR slots; rather, PSD-95's effects on synaptic strength require an activity-dependent process involving mGluR and CaMKII.
Publication types
-
Research Support, N.I.H., Extramural
MeSH terms
-
Animals
-
Animals, Newborn
-
Biophysics
-
CA1 Region, Hippocampal / cytology*
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
-
Disks Large Homolog 4 Protein
-
Electric Stimulation
-
Electroporation
-
Enzyme Inhibitors / pharmacology
-
Excitatory Amino Acid Agonists / pharmacology
-
Excitatory Amino Acid Antagonists / pharmacology
-
Excitatory Postsynaptic Potentials / drug effects
-
Excitatory Postsynaptic Potentials / genetics
-
Gene Expression Regulation / drug effects
-
Intracellular Signaling Peptides and Proteins / genetics
-
Intracellular Signaling Peptides and Proteins / metabolism*
-
Long-Term Potentiation / drug effects
-
Long-Term Potentiation / genetics
-
Long-Term Potentiation / physiology
-
Luminescent Proteins / genetics
-
Luminescent Proteins / metabolism
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Microscopy, Confocal
-
Neurons / drug effects
-
Neurons / physiology*
-
Organ Culture Techniques
-
Patch-Clamp Techniques
-
Peptides / genetics
-
Peptides / metabolism
-
Rats
-
Rats, Sprague-Dawley
-
Sodium Channel Blockers / pharmacology
-
Synapses / drug effects
-
Synapses / genetics
-
Synapses / physiology*
-
Tetrodotoxin / pharmacology
-
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
-
Disks Large Homolog 4 Protein
-
Dlg4 protein, rat
-
Enzyme Inhibitors
-
Excitatory Amino Acid Agonists
-
Excitatory Amino Acid Antagonists
-
Intracellular Signaling Peptides and Proteins
-
Luminescent Proteins
-
Membrane Proteins
-
Peptides
-
Sodium Channel Blockers
-
Tetrodotoxin
-
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
-
Calcium-Calmodulin-Dependent Protein Kinase Type 2