Decreased NR2B subunit synaptic levels cause impaired long-term potentiation but not long-term depression.
The discovery of the molecular mechanisms regulating the abundance of synaptic NMDA receptors is essential for understanding how synaptic plasticity, as well as excitotoxic events, are regulated. However, a complete understanding of the precise molecular mechanisms regulating the composition of the NMDA receptor complex at hippocampal synapse is still missing. Here, we show that 2 h of CaMKII inhibition leads to a specific reduction of synaptic NR2B-containing NMDA receptors without affecting localization of the NR2A subunit; this molecular event is accompanied by a dramatic reduction in the induction of long-term potentiation (LTP), while long-term depression induction is unaffected. The same molecular and functional results were obtained by disrupting NR2B/PSD-95 complex with NR2B C-tail cell permeable peptide (TAT-2B). These data indicate that NR2B redistribution between synaptic and extrasynaptic membranes represents an important molecular disturbance of the glutamatergic synapse and affects the correct induction of LTP.
Gardoni
Fabrizio
F
Department of Pharmacological Sciences and Centre of Excellence on Neurodegenerative Diseases, University of Milan, Milan, Italy. fabrizio.gardoni@unimi.it
Mauceri
Daniela
D
Malinverno
Matteo
M
Polli
Federica
F
Costa
Cinzia
C
Tozzi
Alessandro
A
Siliquini
Sabrina
S
Picconi
Barbara
B
Cattabeni
Flaminio
F
Calabresi
Paolo
P
Di Luca
Monica
M
D000704:Analysis of Variance; D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D000076122:Disks Large Homolog 4 Protein; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006624:Hippocampus / Q000166:cytology; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors
C503464:CaMKII inhibitor AIP; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; D050882:CREB-Binding Protein; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2