Mechanism for long-term memory formation when synaptic strengthening is impaired.
Long-term memory (LTM) formation has been linked with functional strengthening of existing synapses and other processes including de novo synaptogenesis. However, it is unclear whether synaptogenesis can contribute to LTM formation. Here, using α-calcium/calmodulin kinase II autophosphorylation-deficient (T286A) mutants, we demonstrate that when functional strengthening is severely impaired, contextual LTM formation is linked with training-induced PSD95 up-regulation followed by persistent generation of multiinnervated spines, a type of synapse that is characterized by several presynaptic terminals contacting the same postsynaptic spine. Both PSD95 up-regulation and contextual LTM formation in T286A mutants required signaling by the mammalian target of rapamycin (mTOR). Furthermore, we show that contextual LTM resists destabilization in T286A mutants, indicating that LTM is less flexible when synaptic strengthening is impaired. Taken together, we suggest that activation of mTOR signaling, followed by overexpression of PSD95 protein and synaptogenesis, contributes to formation of invariant LTM when functional strengthening is impaired.
Institute of Psychiatry,  King's College London, London SE5 9NU,  United Kingdom.
Kasia
K
Radwanska
Nikolay I
NI
Medvedev
Grace S
GS
Pereira
Olivia
O
Engmann
Nina
N
Thiede
Marcio F D
MF
Moraes
Agnes
A
Villers
Elaine E
EE
Irvine
Nicollette S
NS
Maunganidze
Elżbieta M
EM
Pyza
Laurence
L
Ris
Magda
M
Szymańska
Michał
M
Lipiński
Leszek
L
Kaczmarek
Michael G
MG
Stewart
K Peter
KP
Giese
D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D017781:Genes, Immediate-Early; D051528:Guanylate Kinases / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D008565:Membrane Proteins / Q000494:pharmacology; D057567:Memory, Long-Term; D051379:Mice; D010766:Phosphorylation; D020123:Sirolimus / Q000494:pharmacology; D013569:Synapses / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D008565:Membrane Proteins; D058570:TOR Serine-Threonine Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051528:Guanylate Kinases; D020123:Sirolimus