Neurobiology of Learning and Memory

abstract NMDA receptor-dependent long-term potentiation (LTP) at hippocampal CA1 synapses is a well-accepted 27 mechanism underlying long-term memory (LTM) formation. However, studies with mice that lack thre- 28 onine-286 autophosphorylation of a CaMKII have shown that hippocampal LTM can be formed despite 29 absence of NMDA receptor-dependent CA1 LTP. After multiple training trials, LTM formation in these 30 mutants is linked to the generation of multi-innervated dendritic spines (MIS), a spine that receives typ- 31 ically two presynaptic inputs. PSD-95 overexpression is sufcient for MIS generation and depends on 32 mTOR signaling. LTM that involves MIS generation appears less modiable upon retrieval in comparison 33 to LTM without MIS generation. Taken together, MIS generation appears to be a novel LTM mechanism 34 after multiple training trials, which may occur in diseases with impaired LTP or conditions affecting neg- 35 ative feedback CaMKII signaling at the synapse. 36 2015 Published by Elsevier Inc.