Generation of multi-innervated dendritic spines as a novel mechanism of long-term memory formation.

NMDA receptor-dependent long-term potentiation (LTP) at hippocampal CA1 synapses is a well-accepted mechanism underlying long-term memory (LTM) formation. However, studies with mice that lack threonine-286 autophosphorylation of αCaMKII have shown that hippocampal LTM can be formed despite absence of NMDA receptor-dependent CA1 LTP. After multiple training trials, LTM formation in these mutants is linked to the generation of multi-innervated dendritic spines (MIS), a spine that receives typically two presynaptic inputs. PSD-95 overexpression is sufficient for MIS generation and depends on mTOR signaling. LTM that involves MIS generation appears less modifiable upon retrieval in comparison to LTM without MIS generation. Taken together, MIS generation appears to be a novel LTM mechanism after multiple training trials, which may occur in diseases with impaired LTP or conditions affecting negative feedback CaMKII signaling at the synapse.