Deleting learning-induced dendritic spines disrupts the memory they encode

Long-term memory is widely thought to depend on activity-dependent synaptic plasticity and the structural remodeling that accompanies it, yet direct causal evidence that this remodeling is required for memory storage has been lacking. A case in point is the formation of dendritic spines: new spines appear following learning, but whether they constitute a physical substrate of memory remains unresolved. To address this, we developed the New Spine Elimination Tool (NSET), a chemical-genetic strategy, that ablates dendritic spines formed within a defined window of synaptic plasticity. NSET combines inducible expression of a degradable form of the actin-binding protein Drebrin with ligand-triggered proteasomal degradation. Because mainly nascent spines incorporate the degradable proteins into their cytoskeleton, ligand application eliminates them while sparing pre-existing ones. In hippocampal slice cultures, NSET eliminated recently formed spines without altering overall spine density or affecting pre-existing spines. Applied in vivo in the mouse basolateral amygdala, selective removal of learning-induced spines disrupted auditory fear memory, whereas consolidated memories and the capacity for new learning remained intact. These findings provide direct causal evidence that newly formed dendritic spines are required for long-term memory storage.