LARGE protein drives homeostatic scaling-down after long-term potentiation

In the brain, memory can be coded as relative differences in synaptic strength produced by Hebbian plasticity (e.g. LTP). However, changes in neuronal activity, including the saturation of synaptic strength by the positive-feedback nature of Hebbian plasticity, could deteriorate the encoded memory. Synaptic scaling, a type of homeostatic plasticity, is thought to contribute to the stability of the encoded memory by maintaining the relative differences in synaptic strength against persistent destabilizing changes in neuronal activity. However, it remains unclear how and when these two types of plasticity work together in the context of memory. Here, we have demonstrated that LARGE, a protein associated with intellectual disability, drives homeostatic scaling-down several hours after LTP by downregulating AMPA-receptor trafficking via the Golgi apparatus. Importantly, LARGE deficiency impairs long-term memory formation in mice. Our study reveals a potential molecular mechanism underlying the stability of memory mediated by crosstalk between Hebbian and homeostatic plasticity.