Brain-wide measurement of protein turnover with high spatial and temporal resolution

Synaptic plasticity underlies learning and memory by altering neuronal connections in response to experiences1. However, the loci of learning-induced synaptic plasticity, and the degree to which plasticity is localized or distributed, remain largely unknown2. We developed a method (DELTA) for mapping brain-wide changes in synaptic protein turnover with single-synapse resolution, based on Janelia Fluor dyes and HaloTag knock-in mice. During associative learning, the turnover of the ionotropic glutamate receptor GluA2, an indicator of synaptic plasticity, was enhanced in several brain regions, most markedly in the hippocampal area CA1. More broadly distributed increases in turnover of synaptic proteins were observed in response to environmental enrichment. In CA1, GluA2 stability was regulated in an input specific manner, with more turnover in layers containing input from CA3 compared to entorhinal cortex. DELTA will facilitate exploration of the molecular and circuit basis of learning and memory and other forms of adaptive and maladaptive plasticity at scales ranging from single synapses to the entire brain.