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The modification of synaptic weights is critical for learning, while synaptic stability is required to maintain acquired knowledge. Single neurons have thousands of synapses within their dendritic arbors, and how the weights of specific inputs change across experience is poorly understood. Here we report that dendritic compartments receiving input from different presynaptic populations acquire distinct synaptic plasticity and integration rules across maturation. We find that apical oblique dendrites of layer 5 pyramidal neurons in adult mouse primary visual cortex receive direct monosynaptic projections from the dorsal lateral geniculate nucleus (dLGN), linearly integrate input, and lack synaptic potentiation. In contrast, basal dendrites, which do not receive dLGN input, exhibit NMDA receptor (NMDAR)-mediated supralinear integration and synaptic potentiation. Earlier in development, during thalamic input refinement, oblique and basal dendrites exhibited comparable NMDAR-dependent properties. Oblique dendrites gain mature properties with visual experience, and over the course of maturation, spines on oblique dendrites develop higher AMPA/NMDA ratios relative to basal dendrites. Our results demonstrate that cortical neurons possess dendrite-specific integration and plasticity rules that are set by the activity of their inputs. The linear, non-plastic nature of mature synapses on oblique dendrites may stabilize feedforward sensory processing while synaptic weights in other parts of the dendritic tree remain plastic, facilitating robust yet flexible cortical computation in adults.

Recent developments in super-resolution microscopy have revolutionized the study of cell biology. However, dense tissues require exogenous protein expression for single cell morphological contrast. In the nervous system, many cell types and species of interest - particularly human - are not amenable to genetic modification and/or exhibit intricate anatomical specializations which make cellular delineation challenging. Here, we present a method for full morphological labeling of individual neurons from any species or cell type for subsequent cell resolved protein analysis without genetic modification. Our method, which combines patch clamp electrophysiology with epitope-preserving magnified analysis of proteome (eMAP), further allows for correlation of physiological properties with subcellular protein expression. We applied Patch2MAP to individual spiny synapses in human cortical pyramidal neurons and demonstrated that electrophysiological AMPA-to-NMDA receptor ratios correspond tightly to respective protein expression levels. Patch2MAP thus permits combined subcellular functional, anatomical, and proteomic analyses of any cell, opening new avenues for direct molecular investigation of the human brain in health and disease.