Structural Principles of Synaptic Connectivity Across Hippocampal and Cortical Circuits

Understanding the structural rules that govern synaptic connectivity remains a central challenge in neuroscience. Using large-scale volume electron microscopy (vEM), I examined how neuronal morphology, synapse organization, and circuit topology interact in distinct brain regions. In the dentate gyrus (DG), I tested whether morphological and positional features could stratify granule cells by developmental origin. Adult-born neurons in the dorsal DG are known to reside closer to the hilus, exhibit longer primary trunks, and display more acute branching angles. However, no single morphological metric, or combination of metrics, reliably separates unlabeled granule cells into adult- versus embryonic-born categories. Instead, granule cells formed continuous distributions of morphology, with dorsal and ventral populations showing overlapping but distinct gradients. Notably, axons of dendritic origin were observed exclusively in a subset of ventral DG granule cells, suggesting specialized mechanisms of input prioritization. At the synaptic level, I found that although global synapse density was stable between postnatal day (P) 30, 56, and 115, dorsal DG networks underwent dynamic remodeling. Spine pruning was buffered by sequential increases in granule cell number and dendritic arborization, while multisynaptic boutons (MSBs) reshaped patterns of shared input. Redundant innervation via MSBs peaked at P56 before sparsifying by P115, a non-monotonic trajectory that may balance redundancy for binding of related inputs with later specificity for pattern separation. In mouse primary visual cortex (V1), I mapped synaptic inputs onto pyramidal neurons and identified strong compartmental biases. Across cortical depths, the majority of synapses were made on basal dendrites, with exceptions in layer 1 and at the border between layers 4 and 5, where apical dendrites predominated. The proportion of synapses occurring on basal dendrites generally followed pyramidal cell density, but individual axons deviated from this, reflecting a balance between geometric constraints and selective targeting mechanisms. Together, these findings highlight the interplay of morphology, developmental history, and geometric constraints in shaping connectivity. They emphasize the limits of morphology-only classification, particularly in heterogeneous circuits such as the DG. They also highlight how specific circuitry features, such as MSBs, can give rise to different circuit topologies in spite of stable synapse and axon bouton densities in young adult DG. In contrast, the analysis of V1 underscores the role of dendritic geometry in predicting cortical wiring, with basal inputs prevailing across most layers and apical inputs confined to specific laminar contexts. More broadly, these results reveal that structural rules of connectivity in the DG shift dynamically during early adulthood, while in V1 they manifest as compartment- and layer-specific biases.