Axonal synapse sorting in medial entorhinal cortex

Research on neuronal connectivity in the cerebral cortex has focused on the existence and strength of synapses between neurons, and their location on the cell bodies and dendrites of postsynaptic neurons. The synaptic architecture of individual presynaptic axonal trees, however, remains largely unknown. Here we used dense reconstructions from three-dimensional electron microscopy in rats to study the synaptic organization of local presynaptic axons in layer 2 of the medial entorhinal cortex, the site of grid-like spatial representations. We observe path-length-dependent axonal synapse sorting, such that axons of excitatory neurons sequentially target inhibitory neurons followed by excitatory neurons. Connectivity analysis revealed a cellular feedforward inhibition circuit involving wide, myelinated inhibitory axons and dendritic synapse clustering. Simulations show that this high-precision circuit can control the propagation of synchronized activity in the medial entorhinal cortex, which is known for temporally precise discharges. Path-length-dependent axonal synapse sorting of local presynaptic axons of excitatory neurons in the rat medial entorhinal cortex results in sequential targeting of inhibitory and excitatory neurons, which are connected by a cellular feedforward inhibition circuit. Spatio-temporal order in the wiring of the cerebral cortex Specific neuronal connectivity is thought to be essential to computation by the cerebral cortex, but electrophysiological measurements have provided only partial views of it. Moritz Helmstaedter and colleagues have produced a large-scale three-dimensional electron-microscopy dataset of the rat medial entorhinal cortex, the grid-cells of which contribute to spatial navigation. This exhaustive connectomics mapping reveals a high degree of specificity in axonal projections, with interneurons being targeted before excitatory neurons, dendritic synapse clustering, and differential conduction velocities. These features should endow cortical circuits with exquisite spatial and temporal control in neuronal firing.