Genetic diversity of principal neurons in the hippocampus

The extent to which individual neurons are interconnected in a selective manner within brain circuits is an unsolved problem in neuroscience. Two opposite views posit dedicated labeled lines of specifically interconnected neurons, versus tabula rasa models of randomly interconnected networks. Even in dense mammalian cortical circuits, apparently equivalent neurons can be organized into preferentially interconnected microcircuits. However, it has remained unclear whether microcircuits might reflect genetically defined subpopulations of selectively interconnected neurons, as opposed to self-organizing random networks. Here we show that the principal neurons of the major hippocampal subdivisions consist of genetically distinct subpopulations that interconnect selectively across subdivisions. In two Thy1 mouse lines, transgene expression in each subdivision visualizes matched principal neuron subpopulations that exhibit unique patterns of gene expression, and share neurogenesis windows, and temporal schedules of synaptogenesis. Marker genes shared among the matched subpopulations map near olfactory receptor gene clusters, a property which we find preferentially associated with neuronal subtype markers. Matched subpopulations exhibit selective connectivity at mossy fiber-to-pyramidal neuron synapses in CA3. Our results provide genetic, developmental and anatomical evidence for the existence of selectively interconnected principal neuron subpopulations in a cortical structure. The results further suggest that unique and co-ordinate schedules of neurogenesis and circuit assembly may underlie the establishment of specific microcircuits in the brain.