Cell Type-Specific Circuit Mapping Reveals the Presynaptic Connectivity of Developing Cortical Circuits.

The mammalian cerebral cortex is a dense network composed of local, subcortical, and intercortical synaptic connections. As a result, mapping cell type-specific neuronal connectivity in the cerebral cortex in vivo has long been a challenge for neurobiologists. In particular, the development of excitatory and inhibitory interneuron presynaptic input has been hard to capture. We set out to analyze the development of this connectivity in the first postnatal month using a murine model. First, we surveyed the connectivity of one of the earliest populations of neurons in the brain, the Cajal-Retzius (CR) cells in the neocortex, which are known to be critical for cortical layer formation and are hypothesized to be important in the establishment of early cortical networks. We found that CR cells receive inputs from deeper-layer excitatory neurons and inhibitory interneurons in the first postnatal week. We also found that both excitatory pyramidal neurons and inhibitory interneurons received broad inputs in the first postnatal week, including inputs from CR cells. Expanding our analysis into the more mature brain, we assessed the inputs onto inhibitory interneurons and excitatory projection neurons, labeling neuronal progenitors with Cre drivers to study discrete populations of neurons in older cortex, and found that excitatory cortical and subcortical inputs are refined by the fourth week of development, whereas local inhibitory inputs increase during this postnatal period. Cell type-specific circuit mapping is specific, reliable, and effective, and can be used on molecularly defined subtypes to determine connectivity in the cortex.