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Conscious coupling: The early path to circuit formation in the neocortex

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Catapulting human intelligence above all other creatures is the highly precise formation of neuronal circuits in the cerebral cortex. This is not an easy feat since an estimated 16 billion molecularly distinct neurons are packed within the cerebral cortex. The nature of the connections between these neurons is largely unknown. In fact, President Barack Obama launched the Human Connectome Project in 2009 to map the entire brain circuitry and shed light into the brain’s “impenetrable jungles”.1

Excitatory neurons, the largest neuronal population in the cerebral cortex, arise from radial glial progenitor (RGP) cells and travel to their cortical destination along long fibers extending from the body of the “mother” RGP cells. As newly born excitatory neurons make this journey, they form electrical connections with “sister” neurons arising from the same RPG lineage. Song-Hai Shi of Memorial Sloan Kettering Cancer Center and colleagues examined the factors contributing to the ability of sister neurons to recognize and preferentially synapse with each other in the mature cortex.

First, the researchers recognized that electrical coupling occurred preferentially between daughter neurons and mother RGPs and that the coupling depended on the formation of gap junctions between mother and daughter cells. These gap junctions have molecularly distinct properties that make daughter neurons recognizable to their mother RGP. The team postulated that recognition of gap junctions unique to neurons derived from the same lineage is also key to the preferential electrical coupling of sister neurons in the neocortex.  Indeed, the investigators found that physical interaction must occur between sister neurons, which are typically born at different times in the developing neocortex, since electrical coupling between sister neurons fails to form if neurons have lost their way due to abnormal neuronal migration or become too dispersed in the neocortex during development.   

This work reveals that gap junctions facilitate the tight coordination between neurogenesis and synapse formation between excitatory neurons in the developing neocortex. It is likely that this process is also under the influence of still unidentified factors that ensure lineage-specific electrical coupling between sister excitatory neurons and other target cells. Future studies must focus on the identification and characterization of these additional factors to better understand the developmental and cellular origins of electrical coupling between neurons and how this leads to the assembly of the mature cortical circuitry.


  1. He S et al. (2015) Inside-Out Radial Migration Facilitates Lineage-Dependent Neocortical Microcircuit Assembly. Neuron 86(5):1159-1166. doi: 10.1016/j.neuron.2015.05.002
  1. 1. Yuste R et al. (2012) The brain activity map project and the challenge of functional connectomics. Neuron 74(6):970-974. doi: 10.1016/j.neuron.2012.06.006