Cortical Connections Conference 2019

Axons of the corpus callosum (CC) establish selective interhemispheric connections that facilitate the high functions of the cerebral cortex. How developing cortical neurons wire such stereotyped networks following ostensibly strict rules of target selection, yet are capable of remarkable early plasticity enabling optimal functional circuits and alternative rewiring in non-canonical scenarios, has not been reconciled. Current models establish that early fate-restrictions on axonal development preemptively sort callosal or non-callosal identities at a neuron‚Äôs birth and impose fundamental limitations to the possible interhemispheric maps. Using a novel axonal-retrotracing strategy we instead demonstrate that virtually all cortical pyramidal neurons project calosally initially. Precise adult connectivity emerges when developmental contralateral axons are extensively refined in area- and layer-specific manners under the influence of circuit activity. Surgical and genetic interventions demonstrate that refinement is plastic and depends on specific sensory input. Loss of thalamic innervation results in structural and functional interhemispheric hyperconnectivity, demonstrating the bonafide early callosal potential of most cortical neurons.  
Thus, we show that during their selective wiring, most young cortical neurons overshoot and subsequently discard primed alternative circuits as instructed by circuit input. This uncommitted wiring mode may ensure the optimal formation of complex functional circuits and explains the higher plasticity observed in young brains. It helps to understand how diverse non-canonical alternative circuits can emerge in the context of neurodevelopmental diseases, and suggest that impaired sensory integration, early damage of sensory organs, failures of plasticity, or defects in neuromodulatory signals during development, lead to aberrant interhemispheric maps yet to comprehend.

Acknowledgements: This work was funded by grants from MINECO BFU2016-81887-REDT, PCIN-2015-176-C02-02/ERA-Net Neuron (Era-Net, MINECO), MICINN SAF2017-83117-R, BES-2015-071690 and a grant from Ramon Areces Foundation.