Specificity and Plasticity of Thalamocortical Connections in Sema6A Mutant Mice

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Abstract
The establishment of connectivity between specific thalamic nuclei and cortical areas involves a dynamic interplay between the guidance of thalamocortical axons and the elaboration of cortical areas in response to appropriate innervation. We show here that Sema6A mutants provide a unique model to test current ideas on the interactions between subcortical and cortical guidance mechanisms and cortical regionalization. In these mutants, axons from the dorsal lateral geniculate nucleus (dLGN) are misrouted in the ventral telencephalon. This leads to invasion of presumptive visual cortex by somatosensory thalamic axons at embryonic stages. Remarkably, the misrouted dLGN axons are able to find their way to the visual cortex via alternate routes at postnatal stages and reestablish a normal pattern of thalamocortical connectivity. These findings emphasize the importance and specificity of cortical cues in establishing thalamocortical connectivity and the spectacular capacity of the early postnatal cortex for remapping initial sensory representations. During brain development, the emergence of distinct areas in the cerebral cortex involves an interplay between patterning of the cortical sheet in the early embryo and later influences of incoming connections made from other brain areas, namely the thalamus. Connectivity between the thalamus and the cortex is initially smooth and graded, and a prominent model for how thalamocortical connectivity is established proposes thalamic axons are topographically sorted as they course through subcortical regions and then passively delivered to appropriate areas of the cortical sheet. We have used mutant mice lacking the guidance molecule Semaphorin-6A to test this model. In these mutants, Semaphorin-6A axons from the visual part of the thalamus are subcortically misrouted and fail to innervate the presumptive visual cortex, which is instead invaded by somatosensory thalamic axons. Despite this major disruption in initial connectivity, many visual thalamic axons find their way specifically to visual cortex, arriving several days later than usual. These late-arriving axons often follow alternate routes, and upon arrival are able to out-compete earlier-arriving somatosensory axons to reestablish grossly normal thalamocortical connectivity. These results argue strongly against an essential role for early subcortical targeting in the establishment of thalamocortical connectivity patterns and suggest instead the existence of highly specific target-selection mechanisms that match thalamic axons with appropriate cortical areas.