Maturation of cortical circuits requires Semaphorin 7A

Abnormal cortical circuits underlie some cognitive and psychiatric disorders, yet the molecular signals that generate normal cortical networks remain poorly understood. Semaphorin 7A (Sema7A) is an atypical member of the semaphorin family that is GPI-linked, expressed principally postnatally, and enriched in sensory cortex. Significantly, SEMA7A is deleted in individuals with 15q24 microdeletion syndrome, characterized by developmental delay, autism, and sensory perceptual deficits. We studied the role that Sema7A plays in establishing functional cortical circuitry in mouse somatosensory barrel cortex. We found that Sema7A is expressed in spiny stellate cells and GABAergic interneurons and that its absence disrupts barrel cytoarchitecture, reduces asymmetrical orientation of spiny stellate cell dendrites, and functionally impairs thalamocortically evoked synaptic responses, with reduced feed-forward GABAergic inhibition. These data identify Sema7A as a regulator of thalamocortical and local circuit development in layer 4 and provide a molecular handle that can be used to explore the coordinated generation of excitatory and inhibitory cortical circuits. Significance Sensory experience exerts profound control over the structure and function of developing cortical circuits during an early postnatal critical period. Abnormalities in this process contribute to perceptual and cognitive deficits, but molecular mechanisms generating excitatory and inhibitory cortical networks during this period remain poorly understood. We show here that Semaphorin 7A (Sema7A) is highly expressed in mouse somatosensory cortex when tactile information conveyed by the thalamus shapes development of somatosensory cortical networks. In mice lacking Sema7A, the anatomical layout of the somatosensory cortex is disrupted, dendritic arbors are misoriented, inhibitory connections develop abnormally, and thalamocortical activity fails to elicit a normal balance of excitation and inhibition. Taken together, our data indicate that maturation of thalamocortical and local circuits in cortex requires Sema7A.