Semaphorin 3E–Plexin-D1 signaling controls pathway-specific synapse formation in the striatum

The proper formation of synaptic connectivity in the mammalian brain is critical for complex behavior. In the striatum, balanced excitatory synaptic transmission from multiple sources onto two classes of principal neurons is required for coordinated and voluntary motor control. Here we show that the interaction between the secreted semaphorin 3E (Sema3E) and its receptor Plexin-D1 is a critical determinant of synaptic specificity in cortico-thalamo-striatal circuits in mice. We find that sema3E is highly expressed in thalamostriatal projection neurons whereas, in the striatum, plexin-D1 is selectively expressed in direct pathway medium spiny neurons (MSNs). Despite physical intermingling of the MSNs, genetic ablation of plexin-D1 or sema3E results in functional and anatomical rearrangement of thalamostriatal synapses specifically in direct pathway MSNs without effects on corticostriatal synapses. Thus, our results demonstrate that Sema3E and Plexin-D1 specify the degree of glutamatergic connectivity between a specific source and target within the complex circuitry of the basal ganglia.