Reelin restricts dendritic growth of interneurons in the neocortex

Reelin is a large secreted glycoprotein that regulates neuronal migration, lamination and establishment of dendritic architecture in the embryonic brain. Reelin expression switches postnatally from Cajal-Retzius cells to interneurons. However, reelin function in interneuron development is still poorly understood. Here, we have investigated the role of reelin in interneuron development in the postnatal neocortex. To preclude early cortical migration defects caused by reelin deficiency, we employed a conditional reelin knockout (Reln^cKO) mouse to induce postnatal reelin deficiency. Induced reelin deficiency caused dendritic hypertrophy in distal dendritic segments of neuropeptide Y-positive (NPY⁺) and calretinin-positive (Calr⁺) interneurons, and in proximal dendritic segments of parvalbumin-positive (Parv⁺) interneurons. Chronic recombinant Reelin treatment rescued dendritic hypertrophy in Reln^cko interneurons. Moreover, we provide evidence that Reln^cKO interneuron hypertrophy is due to presynaptic GABA_BR dysfunction. Thus, GABA_BRs in Reln^cKO interneurons were unable to block N-type (Ca_v2.2) Ca²⁺ channels that control neurotransmitter release. Consequently, the excessive Ca²⁺ influx through AMPA receptors, but not NMDA receptors, caused interneuron dendritic hypertrophy. These findings suggest that reelin acts as a 'stop-growth-signal' for postnatal interneuron maturation.