Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development.

Sensory experience physically rewires the brain in early postnatal life through unknown processes. Here, we identify a robust anatomical consequence of monocular deprivation (MD) in layer II/III of visual cortex that corresponds to the rapid, functional loss of responsiveness preceding any changes in axonal input. Protrusions on pyramidal cell apical dendrites increased steadily after eye opening, but were transiently lost through competitive mechanisms after brief MD only during the physiological critical period. Proteolysis by tissue-type plasminogen activator (tPA) conversely declined with age and increased with MD only in young mice. Targeted disruption of tPA release or its upstream regulation by glutamic acid decarboxylase (GAD65) prevented MD-induced spine loss that was pharmacologically rescued concomitant with critical period plasticity. An extracellular mechanism for structural remodeling that is limited to the binocular zone upon proper detection of competing inputs thus links early sensory experience to visual function.

The serine protease, tissue-type plasminogen activator (tPA) is a key regulator of extracellular proteolytic cascades. We demonstrate a requirement for tPA signaling in the experience-dependent plasticity of mouse visual cortex during the developmental critical period. Proteolytic activity by tPA in the binocular zone was typically increased within 2 days of monocular deprivation (MD). This regulation failed to occur in glutamic acid decarboxylase (GAD) 65 knockout mice, an animal model of impaired ocular dominance plasticity because of reduced ␥-aminobutyric acid (GABA)-mediated transmission described previously. Loss of responsiveness to the deprived eye consequent to MD was conversely suppressed in mice lacking tPA despite normal levels of neuronal activity. Plasticity was restored in a gene dose-dependent manner, or by direct tPA infusion. Permissive amounts of tPA may, thus, couple functional to structural changes downstream of the excitatory-inhibitory balance that triggers visual cortical plasticity. Our results not only support a molecular cascade leading to neurite outgrowth after sensory deprivation, but also identify a valuable tool for further proteomic and genomic dissection of experiencedependent plasticity downstream of electrical activity.