Experience-dependent plasticity is a critical feature of the developing and mature mammalian CNS. This plasticity is prevalent in the cerebral cortex dedicated to sensory processing, where use-dependent mechanisms refine cortical circuitry during precise intervals of development. During this interval, or ‘critical period’, perturbations to sensory input can have profound and long-lasting effects upon the response properties of the cortex. For example, closing one eye (monocular deprivation) shifts the ocular dominance of visual cortex to increase cortical responsiveness to the open eye. How the sensitivity of cortical circuitry to input is restricted to the critical period is not understood. Although recent studies indicate that the maturation of inhibitory neuronal activity is essential for initiating the critical period, the factors responsible for closing the critical period for ocular dominance plasticity have not been determined.

Recently, we (primarily Aaron McGee, a postdoctoral fellow from my laboratory) demonstrated that the Nogo-66 Receptor (NgR) and myelin restrict this experience-dependent plasticity to the developmental critical period (Science 309: 2222-2226). Several inhibitors of axonal outgrowth present in myelin membranes signal through NgR; genetic disruption or pharmacological blockade of this signaling pathway promotes axon regeneration and improves behavioral recovery after traumatic injury to the CNS. Working in collaboration with Yupeng Yang, a postdoctoral associate from Nigel Daw’s lab in the department of ophthalmology here at Yale, we examined ocular dominance plasticity in mice lacking either NgR or its principal ligand, Nogo, with field recordings from visual cortex in anesthetized mice. Both these strains of knock out mice exhibit plasticity well into adulthood, months beyond the end of the traditional critical period. While this study identifies NgR and myelin as regulators of plasticity within adult cortex, many questions remain regarding the mechanisms that subserve cortical plasticity.

Both synaptic and anatomical modifications to neurons contribute to ocular dominance plasticity. Many of the proteins implicated in two forms of synaptic plasticity in the hippocampus, long-term depression (LTD) and long-term potentiation (LTP) also are required for ocular dominance plasticity. However, the precise relationship between this synaptic plasticity and experience-dependent plasticity has been difficult to elucidate. The persistent ocular dominance plasticity retained in the NgR mutant mice provides a unique opportunity to distinguish the mechanisms that mediate this experience-dependent plasticity. In order to examine synaptic plasticity in NgR mutant mice, my Postdoctoral Fellow Aaron McGee wishes to initiate experiments in collaboration with Mark Yeckel’s laboratory. With Mark’s guidance, Aaron will examine LTD and LTP within the intracortical circuitry of NgR mutant mice with whole-cell patch clamp electrophysiology. These experiments may provide the first evidence describing the intracortical synaptic plasticity required for experience-dependent plasticity and refine current models of the function of this circuitry. This novel ine of work cannot be initiated with Kavli support.