The maturation of GABAergic interneurons regulates cortical plasticity and development of visual acuity. Recently, it has been proposed that neuregulin1 (NRG1)/ErbB4-mediated circuit disinhibition involving parvalbumin (PV) interneurons is required for ocular dominance plasticity (ODP) in developing visual cortex. Previous studies in our lab and others demonstrate that interneuron transplantation reactivates cortical plasticity in adult animals and enables recovery of normal visual acuity in animals that were visually deprived in development. The long-term goal of my proposal is to understand the mechanisms of transplant-induced cortical plasticity. In my current proposal, I hypothesize that NRG1/ErbB4-dependent circuit disinhibition involving transplanted PV interneurons is responsible for the transplant-reactivated cortical plasticity and recovery of visual acuity. To test this hypothesis, I will: (1) determine whether circuit disinhibition triggers the initiation of transplant- induced ODP in adult animals (Aim 1), (2) determine whether NRG1/ErbB4-mediated circuit disinhibition underlies transplant-induced ODP (Aim 2a and 2b), and (3) test the role of NRG1/ErbB4 signaling in the transplant-induced recovery of visual acuity in adult animals that experienced visual deprivation (Aim 3). If successful, these experiments will provide insight into the cell type-specific effects of NRG1/ErbB4 signaling in transplant-induced cortical plasticity in fully mature animals, and validate the therapeutic potential of GABAergic interneuron transplantation.
Dysfunction of GABAergic inhibitory circuit has been implicated in many neurodevelopmental and neuropsychiatric disorders, such as amblyopia, autism spectrum disorders, and schizophrenia. This proposal aims to elucidate the cell type-specific mechanisms of neuregulin1/ErbB4 signaling in interneuron transplant- reactivated cortical plasticity. By using interneuron transplantation, our experimental approach may open novel therapeutic avenues for neurodevelopmental and other brain related disorders.
