Transplantation of developing interneurons, specifically those expressing parvalbumin (PV) or somatostatin (SST), into a host visual cortex has been shown to induce a new period of ocular dominance plasticity (ODP). This newfound plasticity can also enhance the brain's ability to recovery from trauma; interneuron transplantation has been shown to ameliorate phenotypes in animal models of epilepsy, Parkinson's disease, and amblyopia. Given that specific changes in the activity of interneurons are known to be essential for mediating plasticity in the normal critical period, it is necessary to study the activity of the transplanted interneurons in order to understand the reintroduction of plasticity over the second critical period. Here, I propose to study the functional integration of PV and SST transplanted interneurons in vivo as they reopen the critical period for ODP.
Aim 1 will determine the timeline for establishing and maintaining visually driven responses in transplanted PV and SST interneurons that express a genetically encoded calcium indicator. The intrinsic nature of this process will also be addressed by comparing the activity of PV and SST transplanted interneurons to each other and to the older host interneurons.
Aim 2 will identify how the transplanted interneurons mediate ODP by studying how the activity timelines of PV and SST transplants are affected when one eye is occluded (monocular deprivation) over the second critical period. To determine if the activity of the transplants are causal for the induction of the second critical period, the firing properties of the transplants will be manipulated in Aim 3. This will be achieved by activating either channelrhodopsin (a light- activated non-specific cation channel that depolarizes neurons) or archaerhodopsin (a light-activated proton pump that hyperpolarizes neurons) in the respective transplanted interneuron at time points of interest reported for endogenous interneurons over the normal critical period and from the activity timeline in Aim 2. The ability of transplanted interneurons to induce plasticity de novo offers a powerful tool to study the mechanisms and limits of cortical plasticity.
The goal of this application is to understand how the activity of transplanted parvalbumin and somatostatin interneurons creates plasticity within an existing neuronal circuit. This will be accomplished by studying the activity of the transplanted interneurons in terms of their functional integration, using in vivo 2-photon microscopy, genetically encoded calcium indicators, and optogenetics. Establishing how the activity of these cells relates to the plasticity they mediate will contribute to our understanding of each cell type's role in the normal critical period, how new neurons can functionally integrate into postnatal cortex, and optimize interneuron transplantation as a cell therapy.
