Mechanisms of Transplanted Cortical Interneuron Survival and Function

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Project Summary Cortical interneurons (cINs) are inhibitory cells that are born in surplus far from the cortex. During prenatal timepoints, cIN precursors migrate into the mouse visual cortex (V1) where only a fraction are selected to survive. Once integrated into the V1 circuit, cINs expressing parvalbumin (PV) or somatostatin (SST) trigger a temporally restricted period of plasticity that is required for normal visual experience. The underlying molecular factors and the role cellular activity plays in the selection of cIN survival and cIN-mediated plasticity are not fully understood. PV and/or SST cIN precursors that are heterochronically transplanted into a recipient cortex have been shown to follow a similar timeline for survival and create a temporally restricted window of plasticity in the “host” that follows the timeline of the “donor”, revealing that transplanted cINs develop at a normal rate and may be used as a proxy for cIN development. Here, I propose to use cIN transplantation to study the transcriptional changes and the molecular factors responsible in selecting cINs for survival (Aim 2) and for the capacity of cINs to induce plasticity (Aim 1). During the mentored phase of this award, Aim 1a will study the differential expression of transcripts from transplanted PV and SST cINs as they trigger plasticity in the host visual cortex. Aim 1b will compare these transcriptional changes to the transplant recipient’s PV and SST cINs to test whether similar genes are expressed and to characterize how host cINs are being affected at the molecular level by transplant-mediated plasticity. Aim 1c will compare the transcriptional changes in transplanted PV and SST cINs to endogenous PV and SST cINs at corresponding developmental ages over the juvenile critical period, to compare the temporal gene expression between transplanted CINs as they open a second critical period and endogenous cINs as they open the juvenile critical period. During the independent phase of this award, Aim 2a will track the excitability of transplanted cINs in vivo during the period of programmed cell death to identify a timeline of activity related to the selection for survival. Aim 2b will generate gene expression profiles over this timeline to characterize transcriptional signatures for survival versus death. To determine whether the genes of interest from Aim 2b are required for the selection of survival, their expression will be manipulated in Aim 2c. Transplanted cINs will be targeted with RNAi and their activity and survival will be measured. This proposal will identify novel therapeutic targets necessary for the formation of functional visual circuits and for developing more accessible ways to promote cortical plasticity.