Inhibitory cortical interneurons (CINs) modulate neural circuits and are key in the regulation of excitatory- inhibitory balance. Their dysregulation is associated to a wide range of neurological disease including epilepsy, autism and schizophrenia. CINs are derived from the embryonic medial and caudal ganglionic eminences (MGE & CGE). When transplanted in the juvenile or adult brain, MGE cells disperse and undergo a period of programmed cell death before differentiating, primarily, into parvalbumin (PV) and somatostatin (SST) CINs. Transplantation of CINs offers a new tool to repair hyperactivity in multiple neurological disorders. In previous work we have shown that cell death of transplanted MGE CINs is intrinsically controlled. We have also shown PV or SST CINs, but not CINs derived from CGE, transplanted into the visual cortex to induce a new period of ocular dominance plasticity (ODP). Here we propose to investigate the mechanisms that regulate the survival, integration and induction of plasticity of transplanted MGE CINs.
Aim 1 will determine the function of clustered protocadherins (Pcdhs) in the regulation of CIN survival. Preliminary data reveals a major role for members of the Pcdhs-? cluster. The contribution of the Pcdh-? and Pcdh-? clusters to CIN survival will be determined. We developed a co-transplantation assay to study the behavior and survival of WT and Pcdhs mutant CINs in an identical environment. We will confirm and extend preliminary data showing that Pcdh-? isoforms C3, C4 and C5 are required for CIN survival and will investigate whether the C5 isoform, which is upregulated during CIN cell death, is sufficient to rescue the death induced by the loss Pcdhs-?.
Aim 2 will identify structural and functional changes that precede cell death in Pcdh-?-deficient CINs. Using state of the art morphometric analysis and live in vitro and in vivo imaging we will determine whether the loss of Pcdh-? in CINs impairs morphological maturation and cellular behavior. We will also investigate changes in connectivity and physiological properties of CINs before, during and after the period of cell death and whether these are affected in Pcdh-? deficient cells.
Aim 3 will determine how the structure and physiology of transplanted CINs change during the subsequent period when transplanted cells induce a second period of plasticity in visual cortex. We will start by determining the timeline of maturation and visual responsiveness and will optogenetically excite them to determine how their activity mediates plasticity. We will compare the surviving Pcdh-y-/- CINs to wild type before, during, and after the second ODP in acute brain slices and in vivo; will then test whether transplanted Pcdh-y-/- CINs differ in their ability to induce plasticity. The work will provide new molecular information on the mechanism of survival of MGE CINs, their synaptic integration and physiological properties, and the sufficiency of their activity for the induction of cortical plasticity. This new knowledge will help understand the key contribution CINs make to brain plasticity and repair.
When transplanted into juvenile or adult brain, precursors of cortical interneurons (CINs) migrate, integrate and induce a new period of plasticity. We propose experiments to identify molecular mechanisms that determine the number of CINs that survive and how they integrate to induce plasticity, key to using CINs for brain repair.
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