Comprehensive transcriptional profiling of the NPCs’ therapy underlying mechanism for the development of a new rationalized approach: Optogenetically inducible cAMP levels for the treatment of the Spinal Cord Injury.

Neural progenitor cell (NPC) transplantation represents a promising treatment for spinal cord injury (SCI); however, the underlying therapeutic mechanisms remain incompletely understood. We have demonstrated that severe spinal contusion in adult rats causes the transcriptional dysregulation of nearly 20,000 genes, affecting several key components of the cAMP signaling. The ectopic transplantation of spinal cord-derived NPCs after SCI induces a significant transcriptional impact in spinal tissue, rescuing the expression of a large proportion of SCI-affected genes. The transcriptional modulation driven by NPC transplantation comprises the rescued expression of cAMP signaling genes, especially EPAC2 (exchange protein directly activated by cAMP). Then, we explored how the sustained inhibition of EPAC2 in vivo by ESI-05 administration impacts the therapeutic outcomes resulting from NPC therapy. Compared to transplanted animals, NPCs+ESI-05 treatment increases the scar area, polarizes microglia into an inflammatory phenotype, and increases the magnitude of the gap between NeuN+ cells across the lesion. Overall, these results indicate that the NPC-associated therapeutic mechanisms in the context of SCI partly relies on the cAMP signaling, reducing inflammation and providing a more neuropermissive environment through an EPAC2-dependent mechanism. Next, to further promote a pro-regenerative program after SCI context we have implement a photoactivatable adenylate cyclase (bPAC) to induce in vivo on-demand cAMP increases in two different manners: in the corticospinal neurons to induce the regeneration of the injured corticospinal tract (CST) or in transplanted NPCs to potentiate their therapeutic properties. Our preliminary results show that the stimulation of bPAC in injured animals promotes significant locomotor improvements compared to control rats, evidencing that bPAC is as a new promising tool for SCI repair.

NRG1 signaling promotes the neurites development of cortical neurons, Laboratory of Cortical Circuits in Health and Disease

Schizophrenia is a developmental disorder characterized by atrophy of neuronal processes and alterations in connections between cortical neurons. Neuregulin 1 (NRG1) was identified as a major schizophrenia risk gene and we and others showed that NRG1 intracellular signaling is required for dendritic elongation, excitatory transmission and synaptic plasticity. Here, we studied the role of NRG1 intracellular signaling in the axonal development in vitro and in vivo taking advantage of multiple approaches, including culture of primary cortical neurons, in utero electroporation and neuronal tracing with Dil in newborn NRG1 knockout mice. Our study suggests that NRG1 expression in cortical neurons regulates de neurites growth in vitro and in vivo, promoting and being necessary for the formation of the axonal projections. From a molecular point of view, we are currently studying the NRG1 signaling pathways underlying the neurites growth that characterizes our phenotype. These results expand the knowledge about NRG1 signaling, hopefully contributing to the understanding of its molecular role in schizophrenia.