Neurotransmitter-mediated calcium signaling in apical dendrite initiation of cortical projection neurons and proposal for the role of Cajal-Retzius neurons

Abstract

This thesis investigates the developmental processes in the mouse cortex during embryonic days 13 to 15, corresponding to human gestational weeks 8 to 11. The primary focus is on the calcium signaling pathways in neurons, particularly as they transition from the migratory phase to the dendrite initiation and growth phase. The study places special emphasis on Cajal-Retzius neurons (CRNs), a transient population of excitatory neurons in the developing cortex. These neurons are known for their secretion of Reelin, a glycoprotein that has a role in regulating the position of glutamatergic neurons of the cortex. While the role of Reelin and its downstream effects on cortical organization have been well-documented, this work investigates a previously unexplored transient circuit between CRNs and cortical projection neurons (CPNs). The central questions addressed in this thesis include: What is the calcium signal as neurons transition from the migratory phase to dendrite initiation and growth? Is the signal important for CPN maturation and dendrite growth? How does the activity and neurotransmitter release by CRNs serve as a mechanistic substrate that informs and coordinates CPN development during the foundational phases of cortical development? What neurotransmitter systems are involved and how are they functioning? Our research employs a multidisciplinary approach, leveraging whole embryonic hemisphere explants and multiphoton microscopy to study the calcium signaling profiles of CRNs and CPNs. The findings reveal that CRNs not only secrete Reelin but also exhibit spontaneous activity and the potential for neurotransmitter release, specifically glutamate. This activity significantly influences intracellular calcium levels in CPNs, thereby affecting their dendritic growth and migration patterns. This work opens up a new avenue for understanding early cortical development by offering a novel framework that extends beyond the established role of CRNs and Reelin secretion. It provides compelling evidence that CRNs play a more multifaceted role in cortical development than previously thought, serving in a transient circuit that informs and coordinates CPN development. This thesis, therefore, not only fills a gap in our understanding of early cortical development but also sets the stage for future research into the pathophysiology of neurodevelopmental disorders.