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Neurotransmitter-mediated calcium signaling in apical dendrite initiation of cortical projection neurons and proposal for the role of Cajal-Retzius neurons
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Olson, Eric
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Fall 2023
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2023-12
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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.