Semester Award Granted

Spring 2025

Submission Date

May 2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Thesis/Dissertation Advisor [Chair]

Sathyanarayanan Puthanveettil

Thesis/Dissertation Co-Chair

Robert Stackman

Abstract

Neurons are specialized, polarized cells necessary for our function, cognition, and behavior. Moreover, neurons are non-mitotic cells and must be maintained for a lifetime. Within the neuron, organelles, such as mitochondria and lysosome-vesicles (LV), undergo bidirectional transport between the soma and synapses and contribute to neuronal health, energy demand, macromolecule clearance, intracellular signaling, and cell-to-cell communication. Decades of research have revealed the significance of mitochondria and LV during aging, neurological disorders, neurodegenerative diseases, and recently, novel implications in neuropsychiatric disorders. While these studies highlight the role of mitochondria and LV during aging and neurological conditions, less is known about the role of mitochondrial and LV in preserving the neuron during basal and learning conditions. Novel insight into whether and how basal versus learning conditions influence mitochondrial and LV abundance, spatial distribution, and soma-to-synapse bidirectional trafficking can strengthen our fundamental understanding of the neuron and can offer potential therapy targets for combatting the transport impairments observed in aging and neurological diseases.

Here, we employ the large identified sensory and motor neurons of the Aplysia californica gill withdrawal reflex by recapitulating the reflex monosynaptic circuity in vitro. We simultaneously imaged mitochondrial and LVs trafficking during basal synapse formation, maintenance, and activity-dependent excitatory plasticity. We found that the basal formation of functional synapses leads to a bidirectional enhancement in mitochondrial flux and a decrease in LV retrograde flux. Enhanced bidirectional mitochondrial transport persists through basal synapse maintenance. Additionally, retrograde LROs flux is persistently reduced during basal synapse maintenance. During synapse maintenance, differentially compartmentalized cAMP-PKA pools are necessary and sufficient for bidirectionally enhanced mitochondrial transport and for the reduction of retrograde LV trafficking. Lastly, excitatory synaptic plasticity temporally modulates direction-specific enhancements in mitochondrial flux and reductions in retrograde LRO flux. These results demonstrate modulation of mitochondria and LV's spatial and temporal distribution during basal and excitatory synapse activities.

These data offer insight into how the transport of essential organelles between the soma and synapse is regulated to support synaptic activity. Importantly, these data provide the fundamental basis for characterizing mitochondrial and LVs trafficking during basal activity and excitatory plasticity.

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