Advisor(s)
Laura Volpicelli-Daley
Committee Member(s)
Andrew Hardaway
Karen Jaunarajs
Mark Moehle
Talene Yacoubian
School
Joint Health Sciences (Interdisciplinary)
Document Type
Dissertation
Department (new version)
Joint Health Sciences
Date of Award
9-11-2025
Abstract
Lewy Body Dementias (LBDs), including Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB), are defined by α-synuclein (α-syn) accumulation in Lewy Pathology (LP). LP is abundant in cortical layer V intratelencephalic (IT) neurons, a subset of neurons that also degenerate in the pre-supplementary motor area (preSMA) in humans, which is homologous to the secondary motor cortex (M2) in mice, as observed in PD postmortem tissue. IT neuron projections to the striatum are an intrinsic part of the motor basal ganglia circuitry, believed to modulate cognitive aspects of executive motor control, such as updating motor plans. M2 projections to the striatum play a critical role in goal-directed movement, one of the most common cognitive domains affected in LBDs. Corticostriatal projections innervate spiny projection neurons (SPNs) in the striatum, and these SPNs exhibit spine loss in postmortem LBD tissue as well as in dopaminergic denervation studies. Using preformed fibrils (PFF) to model abnormal α-syn accumulation, we and others have demonstrated detrimental defects in excitatory synaptic function and loss of excitatory spines, along with a decrease in the expression of SNARE proteins VAMP2 and Snap25. Templated formation of α-syn inclusions produces aggregates in cortical layer V projection neurons. However, the impact of abnormal α-syn aggregates on corticostriatal synaptic function remains unclear. In this study, we aim to understand how cortex-to-striatum connections are impaired by the corruption of presynaptic ɑ-syn into pathological aggregates. In two independent approaches, we used striatal and M2 cortical PFF injections to induce α-syn pathology formation and used physiological, biochemical and morphological approaches to investigate corticostriatal synaptic function and structural integrity. Striatal PFF injections caused α-syn pathology accumulation in both cortical layer V neurons and striatal SPNs, along with reduced evoked corticostriatal glutamatergic transmission and a loss of functional release sites, suggesting a breakdown of synapses. Immunoblot quantification further supported this, as multiple presynaptic proteins were significantly reduced upon striatal PFF injections. Using high resolution imaging and 3D rendering of synaptic pairs, we found a significant reduction of corticostriatal synaptic density and morphological changes in animals harboring pathology six weeks post intrastriatal injections. We did not observe any changes in density of thalamostriatal synapses, but observed morphological changes, too. The presence of pathological α-syn aggregates in synaptic compartments was accompanied by morphological alterations in those compartments for corticostriatal and thalamostriatal synapses, but presynaptic α-syn aggregates were more common in cortical terminals. Downstream of corticostriatal synaptic function, we observed a significant decrease in SPN intrinsic excitability in striatally PFF-injected mice. We also observed dopaminergic denervation as early as six weeks post striatal PFF injections and abundant somal pathology in SPN neurons, thus we were unable to isolate which pathological consequence of striatal PFF injections caused corticostriatal synaptic deficits. Using unilateral M2 PFF injections, we procured a synucleinopathy model with cortical dominant pathology, with no DA loss or pathology accumulation in SPNs. Six weeks after M2-PFF injections, we found robust accumulation of α-syn pathology in cortical layer V neurons and their projections and terminals in the striatum. Using optogenetics, we co-expressed the infrared-shifted channelrhodopsin Chrimson-R in M2 and found significant impairment in M2-to striatum excitatory transmission, while also observing a significant loss in functional release sites in mice harboring cortical-dominant α-syn pathology. Synaptic morphology analysis revealed a loss of corticostriatal synaptic pairs in M2-PFF injected animals, in line with our physiological recordings indicating corticostriatal synapse loss as an early consequence of cortical formation of α-syn pathology. Our combined efforts in physiology and high-resolution imaging point to a critical dysfunction of corticostriatal synapses in animals harboring α-syn inclusions. Our novel approach in inducing pathology in M2 cortex shows that cortical α-syn alone, and independent of striatal DA innervation, is sufficient to drive early corticostriatal synaptic deficits.
ProQuest ID
Recommended Citation
Brzozowski, Charlotte Franziska, "Impact Of Alpha-Synuclein Aggregation On Corticostriatal Synaptic Function And Morphology" (2025). All ETDs from UAB. 7363.
https://digitalcommons.library.uab.edu/etd-collection/7363
