Abstract
Parkinson’s disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-synuclein pre-formed fibrils (PFFs) into the striatum induces robust α-synuclein aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-synuclein show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that PFF-injected mice showed reduced intervesicular distances similar to a recent study showing phospho-serine-129 α-synuclein increases synaptic vesicle clustering. Thus, pathologic α-synuclein causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.
Competing Interest Statement
This work was supported by the National Institutes of Health (NINDS grant R56NS117465) American Parkinson Disease Association (grant 977962) Aligning Science Across Parkinsons Disease-Team Thomas Biederer (ASAP 020616) through the Michael J Fox Foundation for Parkinsons Research to LVD and Alzheimers of Central Alabama
Footnotes
Nolwazi Gcwensa: gcwenolw{at}uab.edu, Dreson Russell: dre28{at}uab.edu, Khaliah Long: klonguab{at}uab.edu, Charlotte Brzozowski: cfbrzozo{at}uab.edu, Rita Cowell: ritacowell{at}uabmc.edu, Karen Gamble: karengamble{at}uabmc.edu, Xinran Liu: xinran.liu{at}yale.edu
Abbreviations
- α-syn
- α-synuclein
- BLA
- basolateral amygdala
- DLB
- Dementia with Lewy Bodies
- MON
- monomeric α-synuclein
- MRI
- Magnetic Resonance Imaging
- NPTN
- neuroplastin
- PD
- Parkinson’s Disease
- p-α-syn
- phosphorylated-α-synuclein
- PBS
- phosphate buffered saline
- PET
- positron emission tomography
- PFA
- paraformaldehyde
- PFFs
- preformed fibrils
- PSD
- post synaptic density
- PSD95
- post synaptic density protein 95
- SNc
- substantia nigra pars compacta
- SVs
- synaptic vesicles
- TBS
- tris-buffered saline
- TEM
- transmission electron microscopy
- VGLUT
- vesicular glutamate transporter
- w p-α-syn
- with phophorylated-α-synuclein
- wo p-α-syn
- without phosphorylated-α-synuclein