Preprint
Enhanced spine stability and survival lead to increases in dendritic spine density as an early response to local alpha-synuclein overexpression in mouse prefrontal cortex
bioRxiv
Cold Spring Harbor Laboratory
09/28/2023
DOI: 10.1101/2023.09.28.559765
PMCID: PMC10557684
PMID: 37808820
Abstract
Lewy Body Dementias (LBD), including Parkinson’s disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. Patients with LBDs develop cognitive changes, including abnormalities in executive function, attention, hallucinations, slowed processing, and cognitive fluctuations. The causes of these non-motor symptoms remain unclear; however, accumulation of alpha-Synuclein aggregates in the cortex and subsequent interference of synaptic and cellular function could contribute to psychiatric and cognitive symptoms. It is unknown how the cortex responds to local pathology in the absence of significant secondary effects of alpha-Synuclein pathology in the brainstem. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used
in vivo
2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of
Thy1-YFP
transgenic mice at 1-week intervals from 1-2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.
Details
- Title: Subtitle
- Enhanced spine stability and survival lead to increases in dendritic spine density as an early response to local alpha-synuclein overexpression in mouse prefrontal cortex
- Creators
- Peter J. Bosch - University of IowaGemma KerrRachel Cole - University of IowaCharles A. Warwick - University of IowaLinder H Wendt - University of IowaAkash Pradeep - University of IowaEmma Bagnall - University of IowaGeorgina M. Aldridge - University of Iowa
- Resource Type
- Preprint
- Publication Details
- bioRxiv
- DOI
- 10.1101/2023.09.28.559765
- PMID
- 37808820
- PMCID
- PMC10557684
- Publisher
- Cold Spring Harbor Laboratory
- Language
- English
- Date posted
- 09/28/2023
- Academic Unit
- Neurology; Iowa Neuroscience Institute; Biology; Internal Medicine
- Record Identifier
- 9984474910302771
Metrics
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