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Alpha-synuclein pathology, microgliosis, and parvalbumin neuron loss in the amygdala associated with enhanced fear in the Thy1-aSyn model of Parkinson's disease

Torres, Eileen Ruth S. and Stanojlovic, Milos and Zelikowsky, Moriel and Bonsberger, Jana and Hean, Sindalana and Mulligan, Caitlin and Baldauf, Leonie and Fleming, Sheila and Masliah, Eliezer and Chesselet, Marie-Francoise and Fanselow, Michael S. and Richter, Franziska (2021) Alpha-synuclein pathology, microgliosis, and parvalbumin neuron loss in the amygdala associated with enhanced fear in the Thy1-aSyn model of Parkinson's disease. Neurobiology of Disease, 158 . Art. No. 105478. ISSN 0969-9961. PMCID PMC8447919. doi:10.1016/j.nbd.2021.105478.

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In Parkinson's disease (PD), the second most common neurodegenerative disorder, non-motor symptoms often precede the development of debilitating motor symptoms and present a severe impact on the quality of life. Lewy bodies containing misfolded α-synuclein progressively develop in neurons throughout the peripheral and central nervous system, which may be correlated with the early development of non-motor symptoms. Among those, increased fear and anxiety is frequent in PD and thought to result from pathology outside the dopaminergic system, which has been the focus of symptomatic treatment to alleviate motor symptoms. Alpha-synuclein accumulation has been reported in the amygdala of PD patients, a brain region critically involved in fear and anxiety. Here we asked whether α-synuclein overexpression alone is sufficient to induce an enhanced fear phenotype in vivo and which pathological mechanisms are involved. Transgenic mice expressing human wild-type α-synuclein (Thy1-aSyn), a well-established model of PD, were subjected to fear conditioning followed by extinction and then tested for extinction memory retention followed by histopathological analysis. Thy1-aSyn mice showed enhanced tone fear across acquisition and extinction compared to wild-type littermates, as well as a trend to less retention of fear extinction. Immunohistochemical analysis of the basolateral nucleus of the amygdala, a nucleus critically involved in tone fear learning, revealed extensive α-synuclein pathology, with accumulation, phosphorylation, and aggregation of α-synuclein in transgenic mice. This pathology was accompanied by microgliosis and parvalbumin neuron loss in this nucleus, which could explain the enhanced fear phenotype. Importantly, this non-motor phenotype was detected in the pre-clinical phase, prior to dopamine loss in Thy1-aSyn mice, thus replicating observations in patients. Results obtained in this study suggest a possible mechanism by which increased anxiety and maladaptive fear processing may occur in PD, opening a door for therapeutic options and further early biomarker research.

Item Type:Article
Related URLs:
URLURL TypeDescription
Torres, Eileen Ruth S.0000-0002-5340-8734
Stanojlovic, Milos0000-0001-5261-3712
Zelikowsky, Moriel0000-0002-0465-9027
Mulligan, Caitlin0000-0002-7164-6090
Masliah, Eliezer0000-0002-2117-5569
Fanselow, Michael S.0000-0002-3850-5966
Richter, Franziska0000-0003-0803-4398
Additional Information:© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( Received 19 February 2021, Revised 20 July 2021, Accepted 9 August 2021, Available online 11 August 2021. We thank Ivo Denden and Edith Kaczmarek for excellent technical assistance. This work was supported by the National Institutes of Health [PHS grants NS-P50 NS38367, UCLA Morris K. Udall Parkinson's disease Research Center of Excellence], and gifts to the Center for the Study of Parkinson's Disease at UCLA. Authors' contributions: Conceptualization: MFC, FR, MSF, MZ, SF; Funding acquisition: MFC; Supervision: FR, MZ; Investigation: EST, MS, MZ, SH, CT, SF, JB, LB; Statistical Analysis and Visualization: FR, ERT, MS, MZ, JB, LB; Resources: EM; Manuscript preparation: Writing of first draft ERT, MS; Writing-Reviewing and editing: FR, MZ, MFC, MS. The authors declare no competing interests. Data availability: Data supporting the figures of this manuscript are available from the corresponding author upon reasonable request.
Funding AgencyGrant Number
NIHNS-P50 NS38367
Subject Keywords:Anxiety; Synucleinopathy; Fear conditioning; Line 61
PubMed Central ID:PMC8447919
Record Number:CaltechAUTHORS:20210823-224325421
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Official Citation:Eileen Ruth S. Torres, Milos Stanojlovic, Moriel Zelikowsky, Jana Bonsberger, Sindalana Hean, Caitlin Mulligan, Leonie Baldauf, Sheila Fleming, Eliezer Masliah, Marie-Francoise Chesselet, Michael S. Fanselow, Franziska Richter, Alpha-synuclein pathology, microgliosis, and parvalbumin neuron loss in the amygdala associated with enhanced fear in the Thy1-aSyn model of Parkinson's disease, Neurobiology of Disease, Volume 158, 2021, 105478, ISSN 0969-9961,
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110396
Deposited By: Tony Diaz
Deposited On:24 Aug 2021 17:36
Last Modified:22 Nov 2021 23:19

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