The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease

• Type of Material: Article
• Authors: Alexa F Iannitelli, Emory University; Michael A Kelberman, Emory University; Daniel J Lustberg, Emory University; Anu Korukonda, Emory University; Katharine McCann, Emory University; Bernard Mulvey, Washington University; Arielle Segal, Emory University; Cameron L Liles, Emory University; Steven Sloan, Emory University; Joseph D Dougherty, Washington University; David Weinshenker, Emory University
• Language: English
• Date: 2023-01-01
• Publisher: SOC NEUROSCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Iannitelli et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/ENEURO.0483-22.2022
• Title of Journal or Parent Work: ENEURO
• Volume: 10
• Issue: 1
• Keywords: Science & Technology; locus coeruleus; NEUROPATHOLOGY; norepinephrine; RAT-BRAIN; Neurosciences & Neurology; Parkinson?s disease; BETA-ADRENOCEPTOR BINDING; mice; Alzheimer?s disease; ALZHEIMERS-DISEASE; DEGENERATION; COGNITIVE DEFICITS; PROTEIN; CERULEUS NEURONS; Life Sciences & Biomedicine; NORADRENALINE; DSP-4; NORADRENERGIC NEURONS; Neurosciences
• Research Categories: Health Sciences, Mental Health

Abstract

The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and alpha- synuclein pathology in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin DSP-4, which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (2 doses of 50 mg/kg, 1 week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms.