Dopaminergic neurotransmission dysfunction induced by amyloid-β transforms cortical long-term potentiation into long-term depression and produces memory impairment
Abstract
Alzheimer's disease (AD) is a neurodegenerative condition manifested by synaptic dysfunction and memory loss, but the mechanisms underlying synaptic failure are not entirely understood. Although dopamine is a key modulator of synaptic plasticity, dopaminergic neurotransmission dysfunction in AD has mostly been associated to noncognitive symptoms. Thus, we aimed to study the relationship between dopaminergic neurotransmission and synaptic plasticity in AD models. We used a transgenic model of AD (triple-transgenic mouse model of AD) and the administration of exogenous amyloid-β (Aβ) oligomers into wild type mice. We found that Aβ decreased cortical dopamine levels and converted in vivo long-term potentiation (LTP) into long-term depression (LTD) after high-frequency stimulation delivered at basolateral amygdaloid nucleus-insular cortex projection, which led to impaired recognition memory. Remarkably, increasing cortical dopamine and norepinephrine levels rescued both high-frequency stimulation -induced LTP and memory, whereas depletion of catecholaminergic levels mimicked the Aβ-induced shift from LTP to LTD. Our results suggest that Aβ-induced dopamine depletion is a core mechanism underlying the early synaptopathy and memory alterations observed in AD models and acts by modifying the threshold for the induction of cortical LTP and/or LTD.
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Loss of TH-containing neurons has also been observed in the 3×Tg-AD and APPswe/PS1ΔE9 mouse models of AD.
“loss of neurons that contain tyrosine-hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, has also been observed in two other commonly-used AD models, the 3 × Tg-AD and APPswe/PS1 Δ E9 mice”
From Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer’s Disease (2021) · cites this paper as Moreno-Castilla et al., 2016
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“Additionally, whether the selective degeneration at 3 months of age starts locally in the midbrain and/or is the result of a dying-back mechanism starting from the axonal terminals (Liu et al., 2008; Moreno-Castilla et al., 2016), is yet to be defined.”
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- Authors
- Moreno-Castilla, P., Rodriguez-Duran, L. F., Guzman-Ramos, K., Barcenas-Femat, A., Escobar, M. L., & Bermudez-Rattoni, F.
- Affiliations
- Universidad Nacional Autónoma de México (MX)
- ORCID
- Escobar, Martha L.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2016-05
- Volume
- 41
- Pages
- 187-199
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2288964146
- Cited by
- 84
- References
- 69
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 7 · 2023: 8 · 2022: 10 · 2021: 11 · 2020: 8 · 2019: 6 · 2018: 9 · 2017: 8 · 2016: 1
- FWCI
- 6.45
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- CONACYT (155242 and CB 250870)
- PAPIIT-UNAM (IN209413, IN208616, IN215816)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- Alzheimer's disease, amyloid-beta oligomers, dopamine signaling, dopamine depletion, long-term potentiation, long-term depression, synaptic plasticity, recognition memory impairment, norepinephrine, synaptopathy, triple transgenic mouse model
- MeSH terms
- Alzheimer Disease, Animals, Cerebral Cortex, Disease Models, Animal, Dopamine, Male, Memory Disorders, Mice, Transgenic, Synaptic Transmission, Neuronal Plasticity, Amyloid beta-Peptides, Long-Term Potentiation, Long-Term Synaptic Depression, Mice, Dopaminergic Neurons
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