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Article Abstract
Introduction: Ventral tegmental area (VTA) dopamine has been implicated in neuropsychiatric symptoms observed in Alzheimer's disease (AD) patients. Dopaminergic dysfunction and aberrant firing are observed in mouse AD models, but the specific roles of Aβ and tau have not been determined.
Methods: We performed electrophysiological recordings of single VTA dopamine neuron firing in the 3xTg-AD model, followed by recordings in amyloid (APP)- and human tau (hTau)-based models to determine the pathological triggers of impaired firing.
Results: dopamine neuron recordings showed fewer spikes in defined bursts in 3xTg-AD mice versus controls. studies showed an impaired ability to sustain firing during depolarization, which was mimicked with depolarized current in wild type neurons. Dopamine neurons transduced with hTau reflected firing aberrations and impaired bursting, but the effects were not recapitulated in the APP model.
Discussion: These results suggest that hTau specifically induces hyperexcitable states within individual dopamine neurons, disrupting burst firing. This dopaminergic dysfunction could compromise reward learning and contribute to the psychiatric symptoms observed in AD.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12324307 | PMC |
| http://dx.doi.org/10.1101/2025.07.28.666953 | DOI Listing |
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