Kennedy William M, Troyano-Rodriguez Eva, Higgs Matthew H, Blankenship Harris E, Korukonda Anu, Weinshenker David, Rice Heather C, Beckstead Michael J
Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104.
Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104.
bioRxiv. 2025 Jul 31:2025.07.28.666953. doi: 10.1101/2025.07.28.666953.
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.
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.
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.
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.
腹侧被盖区（VTA）多巴胺与阿尔茨海默病（AD）患者出现的神经精神症状有关。在小鼠AD模型中观察到多巴胺能功能障碍和异常放电，但β淀粉样蛋白（Aβ）和tau蛋白的具体作用尚未确定。
我们在3xTg-AD模型中对单个VTA多巴胺神经元放电进行了电生理记录，随后在基于淀粉样蛋白（APP）和人tau蛋白（hTau）的模型中进行记录，以确定放电受损的病理触发因素。
多巴胺神经元记录显示，与对照组相比，3xTg-AD小鼠在特定爆发中的尖峰较少。研究表明，在去极化过程中维持放电的能力受损，野生型神经元中去极化电流可模拟这种情况。用hTau转导的多巴胺神经元表现出放电异常和爆发受损，但在APP模型中未重现这些效应。
这些结果表明，hTau特异性地诱导单个多巴胺神经元内的过度兴奋状态，破坏爆发式放电。这种多巴胺能功能障碍可能会损害奖赏学习，并导致AD中观察到的精神症状。
