bioRxiv : the preprint server for biology · 2025
Tau conveys intrinsic hyperactivity of VTA dopamine neurons but an inability to sustain burst firing.
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Kennedy William M, Troyano-Rodriguez Eva, Higgs Matthew H, Blankenship Harris E, Korukonda Anu, Weinshenker David, Rice Heather C, Beckstead Michael J
Аннотация
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 (APPNL-G-F)- and human tau (hTau)-based models to determine the pathological triggers of impaired firing.
RESULTS: In vivo dopamine neuron recordings showed fewer spikes in defined bursts in 3xTg-AD mice versus controls. Ex vivo 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 APPNL-G-F 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.
METHODS: We performed electrophysiological recordings of single VTA dopamine neuron firing in the 3xTg-AD model, followed by recordings in amyloid (APPNL-G-F)- and human tau (hTau)-based models to determine the pathological triggers of impaired firing.
RESULTS: In vivo dopamine neuron recordings showed fewer spikes in defined bursts in 3xTg-AD mice versus controls. Ex vivo 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 APPNL-G-F 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.