Blankenship Harris E, Higgs Matthew H, Beckstead Michael J
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Department of Physiology, University of Oklahoma Health Sciences, Oklahoma City, OK, USA.
bioRxiv. 2025 Jul 31:2025.07.24.666429. doi: 10.1101/2025.07.24.666429.
In Alzheimer's disease (AD) models, ventral tegmental area (VTA) dopamine neurons are intrinsically hyperexcitable, yet release less dopamine in projection regions, leading to dysfunctional downstream signaling. Synaptic transmission is broadly disrupted in AD, but it is not known to what extent altered excitatory and inhibitory inputs to the VTA influence dopaminergic activity and output. Here we describe enhanced synaptic excitation in dopamine neurons in the amyloid + tau-driven 3xTg-AD mouse model. AMPAR-mediated excitatory input was enhanced in a subset of connections, while GABAR-mediated inhibition decreased as a function of dendritic atrophy. The strengthened excitation appeared to depend on presynaptic protein kinase C (PKC) activity as well as postsynaptic AMPA receptor enhancement. Biophysical modeling predicted that synaptic changes, in combination with altered dendritic morphology and previously described intrinsic hypersensitivity, produce increased firing and a steeper input-output relationship. These results suggest that AD pathology is associated with increased input-output gain in single dopamine neurons, which may function to maintain phasic dopamine signaling in early stages of axonal degeneration.
在阿尔茨海默病（AD）模型中，腹侧被盖区（VTA）多巴胺能神经元本质上是过度兴奋的，但在投射区域释放的多巴胺较少，导致下游信号传导功能失调。AD中突触传递广泛受损，但尚不清楚对VTA的兴奋性和抑制性输入改变在多大程度上影响多巴胺能活性和输出。在此，我们描述了在淀粉样蛋白+ tau驱动的3xTg-AD小鼠模型中多巴胺能神经元突触兴奋增强的情况。在一部分连接中，AMPA介导的兴奋性输入增强，而GABAR介导的抑制随着树突萎缩而降低。增强的兴奋似乎依赖于突触前蛋白激酶C（PKC）活性以及突触后AMPA受体增强。生物物理模型预测，突触变化与改变的树突形态以及先前描述的内在超敏反应相结合，会导致放电增加和更陡峭的输入-输出关系。这些结果表明，AD病理与单个多巴胺能神经元的输入-输出增益增加有关，这可能在轴突退化早期维持阶段性多巴胺信号传导中发挥作用。
