Alzheimer's Pathology Enhances Excitatory Synaptic Input and Integration in VTA Dopamine Neurons

In Alzheimer's disease (AD) models, ventral tegmental area (VTA) dopamine neurons are intrinsically hyperexcitable yet release less dopamine and exhibit dysfunctional downstream signaling. Synaptic transmission is broadly disrupted in AD, but it is not known to what extent excitatory and inhibitory inputs to the VTA are altered. Here we describe enhanced synaptic excitation in dopamine neurons from male and female 3xTg-AD mice (an amyloid + tau-driven model). AMPAR-mediated excitatory input was enhanced in a subset of connections, while GABA_AR-mediated inhibition decreased as a function of dendritic atrophy. Protein phosphorylation analysis and pharmacology suggested that strengthened excitation depends on both presynaptic protein kinase C activity and postsynaptic enhancement of perisomatic AMPA receptor currents. Biophysical modeling predicted that enhanced excitatory synaptic input in 3xTg-AD dopamine neurons, combined with altered dendritic morphology and intrinsic hypersensitivity, produces increased firing and a steeper input-output relationship. These results suggest that AD pathology is associated with increased sensitivity of single dopamine neurons, which may serve to maintain phasic dopamine signaling in early stages of degeneration.