Enhanced synaptic excitation of VTA dopamine neurons in a mouse model of Alzheimer's disease.

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 GABA(A)R-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.