Abstract

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.

Significance Statement While recent studies describe a suspected role for VTA dopamine neurons in Alzheimer’s disease, the influence of excitatory and inhibitory input as well as single neuron morphology is not known. Using single-cell patch-clamp electrophysiology we find that 3xTg-AD dopamine neurons receive enhanced glutamatergic synaptic input and reduced inhibitory GABA input, thus tipping the balance further toward excitation. By combining this with morphological reconstructions, multicompartmental biophysical modeling, and past findings of intrinsic hypersensitivity, we predict that synaptic changes drive increased burst firing and convey a steeper input-output relationship in 3xTg neurons. These modifications likely alter downstream signaling or serve as a compensatory protective mechanism in the face of degenerative pathology in AD.