PKC-dependent enhancement of glutamate input to VTA dopamine neurons in 3xTg-AD mice

A growing body of work has recently linked ventral tegmental area (VTA) dopamine neuron dysfunction to Alzheimer's disease (AD). Work in AD mouse models suggests that VTA dopamine neurons are intrinsically hyperexcitable, yet release less dopamine and exhibit disrupted downstream signaling. Significant focus has been placed on describing dopamine release in projection regions; however, dopamine neurons somatodendritically integrate vast synaptic input, altering action potential output and ultimately determining neurotransmiter release. 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 in the amyloid + tau-driven 3xTg-AD mouse model. Patch-clamp electrophysiology experiments revealed enhanced AMPAR-mediated excitatory input in a subset of perisomatic connections. In contrast, GABA_AR-mediated inhibition was decreased as a function of dendritic atrophy, determined by single neuron reconstructions. We also detected elevated protein kinase C (PKC) substrate levels in the midbrain, and pharmacological experiments suggested that the strengthened excitation depends on elevated PKC activity. Additionally, postsynaptic AMPA receptor conductance was enhanced and displayed diminished ability to induce plasticity (long-term depression), but this was not dependent upon increased AMPA receptor expression. Morphologically detailed biophysical modeling predicted that synaptic changes, in combination with altered dendritic morphology and intrinsic hypersensitivity, produce increased spontaneous firing rates and a steeper input-output relationship in 3xTg-AD neurons. The results argue against a uniform decrease in synaptic connectivity across the brain in AD, and sheds light on the involvement of deep brain circuits. AD pathology is therefore associated with increased sensitivity of single dopamine neurons, which may help to maintain phasic dopamine signaling in early stages of degeneration.