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Substantia nigra pars compacta (SNc) dopamine neurons are required for voluntary movement and reward learning, and advanced age is associated with motor and cognitive decline. In the midbrain, D2-type dopamine receptors located at dendrodendritic synapses between dopamine neurons control cell firing through G protein-activated potassium (GIRK) channels. We previously showed that aging disrupts dopamine neuron pacemaker firing in mice, but only in males. Here we show that the amplitude of D2-receptor inhibitory postsynaptic currents (D2-IPSCs) are moderately reduced in aged male mice. Local application of dopamine revealed a reduction in the amplitude of the D2-receptor currents in old males compared to young, pointing to a postsynaptic mechanism. Further experiments indicated that reduced D2 receptor signaling was not due to a general reduction in GIRK channel currents or degeneration of the dendritic arbor. Kinetic analysis showed no differences in D2-IPSC shape in old versus young mice or between sexes. Potentiation of D2-IPSCs by corticotropin releasing factor (CRF) was also not affected by age, indicating preservation of one mechanism of plasticity. These findings have implications for understanding dopamine transmission in aging, and reduced D2 receptor inhibition could contribute to increased susceptibility of males to SNc dopamine neuron degeneration in Parkinson’s disease.

ID 55249 Poster Board 134Amyloid-b and tau accumulation accompanied by cortico-hippocampal degeneration comprise the pathological hallmarks of latestage Alzheimer's disease (AD) but do not readily explain all behavioral phenotypes present in Alzheimer's patients. Decades of anecdotal and recent experimental evidence implicate dopamine dysfunction in prodromal stages of AD, suggesting dopaminergic circuits could be potential therapeutic targets. Insight into alterations in structure, function, and molecular phenotype of single living dopamine neurons of the ventral midbrain is vital to understanding the prodromal pathophysiology of AD. Here, we used acute slice patch-clamp electrophysiology, single cell RNA-sequencing, pharmacology, and morphological reconstruction to assess single dopaminergic neuron structure and function in triple transgenic 3xTg-AD mice, a model that expresses both amyloid-b and tau in a characterized spatiotemporal manner. Electrophysiological recordings from 3xTg-AD dopaminergic neurons of the ventral tegmental area displayed hypersensitivity, measured both by gain and number of action potentials generated, to directcurrent injections as early as three months of age. Tonic firing rhythmicity of dopamine neurons in transgenic mice significantly deviated from controls by six months of age. Voltage clamp experiments indicated a decreased small conductance calcium activated potassium channel (SK) current may underly both the irregularity in pacemaking and the hypersensitivity of phasic action potential generation. Interestingly, irregularity was recapitulated by a partial block of SK, though not completely recovered by positive allosteric modulation of the same channel. Additionally, we observed diminished neurite complexity in single dopamine neurons from 3xTg-AD mice, when measured using Sholl analysis. Tandem patch-clamp single-cell RNA-sequencing (Patch-seq) data suggests dopamine neurons with impaired physiology deviate drastically from the molecular profile of their healthy wildtype controls. These results suggest functional and structural degeneration in subpopulations of single dopaminergic neurons across the lifespan of 3xTg-AD mice.

Substantia nigra pars compacta (SNc) dopamine neurons are required for voluntary movement and reward learning, and advanced age is associated with motor and cognitive decline. In the midbrain, D2-type autoreceptors located on dendrodendritic synapses between dopamine neurons control cell firing through G protein-activated potassium (GIRK) channels. We previously showed that aging disrupts dopamine neuron pacemaker firing in mice, but only in males. Here we show that D2-receptor inhibitory postsynaptic currents (D2-IPSCs) in aged male mice are moderately smaller compared to young males as well as females, regardless of age. Local application of dopamine revealed a reduction in the amplitude of the D2-receptor currents in old males compared to young, pointing to a postsynaptic mechanism that could not be explained by impairment of the GIRK channels or degeneration of the dendritic arbor. Kinetic analysis showed no differences in D2-IPSCs in old versus young mice or between sexes. Potentiation of D2-IPSCs by corticotropin releasing factor (CRF) is also conserved in aging, indicating preservation of plasticity mechanisms. These findings have implications for understanding dopamine transmission in aging in both sexes and could explain in part the increased susceptibility of males to SNc degeneration of dopamine neurons in neurodegenerative disorders such as Parkinson's disease (PD).