Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2

Abstract

The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties and whether they act together or independently is unknown. Here we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. As mTOR is involved in several brain disorders caused by dopaminergic dysregulation including Parkinson’s disease and addiction, our results have implications for understanding the pathophysiology and potential therapeutic strategies for these diseases.

Multi-omics analysis identifies LBX1 and NHLH1 as central regulators of human midbrain dopaminergic neuron differentiation

“…Exploration of the data for a common origin of cholesterol biosynthesis and translation downregulation revealed mTOR signaling inhibition as a possible explanation and in line with previous findings (90,91,(95)(96)(97). mTOR signaling was recently shown to play different roles in mDAN biology, controlling their morphology, dopamine release, and electrophysiology (98). Indeed, inhibiting mTOR signaling using rapamycin recapitulated most of the features observed by LBX1 KD.…”