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Research Articles, Cellular/Molecular

Neurotensin Release from Dopamine Neurons Drives Long-Term Depression of Substantia Nigra Dopamine Signaling

Christopher W. Tschumi, Harris E. Blankenship, Ramaswamy Sharma, William B. Lynch and Michael J. Beckstead
Journal of Neuroscience 10 August 2022, 42 (32) 6186-6194; DOI: https://doi.org/10.1523/JNEUROSCI.1395-20.2022
Christopher W. Tschumi
1Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104
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Harris E. Blankenship
1Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104
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Ramaswamy Sharma
2Department of Cell Systems & Anatomy, University of Texas Health, San Antonio, Texas 78229
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William B. Lynch
1Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104
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Michael J. Beckstead
1Aging & Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104
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Abstract

Midbrain dopamine neurons play central physiological roles in voluntary movement, reward learning, and motivated behavior. Inhibitory signaling at somatodendritic dopamine D2 receptor (D2R) synapses modulates excitability of dopamine neurons. The neuropeptide neurotensin is expressed by many inputs to the midbrain and induces LTD of D2R synaptic currents (LTDDA); however, the source of neurotensin that is responsible for LTDDA is not known. Here we show, in brain slices from male and female mice, that LTDDA is driven by neurotensin released by dopamine neurons themselves. Optogenetic stimulation of dopamine neurons was sufficient to induce LTDDA in the substantia nigra, but not the VTA, and was dependent on neurotensin receptor signaling, postsynaptic calcium, and vacuolar-type H+-ATPase activity in the postsynaptic cell. These findings reveal a novel form of signaling between dopamine neurons involving release of the peptide neurotensin, which may act as a feedforward mechanism to increase dopamine neuron excitability.

SIGNIFICANCE STATEMENT Dopamine neurons in the midbrain play a critical role in reward learning and the initiation of movement. Aberrant dopamine neuron function is implicated in a range of diseases and disorders, including Parkinson's disease, schizophrenia, obesity, and substance use disorders. D2 receptor-mediated PSCs are produced by a rare form of dendrodendritic synaptic transmission between dopamine neurons. These D2 receptor-mediated PSCs undergo LTD following application of the neuropeptide neurotensin. Here we show that release of neurotensin by dopamine neurons themselves is sufficient to induce LTD of dopamine transmission in the substantia nigra. Neurotensin signaling therefore mediates a second form of interdopamine neuron communication and may provide a mechanism by which dopamine neurons maintain excitability when nigral dopamine is elevated.

  • dopamine
  • neurotensin
  • plasticity
  • retrograde
  • substantia nigra
  • VTA

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The Journal of Neuroscience: 42 (32)
Journal of Neuroscience
Vol. 42, Issue 32
10 Aug 2022
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Neurotensin Release from Dopamine Neurons Drives Long-Term Depression of Substantia Nigra Dopamine Signaling
Christopher W. Tschumi, Harris E. Blankenship, Ramaswamy Sharma, William B. Lynch, Michael J. Beckstead
Journal of Neuroscience 10 August 2022, 42 (32) 6186-6194; DOI: 10.1523/JNEUROSCI.1395-20.2022

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Neurotensin Release from Dopamine Neurons Drives Long-Term Depression of Substantia Nigra Dopamine Signaling
Christopher W. Tschumi, Harris E. Blankenship, Ramaswamy Sharma, William B. Lynch, Michael J. Beckstead
Journal of Neuroscience 10 August 2022, 42 (32) 6186-6194; DOI: 10.1523/JNEUROSCI.1395-20.2022
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Keywords

  • dopamine
  • neurotensin
  • plasticity
  • retrograde
  • substantia nigra
  • VTA

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