Neurotensin induces presynaptic depression of D2 dopamine autoreceptor-mediated neurotransmission in midbrain dopaminergic neurons

Elisabeth Piccart, Nicholas A. Courtney, Sarah Y. Branch, Christopher P. Ford, Michael J. Beckstead

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Increased dopaminergic signaling is a hallmark of severe mesencephalic pathologies such as schizophrenia and psychostimulant abuse. Activity of midbrain dopaminergic neurons is under strict control of inhibitory D2 autoreceptors. Application of the modulatory peptide neurotensin (NT) to midbrain dopaminergic neurons transiently increases activity by decreasing D2 dopamine autoreceptor function, yet little is known about the mechanisms that underlie long-lasting effects. Here, we performed patch-clamp electrophysiology and fast-scan cyclic voltammetry in mouse brain slices to determine the effects of NT on dopamine autoreceptor-mediated neurotransmission. Application of the active peptide fragment NT8-13 produced synaptic depression that exhibited short- and long-term components. Sustained depression of D2 autoreceptor signaling required activation of the type 2 NT receptor and the protein phosphatase calcineurin. NT application increased paired-pulse ratios and decreased extracellular levels of somatodendritic dopamine, consistent with a decrease in presynaptic dopamine release. Surprisingly, we observed that electrically induced long-term depression of dopaminergic neurotransmission that we reported previously was also dependent on type 2NT receptors and calcineurin. Because electrically induced depression, but not NT-induced depression, was blocked by postsynaptic calcium chelation, our findings suggest that endogenous NT may act through a local circuit to decrease presynaptic dopamine release. The current research provides a mechanism through which augmented NT release can produce a long-lasting increase in membrane excitability of midbrain dopamine neurons.

Original languageEnglish (US)
Pages (from-to)11144-11152
Number of pages9
JournalJournal of Neuroscience
Volume35
Issue number31
DOIs
StatePublished - Aug 5 2015

Keywords

  • Calcineurin
  • Dopamine
  • IPSC
  • Neurotensin
  • Plasticity
  • Presynaptic

ASJC Scopus subject areas

  • Neuroscience(all)

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