Journal
JOURNAL OF NEUROSCIENCE
Volume 35, Issue 31, Pages 11144-11152Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3816-14.2015
Keywords
calcineurin; Dopamine; IPSC; neurotensin; plasticity; presynaptic
Categories
Funding
- National Institute on Drug Abuse [R01 DA32701, DA35821]
- National Institute of Neurological Disorders and Stroke [T32 NS077888]
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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 D-2 autoreceptors. Application of the modulatory peptide neurotensin (NT) to midbrain dopaminergic neurons transiently increases activity by decreasing D-2 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 D-2 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 2 NT 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.
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