Neurotensin speeds inhibition of dopamine neurons through temporal modulation of GABAA and GABAB receptor-mediated synaptic input

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Midbrain dopamine neurons play physiological roles in many processes including reward learning and motivated behavior, and are tonically inhibited by γ-aminobutyric acid (GABA)ergic input from multiple brain regions. Neurotensin (NT) is a neuropeptide which acutely modulates midbrain dopamine neuron excitability through multiple mechanisms, one of which is a decrease of GABA-mediated inhibition. However, the mechanisms through which NT depresses GABA signaling are not known. Here we used whole cell patch-clamp electrophysiology of dopamine neurons in mouse brain slices to show that NT acts both presynaptically to increase GABAA and postsynaptically to decrease GABAB receptor-mediated currents in the substantia nigra. The active peptide fragment NT8-13 enhanced GABAA signaling presynaptically by causing an increase in the size of the readily releasable pool of GABA via activation of the NT type-1 receptor and protein kinase A. Conversely, NT8-13 depressed GABAB signaling postsynaptically via the NT type-2 receptor in a process that was modulated by protein kinase C. Both forms of plasticity could be observed simultaneously in single dopamine neurons. Thus, as the kinetics of GABAA signaling are significantly faster than those of GABAB signaling, NT functionally speeds GABAergic input to midbrain dopamine neurons. This finding contributes to our understanding of how neuropeptide-induced plasticity can simultaneously differentiate and integrate signaling by a single neurotransmitter in a single cell and provides a basis for understanding how neuropeptides use temporal shifts in synaptic strength to encode information.HighlightsNT enhances GABAA receptor-mediated signaling at midbrain dopamine neurons.NT depresses GABAB receptor-mediated signaling at dopamine neurons postsynaptically.NT plasticity mechanism differs for GABAA and GABAB receptor-mediated signaling.NT shifts the strength of inputs to dopamine neurons towards fast GABA signaling.

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