Journal
CELL REPORTS
Volume 17, Issue 12, Pages 3233-3245Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.11.068
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Funding
- NIH [NS081485, NS098516, NS091144, DA037963]
- Department of Veterans Affairs [BX001108, RX002133]
- Klingenstein Foundation
- state of California for medical research on alcohol and substance abuse through UCSF
- A*STAR Scholar Program
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Neural circuits involving midbrain dopaminergic (DA) neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor beta (TGF-beta) signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-beta type II receptor in DA neurons also disrupts the balance in TGF-beta 1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-beta signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus-reward associations. These results support a role for TGF-beta in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders.
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