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Cell Rep. 2016 Dec 20;17(12):3233-3245. doi: 10.1016/j.celrep.2016.11.068.

TGF-β Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning.

Author information

1
Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
2
Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
3
Department of Neurosurgery and Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94304, USA; School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, Korea.
4
Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA; Department of Neurology, University of California San Francisco, San Francisco, CA 94143, USA.
5
Department of Neurosurgery and Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94304, USA.
6
Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA; Neuroscience Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA; Pathology Service 113B, San Francisco VA Medical Center, San Francisco, CA 94121, USA. Electronic address: eric.huang2@ucsf.edu.

Abstract

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 β (TGF-β) signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-β type II receptor in DA neurons also disrupts the balance in TGF-β1 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-β 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-β 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.

KEYWORDS:

TGF-β; axon; dendrite; dopaminergic neurons; inhibitory synapse; phasic firing; reversal learning

PMID:
28009292
PMCID:
PMC5312261
DOI:
10.1016/j.celrep.2016.11.068
[Indexed for MEDLINE]
Free PMC Article

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