title: TGF-β Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning.
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.
authors.affiliation: 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.
authors.forename: Sarah X
authors.initials: SX
authors.lastname: Luo
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Timbang
authors.affiliation: 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.
authors.forename: Jae-Ick
authors.initials: JI
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Yulei
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kadellyn
authors.initials: K
authors.lastname: Sandoval
authors.affiliation: Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Amy A
authors.initials: AA
authors.lastname: Tang
authors.affiliation: 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.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Whistler
authors.affiliation: Department of Neurosurgery and Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Jun B
authors.initials: JB
authors.lastname: Ding
authors.affiliation: 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.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Huang
mesh_terms: D000818:Animals; D003712:Dendrites / Q000235:genetics / Q000502:physiology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000502:physiology; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D008636:Mesencephalon / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D012193:Reversal Learning / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: TGF-β; axon; dendrite; dopaminergic neurons; inhibitory synapse; phasic firing; reversal learning