title: Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit.
abstract: Non cell-autonomous processes are thought to play critical roles in the cellular maintenance of the healthy and diseased brain but mechanistic details remain unclear. We report that the interruption of a non cell-autonomous mode of sonic hedgehog (Shh) signaling originating from dopaminergic neurons causes progressive, adult-onset degeneration of dopaminergic, cholinergic, and fast spiking GABAergic neurons of the mesostriatal circuit, imbalance of cholinergic and dopaminergic neurotransmission, and motor deficits reminiscent of Parkinson's disease. Variable Shh signaling results in graded inhibition of muscarinic autoreceptor- and glial cell line-derived neurotrophic factor (GDNF)-expression in the striatum. Reciprocally, graded signals that emanate from striatal cholinergic neurons and engage the canonical GDNF receptor Ret inhibit Shh expression in dopaminergic neurons. Thus, we discovered a mechanism for neuronal subtype specific and reciprocal communication that is essential for neurochemical and structural homeostasis in the nigrostriatal circuit. These results provide integrative insights into non cell-autonomous processes likely at play in neurodegenerative conditions such as Parkinson's disease.
authors: Department of Psychiatry, Columbia University, New York, NY 10032, USA.
authors: Luis E
authors: LE
authors: Gonzalez-Reyes
authors: Miguel
authors: M
authors: Verbitsky
authors: Javier
authors: J
authors: Blesa
authors: Vernice
authors: V
authors: Jackson-Lewis
authors: Daniel
authors: D
authors: Paredes
authors: Karsten
authors: K
authors: Tillack
authors: Sudarshan
authors: S
authors: Phani
authors: Edgar R
authors: ER
authors: Kramer
authors: Serge
authors: S
authors: Przedborski
authors: Andreas H
authors: AH
authors: Kottmann
mesh_terms: D000818:Animals; D059329:Cholinergic Neurons / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology; D005684:Gait / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D053823:Hedgehog Proteins