Sonic hedgehog maintains cellular and neurochemical homeostasis in the adult nigrostriatal circuit

Neuron. 2012 Jul 26;75(2):306-19. doi: 10.1016/j.neuron.2012.05.018.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholinergic Neurons / metabolism
  • Cholinergic Neurons / pathology
  • Corpus Striatum / metabolism*
  • Corpus Striatum / pathology
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / pathology
  • Gait / physiology
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism*
  • Homeostasis / physiology*
  • Mice
  • Motor Activity / physiology
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Neural Pathways / metabolism
  • Neural Pathways / pathology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism*
  • Parkinson Disease / pathology
  • Signal Transduction / physiology
  • Substantia Nigra / metabolism*
  • Substantia Nigra / pathology


  • Glial Cell Line-Derived Neurotrophic Factor
  • Hedgehog Proteins