Cerebral Dopamine Neurotrophic Factor regulates multiple neuronal subtypes and behavior

Chen, Y.C., Baronio, D., Semenova, S., Abdurakhmanova, S., Panula, P.
The Journal of neuroscience : the official journal of the Society for Neuroscience   40(32): 6146-6164 (Journal)
Registered Authors
Baronio, Diego, Chen, Yu-Chia, Panula, Pertti, Semenova, Svetlana
MeSH Terms
  • Animals
  • Behavior, Animal*
  • Brain/cytology
  • Brain/metabolism
  • Dopaminergic Neurons/metabolism*
  • GABAergic Neurons/metabolism*
  • Gene Deletion
  • Histamine/metabolism
  • Male
  • Nerve Growth Factors/genetics
  • Nerve Growth Factors/metabolism*
  • Parkinson Disease/genetics
  • Parkinson Disease/metabolism*
  • Seizures/genetics*
  • Tyrosine 3-Monooxygenase/genetics
  • Tyrosine 3-Monooxygenase/metabolism
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
32631936 Full text @ J. Neurosci.
Cerebral Dopamine Neurotrophic Factor (CDNF) protects dopaminergic neurons against toxic damage in the rodent brain and is in clinical trials to treat Parkinson's disease patients. Yet the underlying mechanism is poorly understood. To examine its significance for neural circuits and behavior, we examined the development of neurotransmitter systems from larval to male adult mutant zebrafish lacking cdnf Although a lack of cdnf did not affect overall brain dopamine levels, dopaminergic neuronal clusters showed significant abnormalities. The number of histamine neurons that surround the dopaminergic neurons was significantly reduced. Expression of tyrosine hydroxylase 2 in the brain was elevated in cdnf mutants throughout their lifespan. There were abnormally few GABA neurons in the hypothalamus in the mutant larvae, and expression of glutamate decarboxylase was reduced throughout the brain. cdnf mutant adults showed a range of behavioral phenotypes, including increased sensitivity to pentylenetetrazole-induced seizures. Shoaling behavior of mutant adults was abnormal, and they did not display social attraction to conspecifics. CDNF plays a profound role in shaping the neurotransmitter circuit structure, seizure susceptibility, and complex behaviors in zebrafish. These findings are informative for dissecting the diverse functions of this poorly understood factor in human conditions related to Parkinson's disease and complex behaviors.Significance StatementA zebrafish lacking cdnf grows normally and shows no overt morphologic phenotype throughout the life span. Remarkably, impaired social cohesion and increased seizure susceptibility was found in adult cdnf KO fish conceivably associated with significant changes of dopaminergic, GABAergic and histaminergic systems in selective brain areas. These findings suggest that cdnf has broad effects on regulating neurogenesis and maturation of transmitter-specific neuronal types during development and throughout adulthood, rather than ones restricted to the dopaminergic systems.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes