Dopamine Controls Neurogenesis in the Adult Salamander Midbrain in Homeostasis and during Regeneration of Dopamine Neurons

Abstract

Appropriate termination of regenerative processes is critical for producing the correct number of cells in tissues. Here we provide evidence for an end-product inhibition of dopamine neuron regeneration that is mediated by dopamine. Ablation of midbrain dopamine neurons leads to complete regeneration in salamanders. Regeneration involves extensive neurogenesis and requires activation of quiescent ependymoglia cells, which express dopamine receptors. Pharmacological compensation for dopamine loss by L-dopa inhibits ependymoglia proliferation and regeneration in a dopamine receptor-signaling-dependent manner, specifically after ablation of dopamine neurons. Systemic administration of the dopamine receptor antagonist haloperidol alone causes ependymoglia proliferation and the appearance of excessive number of neurons. Our data show that stem cell quiescence is under dopamine control and provide a model for termination once normal homeostasis is restored. The findings establish a role for dopamine in the reversible suppression of neurogenesis in the midbrain and have implications for regenerative strategies in Parkinson's disease.

A Survey of the Molecular Basis for the Generation of Functional Dopaminergic Neurons from Pluripotent Stem Cells: Insights from Regenerative Biology and Regenerative Medicine

“…Additionally, activated ependymoglia cells start to proliferate and differentiate to DA neurons to repair lost DA neurons. This neurogenic potential is activated under conditions of injury-responsive cell-replacement and not under homeostatic conditions [38,39]. These reports indicated that these regenerative animals possess unique stem cells system to regenerative missing DA neurons.…”

“…Although the number of regenerative animals used to investigate DA neuronal regeneration is limited, the cellular mechanisms of DA neuronal regeneration are starting to be understood [22,39]. The cellular and molecular mechanisms for DA neuronal regeneration in regenerative animals provide new ideas for generation of DA neurons in non-regenerative animals.…”

“…In the case of newts, another regenerative animals, quiescent ependymoglia cells can sense degeneration of DA neurons, and re-enter into the cell cycle to restore lost DA neurons [39]. In this case, DA receptor-expressing surrounding cells (i.e., ependymoglia cells) respond to the degeneration of DA neurons via DA receptor signaling, and contribute to regenerate DA neurons.…”

Toward a blueprint for regeneration

“…Andras Simon (Karolinska Institutet, Sweden) described the spectacular regeneration of different types of neurons after injury to the adult newt brain, focusing mainly on dopaminergic neurons. These neurons regenerate from ependymoglial cells in the subventricular layer; once the appropriate number of dopaminergic neurons is restored, neurogenesis ceases (Berg et al, 2011). He proposed that this occurs through a feedback mechanism in which dopamine itself inhibits the formation of more dopamine-producing neurons.…”

Therapeutic Application of Stem Cell Technology toward the Treatment of Parkinson’s Disease

“…In addition, pharmacotherapy cannot delay the progression of the loss of dA neurons, and also cannot recover the lost dA neurons. If human beings had regenerative potential similar to planarians 2) and newts, 3) some neural disorders could be spontaneously resolved by autonomous cells. Since this is not possible, the clinical strategy of "regenerative medicine," including cell transplantation therapy, has been developed to recover the lost neural function and treat neural diseases.…”