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Updated: Aug 13, 2026
Optic Nerve Transection: A Model of Adult Neuron Apoptosis in the Central Nervous System
Published on: May 12, 2011
Ontogenic cell death in the nigrostriatal system
1Department of Neurology, The College of Physicians and Surgeons, Columbia University, 650 West 168th Street, New York, NY 10032, USA. rb43@columbia.edu
Abstract:
Like most neural systems, dopamine neurons of the substantia nigra undergo apoptotic natural cell death during development. In rodents, this occurs largely postnatally and is biphasic with an initial major peak just after birth and a second minor peak on postnatal day 14. As envisioned by classic neurotrophic theory, this event is regulated by interactions with the target of these neurons, the striatum, because a developmental target lesion results in an augmented natural cell death event with fewer nigral dopamine neurons surviving into adulthood. Until recently, the striatal target-derived neurotrophic factors providing developmental support of dopamine neurons were unknown, but there is now growing evidence that glial-cell-line-derived neurotrophic factor (GDNF) serves as a physiologic limiting neurotrophic factor for these neurons during the first phase of natural cell death. During this phase, intrastriatal injection of GDNF diminishes the natural cell death event and neutralizing antibodies augment it. Sustained overexpression of GDNF in the striatum throughout development in a unique double transgenic mouse model results in an increased number of dopamine neurons surviving the first phase of natural cell death. However, this increase does not persist into adulthood. Therefore, other factors or mechanisms must play important roles in the determination of the mature number of nigral dopamine neurons. Further elucidation of these mechanisms will be important in the development of neuroprotective and cell replacement therapies for Parkinson's disease.
Insights
Glial cell line-derived neurotrophic factor (GDNF) supports dopamine neuron survival during early development. However, other factors influence the final number of dopamine neurons in adulthood, crucial for Parkinson's disease therapies.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Death Research
Background:
- Dopamine neurons in the substantia nigra undergo programmed cell death during development.
- This process is biphasic, with peaks shortly after birth and around postnatal day 14.
- Striatal target interactions regulate this cell death, influencing adult neuron numbers.
Purpose of the Study:
- To investigate the role of striatal target-derived neurotrophic factors in dopamine neuron development.
- To identify the specific factors involved in regulating programmed cell death of dopamine neurons.
- To understand mechanisms influencing the mature number of nigral dopamine neurons for potential therapeutic applications.
Main Methods:
- Utilized rodent models to study developmental cell death of dopamine neurons.
- Investigated the effects of glial cell line-derived neurotrophic factor (GDNF) via intrastriatal injections and neutralizing antibodies.
- Employed a double transgenic mouse model for sustained striatal GDNF overexpression during development.
Main Results:
- GDNF acts as a physiological neurotrophic factor during the initial phase of dopamine neuron cell death.
- Intrastriatal GDNF administration reduced cell death, while antibodies increased it.
- Sustained GDNF overexpression increased neuron survival in the first phase but not into adulthood.
Conclusions:
- GDNF is critical for early developmental survival of dopamine neurons.
- Mechanisms beyond GDNF regulate the final number of dopamine neurons surviving into adulthood.
- Further research into these mechanisms is vital for developing Parkinson's disease therapies.
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