The unexpected survival of embryonic neurons transplanted into the brains of newborn mice in a series of experiments at the University of California, San Francisco (UCSF) raises hope for the possibility of using neuronal transplantation to treat diseases like Alzheimer's, epilepsy, Huntington's, Parkinson's and schizophrenia.
The experiments, described this week in the journal Nature, were not designed to test whether embryonic neuron transplants could effectively treat any specific disease. But they provide a proof-of-principle that GABA-secreting interneurons, a type of brain cell linked to many different neurological disorders, can be added in significant numbers into the brain and can survive without affecting the population of endogenous interneurons.
The survival of these cells after transplantation in numbers far greater than expected came as a shock to the team, which was led by UCSF professor Arturo Alvarez-Buylla, PhD, and former UCSF graduate student Derek Southwell, MD, PhD.
The prevailing theory held that the survival of developing neurons is something like a game of musical chairs. The brain has limited capacity for these cells, forcing them to compete with each other for the few available slots. Only those that find a place to "sit" (and receive survival signals derived from other cell types) will survive when the music stops. The rest die a withering death.
Based on this theory, the UCSF team had expected only a fixed and small number of transplanted embryonic interneurons would survive in the brains of older recipient mice, regardless of how many they transplanted. What they found was very different: Regardless of how many they transplanted, a consistent percentage always survived.
"[This constant rate of survival] suggests that these cells, which other collaborative studies have shown have great therapeutic promise, can be added to cortex in significant numbers," said Alvarez-Buylla, who is the Heather and Melanie Muss Professor of Neurological Surgery and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.
Past work at UCSF and elsewhere has shown that transplanting these cells can create a new critical period of plasticity in the recipient brain, reduce seizures in animal models of epilepsy, and reduce Parkinson's-like movement disorders in laboratory rats. The activity of these cells is often disrupted in Alzheimer's disease, and their number is altered in the brains of people with schizophrenia. When transplanted into the spinal cord, they also help decrease pain sensation.
In the current study, the UCSF team found that as they altered the number of cells they transplanted, a constant proportion of these cells survived - rather than a constant number - suggesting that a fraction of the cells is destined to die by cell-autonomous mechanisms or that a survival factor is secreted by the inhibitory neurons themselves. The work shows that these interneurons may be transplanted in far greater numbers than previously thought - an observation that could have important implications for the use of these cells to correct defects in the excitatory/inhibitory valance in the disease brain.
Survival of Cells Depends on Unknown "Signals
GABAergic interneurons are essential for brain function because they balance the action of "excitatory" neurons in the cerebral cortex by producing inhibitory signals. Diseases like epilepsy, Alzheimer's, Huntington's, Parkinson's and schizophrenia are all variously linked to disruptions in this excitatory/inhibitory balance, and problems with the GABAergic interneurons have been documented in all these diseases.