A new study by Harvard University neuroscientist Jeffrey Macklis and colleagues suggests it is possible to transplant fetal neurons into a part of the mouse brain that does not normally generate new brain cells, and they will repair abnormal circuits. In this case, the researchers repaired a genetic defect that causes obesity, but that was not the goal of their work which was to establish proof of principle that transplanted neurons can integrate into existing faulty brain circuits and restore them.
The study, published online in the journal Science on 25 November, challenges the idea that you can’t repair key parts of the mammalian brain.
The researchers, from Harvard University, Massachusetts General Hospital (MGH), Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School (HMS) used mutant mice that had been genetically engineered to lack the receptor for leptin, a hormone that acts on brain cells in the hypothalamus to regulate metabolism and control body weight. Without this receptor, mice become morbidly obese and diabetic.
This type of genetically modified mouse is commonly used as an animal model for researching obesity, diabetes, and dyslipidemia, and is known as the “db/db mouse”.
The researchers took normal hypothalamus neurons, selected at a particular stage development, from the brains of fetal mice that did not lack the leptin receptor, and transplanted them into the hypothalamus of the mutant mice. To put the transplanted cells exactly in the right place, in a microscopically small region of the hypothalamus, they used a method known as “high-resolution ultrasound microscopy”.
The transplanted neurons repaired the defective brain circuits, so the mutant mice could respond to leptin, with the result that they gained substantially less weight.
The mice that received the transplanted cells still grew to be fatter than normal mice, but they were not as fat as morbidly obese-prone mice that did not receive the transplants, and they did not become diabetic. The transplant recipients weighed about 40 to 45 grams a few days after birth, compared with 25 grams for normal mice and 55 to 60 grams for obese-prone mice that underwent a placebo-like operation without receiving any new neurons.
Macklis and colleagues also investigated what happened in the brains of the mice after they received the transplants. They used several markers, including the fact that another gene in the transplanted neurons causes a protein to fluoresce green in a given light, to follow the path the cells took. They found that the transplanted neurons had specialized into several different types normally found in the hypothalamus. Not only this, but they had also formed synapses with other neurons: synaptic connections are essential for brain cells to communicate with each other.
The researchers write in their paper:
“Donor neurons differentiated and integrated as four distinct hypothalamic neuron subtypes, formed functional excitatory and inhibitory synapses, partially restored leptin responsiveness, and ameliorated hyperglycemia and obesity in db/db mice.”
They also showed that the new hypothalamic neurons had the same pattern of electrical activity as normal neurons in response to leptin, and were communicating with the native neurons.
Macklis told Science NOW that the new neurons were behaving like “antennas” for leptin, and sending those signals into the brain. He and his colleagues write in their conclusion:
“These experiments serve as a proof of concept that transplanted neurons can functionally reconstitute complex neuronal circuitry in the mammalian brain.”
They hope the ability to repair brain circuits in this way will open the door to treating a range of of higher level conditions, including spinal cord injury, autism, epilepsy, Huntington’s disease, Parkinson’s disease, and ALS (Lou Gehrig’s disease).
However, the path to such new avenues is likely to bring challenges as well as promises. Within the last month we have had the news that Geron, the Californian biotech company, has pulled out of its trial on using stem cells to repair spinal injury, and it seems lack of funding is why it is withdrawing from stem cell work altogether. And studies testing fetal cell transplants for treating Parkinson’s disease have also not yielded the anticipated promises.
But Macklis and colleagues appear more optimistic, pointing to new lessons learned in their study, such as the importance of harvesting the fetal neurons at precisely the point when they are about to differentiate into different types of hypothalamic neurons. Previous experiments may have failed because the scientists did not realize the importance of this timing. It could be, for instance, that there is a need to match the signals in the new environment to the readiness of the transplanted cells to receive them.
They call their study a “proof of concept” for the broader idea that new neurons can integrate into and modify defective complex circuits in the brains of mammals.
They are now moving onto what they call “controlled neurogenesis”, where scientists direct the growth of new brain cells from inside the brain, thus opening a new route to regenerative therapies.
Macklis told Harvard Gazette:
“The next step for us is to ask parallel questions of other parts of the brain and spinal cord, those involved in ALS and with spinal cord injuries.”
“In these cases, can we rebuild circuitry in the mammalian brain? I suspect that we can,” he added.
Funds from the National Institutes of Health, the Jane and Lee Seidman Fund for Central Nervous System Research, the Emily and Robert Pearlstein Fund for Nervous System Repair, the Picower Foundation, the National Institute of Neurological Disorders and Stroke, Autism Speaks, and the Nancy Lurie Marks Family Foundation, paid for the study.
Written by Catharine Paddock PhD