Neuralstem initiates spinal cord neural stem cell trial in ALS

August 11, 2015

These nascent neurons survived the transplantation process and developed structurally, molecularly, and electrophysiologically into the four cardinal types of neurons central to leptin signaling. The new neurons integrated functionally into the circuitry, responding to leptin, insulin, and glucose. Treated mice matured and weighed approximately 30 percent less than their untreated siblings or siblings treated in multiple alternate ways.

The researchers then investigated the precise extent to which these new neurons had become wired into the brain's circuitry using molecular assays, electron microscopy for visualizing the finest details of circuits, and patch-clamp electrophysiology, a technique in which researchers use small electrodes to investigate the characteristics of individual neurons and pairs of neurons in fine detail. Because the new cells were labeled with fluorescent tags, postdocs Czupryn, Zhou, and Chen could easily locate them.

The Zhou and Anderson team found that the newly developed neurons communicated to recipient neurons through normal synaptic contacts, and that the brain, in turn, signaled back. Responding to leptin, insulin and glucose, these neurons had effectively joined the brain's network and rewired the damaged circuitry.

"It's interesting to note that these embryonic neurons were wired in with less precision than one might think," Flier said. "But that didn't seem to matter. In a sense, these neurons are like antennas that were immediately able to pick up the leptin signal. From an energy-balance perspective, I'm struck that a relatively small number of genetically normal neurons can so efficiently repair the circuitry."

"The finding that these embryonic cells are so efficient at integrating with the native neuronal circuitry makes us quite excited about the possibility of applying similar techniques to other neurological and psychiatric diseases of particular interest to our laboratory," said Anderson.

The researchers call their findings a proof of concept for the broader idea that new neurons can integrate specifically to modify complex circuits that are defective in a mammalian brain.

The researchers are interested in further investigating controlled neurogenesis -- directing growth of new neurons in the brain from within -- the subject of much of Macklis's research as well as Flier's 2005 paper, and a potential route to new therapies.

"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," Macklis said. "In these cases, can we rebuild circuitry in the mammalian brain? I suspect that we can."

Source: Harvard Medical School