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March 8, 2013
By engrafting human glial progenitor cells into the tiny brains of newborn mice, researchers have made the mice smarter, according to a new study published today in Cell Stem Cell.
It’s the first time researchers have used such cells to infiltrate brand-new mouse brains, resulting in a dramatic boost in learning and memory. The system could be a vivid animal model of the human brain, especially for the study of neurodegenerative diseases, stroke, and epilepsy.
“People have not really implicated glia cells in cognition; glia cells are supposed to be a supportive cell, a housekeeping cell,” said co-author Maiken Nedergaard, professor of translational neuromedicine at the University of Rochester. “This paper suggests that human astrocytes [the descendants of the glial progenitor cells] in some way increase cognitive abilities.”
Previously, scientists have found that astrocytes modulate and coordinate the signaling of neurons, acting as lowly water boys to the neuron super-stars. But human astrocytes are unique: they are 20-fold larger than those in mice and much more complex, possessing around 50 arm-like processes to mice’s 25. This disparity spurred a theory that astrocyte evolution might help explain human beings’ cognitive superiority.
“We were very interested in why astrocytes expanded so much during evolution,” said Nedergaard. “We were speculating that since they are larger, they may be integrating more information, making the human brain more powerful for computational analysis.”
To test the theory, Nedergaard, University of Rochester colleague Steven Goldman, and their team engrafted human glial progenitor cells into the brains of neonatal immunodeficient mice. When the mice matured, their brains were chimeric for both mouse and human astroglia. The human astroglia maintained their greater size and complexity even within the mouse brain.
In these chimeric mice, the team found sharply enhanced long-term potentiation (LTP), which is involved in learning and memory, in the human astrocytes. The humanized mice-of-NIMH performed significantly better than mice allografted with murine glial progenitor cells on four different cognitive tasks: auditory fear conditioning, contextual fear conditioning, Barnes maze navigation, and object-location memory.
After testing several of the factors released by astroglia, the team found that TNFalpha, a cytokine that causes AMPA receptors to insert into neuronal membranes and increases excitatory synaptic transmission, plays a role in LTP. When they inhibited TNFalpha production with thalidomide, the excitatory post-synaptic potential was significantly suppressed, as was long-term potentiation.
Nedergaard speculates there’s even more to the story of astrocytes’ role in learning and memory than this single TNFalpha pathway. “What I really believe is that each astrocyte makes a domain and does not allow processes from any other astrocytes to enter that domain. So you have basically small territories where all synapses are covered by a single astrocyte,” she said, like arms enveloping and protecting a precious baby. “Human astrocytes, then, would integrate 20-fold more information than mouse astrocytes.”
In the future, Nedergaard hopes to use induced pluripotent stem cells to create chimeric mouse models of human stroke, epilepsy, and neurodegenerative diseases.
1. Han, X., M. Chen, F. Wang, M. Windrem, S. Wang, S. Shanz, Q. Xu, N. A. Oberheim, L. Bekar, S. Betstadt, A. J. Silva, T. Takano, S. A. Goldman, and M. Nedergaard. 2013. Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12(3):342-353.
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