What makes the human brain so much more intelligent than the brain of animals? When neuroscientist Marian Diamond of UC Berkeley examined tissue from Albert Einstein's brain for clues to his genius she could find no differences in the size or number of neurons in his cerebral cortex, but she counted an unusually high number of non-neuronal cells (called glia) in his brain. This 1985 report was intriguing because glia support neurons in many ways, physically and physiologically, but they are incapable of generating electricity. Therefore glia were thought to have no role in information processing in the brain. In 2006 Argentinian neuroscientist Jeoge Colombo reported that in addition to having more of one type of glial cell called an astrocyte, the astrocytes in Einstein's cerebral cortex were larger and they had a more complex shape than age-matched controls. This was especially interesting in light of his 2004 study reporting that this type of colossal astrocyte was unique to primates. No other animals have such large astrocytes with long tendrils penetrating deeply through several layers of cerebral cortex. These findings about Einstein's brain are intriguing, but alone they prove nothing -- they are observations not conclusions. "It remains a difficult task to provide a link between [astrocytes and] genius," says Colombo, from the analysis of "a single, aged, postmortem brain," but still, these findings provoked expanded thinking about the possibility that information processing, cognition, and human intelligence could involve cells other than neurons. Now a team of neuroscientists has such proof. They grafted human astrocytes into the brain of mice and found that synaptic transmission, learning, and memory are enhanced beyond that of normal mice.
Even though astrocytes cannot generate electrical signals, in theory they might integrate or couple communication among populations of neurons across large expanses of neural networks in ways that other mammals with simpler astrocytes cannot. In fact, the number of astrocytes increases in the brains of animals through evolution. Maiken Nedergaard, a pioneer in research on neuron-astrocyte interactions, was struck by how much different human astrocytes looked compared to those in rodent brains that are typically used in animal research on learning and memory. "Steve [Goldman] and I were culturing human brain cells many years ago and noted that cultured astrocytes were much, much larger than in cultures prepared from rodent brain." Steven Goldman, an expert in neural stem cell research, and Nedergaard are co-authors on the study. Both scientists are at the University Rochester Medical Center.
Commenting on the new study, Alfonso Araque, an expert on interactions between astrocytes and neurons at the Caja Institute in Madrid, explained that a larger number of astrocytes and more complex and larger cells in the human brain could "provide a huge increase in computational powers to [neural] networks. His own experiments in rodents, in addition to research from many other researchers in the last 15 years show that astrocytes can regulate communication between neurons at synapses and participate in the cellular mechanisms of learning and memory. Astrocytes are closely associated with neurons and they enshroud synapses. They are able to release and take up neurotransmitters and other neuro-active substances to suppress or amplify the strength of communication between neurons--the cellular basis of information processing and learning. Nedergaard says that "The volume of human astrocytes is almost 20 fold larger than their rodent counterparts, enabling human astrocytes to integrate input from a comparably staggering number of synapses, 2 million compared with 100,000 in the rodent brain."
Professor Alcino Silva, from the Brain Research Institute at UCLA, who is an expert on learning and memory and one of the co-authors of the study, was surprised by the outcome. "This is a profoundly surprising and unexpected finding," he says. "It is possible to replace mouse astrocytes with human astrocytes and not only get a live mouse, but [get] one that learns and remembers better than normal counterparts." Their results indicated that the human astrocytes inserted themselves properly into the mouse tissue and retained their human size and complex shape in the foreign environment of the mouse brain. "There is a carefully choreographed synaptic signaling dance between astrocytes and neurons, and I find it absolutely amazing that synaptic function was not only not disrupted, but plasticity was actually enhanced by the human astrocytes," says Silva.
The researchers measured synaptic function by using standard electrophysiological tests that measure the minute electrical signal generated when a synapse fires. In mice with human astrocytes transplanted into their brain the synaptic signals peaked faster and to higher amplitudes than in mice that had astrocytes from other mice transplanted as a control. Faster and stronger synaptic signals could increase information processing in neural networks.
Although astrocytes do not use electricity to communicate, they do signal by releasing neurotransmitters that stimulate waves of calcium ions flowing in their cytoplasm. The researchers found that the calcium waves in human astrocytes traveled three times faster than in rodent astrocytes. What's more, the transplanted human astrocytes formed connections with other human and mouse astrocytes, called gap junctions, which permitted rapid cellular signaling through large networks of astrocytes.
Long-term potentiation (LTP) is the widely-studied strengthening of synaptic connections that develops after a neuron is stimulated repeatedly. This phenomenon is thought to be the cellular basis for memory, because repeated stimulation of a synapse, just as repetition in learning new information, helps form lasting memories. In mice engrafted with human astrocytes, less stimulation was needed to cause the synapse to suddenly increase the voltage it produced. Moreover, when the animals were put through a series of tests of learning and memory, the mice with human astrocytes outperformed mice injected with astrocytes taken from other mice.
Commenting on this report, Pritzker Professor at Stanford University School of Medicine and an expert on LTP, Robert Malenka, says that "It is certainly possible that via several different mechanisms, differences in the number and/or properties of astrocytes could contribute to the greater intellectual capacity of humans compared to other species. This work is an important first step in exploring this possibility."
Professor Helmut Kettenmann, at the Max-Delbrück Center for Molecular Medicine in Berlin, and expert on glia, agrees. This is "a really surprising finding," that builds on previous research from Nedergaard's laboratory. "Of course, one is always concerned about the ethical aspect," Kettenmann observes. "If human astrocytes enhance the capacity of mouse brains, how far is one allowed to go?"
Goldman notes, however, that the development of mouse models containing human cells enables better experiments to understand how the human brain functions and how to treat human neurological and psychiatric disorders. "This may permit a significant advance in how both the mechanisms and potential treatments of human-selective brain disorders are evaluated, in that a disease-specific human glial chimera may permit potential therapeutic strategies to be evaluated." He points to disorders such as schizophrenia, which seem to appear in parallel with the human brain and its more complex glial and neuronal architecture. The cellular basis for such human disorders are difficult to study in animal models. "Similarly, we have established mice chimerized with human glia derived from patients with Huntington's disease, to assess the relative contributions of diseased human glia to the neuropsychiatric symptoms and cognitive deterioration noted in patients with late-stage Huntington's Disease," he says.
Whether one can explain Einstein's genius by differences in astrocytes in his brain is debatable. "First, Einstein died at an old age," Araque points out. "So perhaps neurodegeneration made the number of glial cells higher." Glial cells are known to respond to neuronal distress by increases in number and alterations in shape. Colombo notes that such increases in large astrocytes with long tendrils are "also observed in cases with Alzheimer's disease." "Second," says Arague, "I think genius cannot be ascribed to a single characteristic. I consider genius, intelligence, etc., as a multifactorial phenomenon that derives not only from morphological aspects but mostly from functional and developmental processes." Nedergaard agrees with both of these experts.
Nevertheless, Einstein's astrocytes provoked wonder that may prove as pivotal in transforming neuroscientist's thinking about how the brain works as his own revolutionary ideas were for physicists. These new transplantation studies shift the paradigm of thinking about the cellular basis of brain function. Glial cells are integral parts of the brain physiology and they do contribute to information processing, learning (and perhaps genius), in ways that are only now beginning to be explored.
The new study appears in the March 7, 2013 issue of the journal Cell Stem Cell*.
Watch a video clip on this topic showing what glia look like and how they communicate here.
References and more to explore
Colombo, J.A. and Reisin, H.D. (2004) Interlaminar astroglia of the cerebral cortes: a marker of the primate brain. Brain Research 1006, 126-31.
Colombo, J.A. et al., (2006) Cerebral cortex astroglia and the brain of a genius: A propos of A. Einstein's. Brain Res. Rev. 52, 257-63.
Fields, R.D. (2011) The Other Brain, Simon and Schuster, NY (a book about glia for the general audience).
*Han, X. et al., (2013) Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. Cell Stem Cell 12, 342-53.
Oberheim, N.A., et al., (2009) Uniquely hoinid features of adult human astrocytes. J. Neuroscience 29, 3276-87.
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