Human Brain Cells Make Mice 

 By R. Douglas Fields | March 7, 2013 |   

*Study shows that intelligence derives from brain cells other than neurons *

A team of neuroscientists has grafted human brain cells into the brains of 
mice and found that the rodents’ rate of learning and memory far surpassed 
that of ordinary mice.  Remarkably, the cells transplanted were not 
neurons, but rather types of brain cells, called glia, that are incapable 
of electrical signaling.  The new findings suggest that information 
processing in the brain extends beyond the mechanism of electrical 
signaling between neurons.

The experiments were motivated by a desire to understand the functions of 
glia and test the intriguing possibility that non-electric brain cells 
could contribute to information processing, cognitive ability, and perhaps 
even the unparalleled cognitive ability of the human brain, which far 
exceeds that of any other animal.

Current thinking about how the brain operates at a cellular level rests on 
a foundation established over a century ago by the great Spanish 
neuroanatomist and Nobel Prize winner, Ramon ý Cajal, who conceived the 
“Neuron Doctrine.” This doctrine states that all information processing and 
transmission in the nervous system takes place by electrical signals 
passing through neurons in one direction, entering through synapses on the 
neuron’s root-like dendrites and then passing out of the neuron through its 
wire-like axon as high-speed electrical impulses that stimulate the next 
neuron in a circuit through points of close apposition called synapses.  
All thinking of how the brain receives sensory input, performs 
computational analysis, generates thoughts, emotions, and behaviors, rests 
on the Neuron Doctrine.

The possibility that glia, which lack any of the tell-tale attributes of 
neurons (dendrites, synapses, or axons) could contribute to information 
processing and cognition is well beyond traditional thinking.  Glia are 
understood to be cells that support neurons physically and physiologically 
and respond to neuronal disease and injury. In recent years, however, some 
neuroscientists have begun to wonder whether these neuron support 
functions, together with other aspects of the poorly understood glial 
biology, could participate in learning, memory and other cognitive 

*Human glia are different*

Looking through a microscope at a type of glial cell called an astrocyte, 
neuroscientist Maiken Nedergaard, was struck by a peculiar observation.  
“Steve [Goldman] and I were culturing human brain cells many years ago and 
noted that the cultured astrocytes were much, much larger than in cultures 
[of astrocytes] prepared from rodent brain,” she says recalling the moment 
of inspiration for these human-mouse transplant experiments.  Nedergaard is 
a pioneer in research on neuron-glia interactions working together with 
Steven Goldman, an expert in neural stem cells.  Both are members of the 
Center for Translational Medicine at the University of Rochester Medical 
Center.  “Human glia, and astrocytes in particular, are substantially 
different from those of rodents,” Goldman explains. “Human astrocytes are 
larger and more varied in morphology, features that accompanied evolution 
of the human brain.”

The researchers observed that human astrocytes were 20 times larger in 
volume than rodent astrocytes.  This was far greater than the proportionate 
increase in size of human neurons relative to rodent neurons.  Human 
astrocytes looked different too–the shape of human astrocytes is far more 
complex.   Some human astrocytes extend cellular extensions that penetrate 
deep through several layers of grey matter in the cerebral cortex, 
something not seen in the mouse brain.  Argentinian neuroanatomist, Jorge 
Colombo, who was not involved in the new study, had reported in 2004 that 
astrocytes with such deep-penetrating cellular processes were not only 
missing in the mouse brain, but that they were unique to the brain of 
primates.  In fact, according to neuroscientist Alfonso Araque, a 
neuroscientist at the Cajal Institute in Madrid, this difference between 
astrocytes in animals and humans had not escaped the notice of Ramon ý 
Cajal, but this anatomical curiosity had been cast into the dustbin of 
history, absent from all modern texts on the subject.

“Perhaps part of what makes us human resides in astrocytes,” Araque 
conjectures.    The increase in number and complexity of astrocytes in the 
human brain contributes more than neurons do to the large increase in 
cerebral volume in humans and primates.  “During evolution of the human 
brain, its volume expanded by about 300% with respect to their ancestral 
primates; in contrast the estimated number of neurons is only 25% higher 
than in other primates,” Araque says.    By contrast, neurons from the 
brain of mice and men are not very different.  How might astrocytes 
contribute to the quantum leap in human brain power?  Such colossal 
astrocytes spanning large numbers of neurons and millions of synapses might 
contribute another level of integration to neural networks.  “Astroglia 
‘nets’”, says Colombo, could provide “a potential non-neuronal dimension” 
of information processing, in which glia couple neurons and synapse in to 
functional ensembles.  By regulating the concentration of ions and 
neurotransmitters that neurons depend upon for synaptic communication, glia 
could modify the transmission of information through neural networks.  The 
larger scope of influence provided by gigantic human astrocytes might 
provide humans with a higher degree of integration.  “A single human 
astrocyte encompasses 2 million synapses compared to 100,000 in rodents,” 
Nedergaard says.

Human astrocytes are distinguished not only by their large size, but also 
by far superior high-speed communication.  Rather than generating 
electrical signals, astrocytes communicate with other astrocytes and with 
neurons using neurotransmitters.  Signals inside astrocytes are often 
carried by rapid waves of calcium ions that respond to neurotransmitters 
stimulating receptors on their cell membrane.  Nedergaard and her 
colleagues found that these waves of calcium signals travel 3 times faster 
in human astrocytes than in mouse astrocytes.

*Testing the hypothesis with a human/mouse chimaera*

An experiment to replace a significant number of astrocytes in the mouse 
brain with human astrocytes may be the ideal “thought experiment” to test 
the theory, but the practicalities of such an approach are daunting.  Would 
human astrocytes maintain their unique properties inside the mouse brain 
where the cellular environment and mix of growth factors are different from 
those in the human brain?  Would the astrocytes not only retain their human 
properties, but also integrate themselves properly into neuronal networks 
or might they instead grow wildly, disrupt the mouse brain or form tumors?  
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.”

The researchers isolated human glial progenitor cells (cells in the early 
stages of development before maturing into astrocytes) and labeled them 
with a fluorescent protein so that the transplanted cells could be 
identified unambiguously.  A suspension of these cells was then injected 
into the forebrain of newborn mice under anesthesia.  Examination of the 
brain 2 weeks to 20 months later revealed that mature human astrocytes had 
apparently inserted themselves into the rodent brain properly, while 
maintaining their unique human size and shape, including sending long 
twisted cellular processes deeply through the layers of cortical grey 
matter just as they do in the human brain.

Further tests showed that these transplanted astrocytes formed functional 
channels of communication between mouse astrocytes and other human 
astrocytes (gap junctions) that enabled them to communicate with adjacent 
cells and form a large inter-cellular network.  Next the researchers tested 
whether neurotransmitter signaling between neurons was affected by calcium 
signaling inside astrocytes.  Over the last 15 years, researchers from many 
laboratories have found that such astrocytic calcium signals can affect 
synaptic transmission between neurons, by manipulating the release or take 
up of neurotransmitters or other substances acting on neurons.  This 
influence on synaptic transmission is significant, because the basis of 
learning and memory is the formation and breaking of connections between 
neurons in networks that encode different sensory experiences.  The ability 
of astrocytes to boost or diminish the strength of synaptic transmission 
provides the opportunity for these glial cells to participate in learning 
and other cognitive processes.  Using electrodes to measure the voltage 
generated by a synapse in several well-established testes used by 
electrophysiologists who study learning and memory, the researchers 
observed that human astrocytes increased the strength of the synaptic 
signal; that is, the voltage in the postsynaptic neuron generated when a 
synapse fires rose faster and to higher voltages in mice grafted with human 
astrocytes.  Human astrocytes strengthen synaptic connections in the mouse 

Long-term potentiation (LTP) is the widely-studied strengthening of 
synaptic connections that is observed after a neuron is stimulated 
repeatedly.  This fundamental phenomenon of repetitive firing strengthening 
synaptic connections is thought to be the cellular basis for memory, just 
as repetition in learning helps form lasting memories.  In mice engrafted 
with human astrocytes, much less stimulation was needed to cause the 
synapse to suddenly increase the voltage it produced in signaling to the 
postsynaptic neuron and this amplified signal was maintained long after the 
stimulus was delivered (LTP).  When these mice were given standardized 
behavioral tests of learning and memory, the mice engrafted with human 
astrocytes outperformed mice injected with astrocytes from other mice as a 

*This changes everything*

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.”

Colombo notes that in experimental cell transplantation experiments to 
treat Parkinson’s disease, substances released from the transplanted cells 
were found to contribute to the therapeutic effect without the cells 
necessarily becoming integrated into functional connections.  In the 
present studies, Nedergaard and colleagues found that one such substance 
released from astrocytes (TNFalpha) was increased after transplantation, 
and counteracting TNFalpha with drugs erased the enhanced performance of 
these chimeric mice in learning tests and LTP response.  Previous research 
by Malenka and Stellwagen has shown that TNFalpha can enhance synaptic 
transmission in mice.  Nedergaard and colleagues believe the human 
astrocytes could enhance learning by multiple mechanisms and that the 
cellsinserted themselves properly into the mouse tissue.  “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.

These new findings raise many new questions for future research, and as is 
often the case with a new scientific advance, the issues can expand beyond 
the laboratory.  Professor Helmut Kettenmann, at the Max-Delbrück Center 
for Molecular Medicine in Berlin,  and expert on glia, agrees that this is 
“a really surprising finding,” that builds on previous research from 
Nedergaard’s laboratory showing that human astrocytes are much more complex 
than their mouse counterparts.  “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 is 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.

This paper marks a departure from the past century of exclusive focus on 
neurons as the only important cells in information processing and 
cognition.  “When considering how the brain works, we need to analyze and 
understand all the different types of cells in the brain and how they 
interact,” Malenka concludes.

This is something the father of the Neuron Doctrine, Ramon ý Cajal would 
have no doubt endorsed.  In 1913 Cajal wrote “The human cortex differs from 
that of animals not only by the huge amount of astrocytes that it contains, 
but also by their smallness [in animals] and by the rich interstitial glial 
plexus [glial networks penetrating multiple layers of grey matter].” 
(Translation provided by neuroscientist Alfonso Araque.)"

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