Posted comment on ´Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice` by X. Han, 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 published in PMC Mar 7, 2014 (PMCID: PMC3800554; NIHMSID: NIHMS452229)
Astrocytes play a role in supporting and influencing neural transmission in human brain tissue that may be advantageous to the highly complex neural network and functioning required. Grafting human glial cells to mice cells then could enhance neural transmission in mice and this was demonstrated by the authors of this paper. Han and colleagues grafted human glial progenitor cells (GPC) into neonatal immune-deficient mice (rag2-/- immune-deficient mice on a C3h background, visually impaired strain, or rag1-/- immunodeficient mice on a C57/Bl6 background for experiments involving visual behavior.) Markers showed initially an even GPC distribution in the mouse forebrain and by 4-5 months a marked rise in human astrocytes in the hippocampus and deep neocortex layers: By 12 -20 months this was also seen in the areas, amygdala, thalamus, neostriatum and cortex. Large numbers of engrafted hNuclei+ / hGFAP+ protoplasmic cells and hNuclei+ / hNG2+ cells (typical of persistent glial progenitor cells) existed in close proximity, but there were no human oligodendroglia unlike experiments using the hypomyelinated shiverer mice. Support for the presence of engrafted human cells using markers came from investigation of the cell morphology. The engrafted human glial cells had the size and morphology of human astroglia with gap junctions (connexion 443 hemi-channels) coupling to the host astroglia and processes resembling either interlaminar astroglia, or varicose projection astrocytes both typically found in humans.
Astrocytes are not excitable and signaling involves temporary rises in cytosolic calcium ions. The authors investigated calcium signaling in human glia and found calcium signals to be three times faster than in mice. The engrafted human glia demonstrated the same capability as in human cells.
The authors also looked at the synaptic activity in neuronal cells using cells from the hippocampal dentate granule layer because of the large number of engrafted cells observed in this region and the region´s known role in spatial memory and hence, easily observable functional behaviour). A significant increase in the engrafted human glia cell`s basal level of excitatory synaptic transmission was seen.
The authors also investigated synaptic plasticity and found long term potentiation (LTP) in the chimeric mice. This enhancement was not linked to increased NMDA receptor activity (or increased glutamate release), altered adenosine concentrations or, changed D-serine release. However, studies on TNFα showed that it was at an increased level, with corresponding increases in AMPA GluR1. TNFα is known to induce the addition of AMPA receptors to neuronal membranes, thereby enhancing excitatory synaptic transmission and it regulates this insertion through protein kinase C (PKC)-mediated phosphorylation of appropriate sites. The authors found that the chimeric hippocampal cells exhibited a significant increase in Ser831 phosphorylation. The observations were supported by the administration of thalidomide, an inhibitor of TNFα production action.
The increased neuronal activity was mirrored by enhanced learning in the chimeric mice. In the spatial memory test using Barnes maze navigation retention of spatial knowledge was quicker and the mice also showed an increase in object-location memory when they exhibited a greater preference for objects in novel locations than the controls. The chimeric mice also demonstrated quicker contextual fear and tone conditioning. Control mice in the form of mice allografted with mouse GPC showed neither increased LTP, or learning.
The authors concluded that the engrafting of human glial progenitor cells in mice provides a new animal model for investigation of glial and neuron functioning.
This paper is interesting because as Han and colleagues concluded by coupling mouse neurones to human glial cells a new model is elicited which allows human glial functioning to be investigated in a recognised system that is more easily managed and adapted, both in vitro and in vivo. Since glial cell structure and functioning is linked with some human neurodegenerative disorders then such an animal model will provide the foundation for more experimentation and hopefully, further discovery about the role that these types of cells have in brain functioning.
The experiments performed by Han and colleagues demonstrate that neuronal functioning can be influenced not only by stimulation of neurons themselves, but by the non-excitable cells around them. This includes glial cells. It is known that astrocytes play an important house-keeping function (mopping up excess potassium and excess glutamate released on neuronal firing, is in contact with blood vessels which respond to nitrous oxide by expanding, thus increasing blood supply). They can also influence excitatory transmission by the astrocytes releasing ATP which degrades to adenosine which can suppress basal synaptic transmission. They can modulate excitatory transmission via the release of TNFα, inducing the insertion of AMPA receptors to neuronal membranes, or modulate excitatory transmission via their release of D-serine which acts as an endogenous co-agonist of NMDA receptors and facilitates NMDA receptor activation, thereby potentiating the insertion of the additional AMPA receptors into the post-synaptic membrane. Oligodendritic glial cells are responsible for myelination and microglia act in synaptic pruning, overseeing the growth of new neurons and new connections, as well as being involved in the removal of synaptic debris and extraneous cells and connections. Therefore, many aspects of human glial cell structure and functioning can be investigated in vivo with the new chimeric animal model.
Mouse behavioural models also provide an opportunity to look at cognition and physiology and in the experiments demonstrated here, it was shown that increasing the support of the glial cells to the neuronal cells led to enhanced behavioural effects. It appears as expected that the increase in synaptic capability led to speedier learning involving spatial memory as shown by quicker fear and context conditioning.
This paper is also interesting because of the influence of foreign cells on natural cell growth and differentiation. Han and colleagues showed in their experiments not only the important role of glial cells in the overall functioning of neurons, but they also showed that the human glial progenitor cells could take over the natural mice cellular differentiation and in this case, the resulting system was a more efficient neural transmission. This means that the host cells were in the presence of a competing system, and in this case the competing system won with advantageous effects for the mouse. Other research of this type may provide more answers in the investigation of cognition.
Since we`re talking about the topic……………………………..
…since glial cells have signaling mechanisms involving calcium ions, can we assume that calcium blockers may have a pronounced effect on glial functioning in vivo?
…if we use mouse strains with decreased hippocampus functioning (knockout mice) we would expect to see changes in engrafted cell distribution and function in comparison to the rag2-/- immune-deficient mouse strain used here.
…if extinction of the fear conditioning was included in the test would we see a longer extinction time in the case of the chimeric mice than the control.