The last 20 years have witnessed a dramatic departure from the classical thinking: neurons are no longer believed to be the sole substrate of higher brain function and deciphering the role of neuroglia as active contributors to coordinated network activity has emerged as an exciting frontier in the study of neuroscience.
Interest in the study of neuroglia was greatly catalyzed in the 1990s when it was discovered that astrocytes –which throughout evolution increase in proportional makeup, cell size and complexity– respond to stimuli and the release of neurotransmitters via a special form of non-electrical excitability. In early work using cell cultures our group demonstrated that astrocytes respond to stimulation by fluctuations of the intracellular calcium ion (Ca2+) concentration, and that these fluctuations spread through networks of astrocytes physically coupled by gap-junctions. Although limited by the available experimental techniques, we observed that increases in astrocytic Ca2+ corresponded to changes in the synaptic activity of neighboring neurons. This finding, along with similar discoveries from independent labs led to an explosion of interest in the field of neuro-glial signaling that has since resulted in hundreds of publications implicating astrocytes as important contributors to what is now a shifting paradigm of information processing in the central nervous system (CNS).
Numerous follow-up studies have shown that activation of Ca2+ signaling in astrocytes can regulate both excitatory and inhibitory synaptic transmission, mediate essential physiological functions such as control over cerebral blood flow and respiratory rate, and influence state dependent changes in cortical activity during, for example, sleep and working memory. However, the exact mechanism for how astrocytes exert influence over neuronal networks remains a matter of intense controversy.
One popular model known as the
tripartite synapse suggests that astrocytes, which extend processes that ensheathe neuronal synapses, detect the release of neurotransmitters and actively modulate pre- and post-synaptic neurotransmission by the calcium dependent release of
gliotransmitters (i.e. transmitters released from glial cells that facilitate communication between neurons and other glia). However, recent evidence that astrocytes undergo developmental regulation of receptors sensitive to glutamatergic neurotransmission, and thus do not express receptors (e.g. mGluR5) thought to mediate gliotransmitter release in the adult brain, have questioned this model. Additionally, the functional significance of gliotransmission remains unclear due to the non-physiological nature of many of the experiments that gave rise to the concept.
What then might be the physiological function of astrocytic calcium signaling in the adult brain? Current work in our lab has suggested a simpler, but equally potent mechanism for astrocytic control of neuronal networks. In vivo imaging in the live rodent brain indicates that astrocytic calcium signaling corresponds with a decrease in extracellular potassium ion (K+) concentration, which in turn triggers neuronal hyperpolorization and suppression of excitatory synaptic activity. Although ion homeostasis has long been considered one of astrocyte’s passive housekeeping functions, our work suggests that Ca2+-dependent active uptake of K+ represents an active mechanism, capable of dynamically modulating the activity of neural circuits.
Glutamate-dependent neuroglial calcium signaling differs between young and adult brain. Sun W, McConnell E, Pare JF, Xu Q, Chen M, Peng W, Lovatt D, Han X, Smith Y, Nedergaard M. Science (New York, N.Y.). 2013 Jan 11; 339(6116):197-200.
Artifact versus reality--how astrocytes contribute to synaptic events. Nedergaard M, Verkhratsky A. Glia. 2012 Jul 0; 60(7):1013-23. Epub 2012 Jan 06.
Bergmann glia modulate cerebellar Purkinje cell bistability via Ca2+-dependent K+ uptake. Wang F, Xu Q, Wang W, Takano T, Nedergaard M. Proceedings of the National Academy of Sciences of the United States of America. 2012 May 15; 109(20):7911-6. Epub 2012 Apr 30.
Astrocytes modulate neural network activity by Ca2+-dependent uptake of extracellular K+. Wang F, Smith NA, Xu Q, Fujita T, Baba A, Matsuda T, Takano T, Bekar L, Nedergaard M. Sci Signal. 2012 Apr 3;5(218):ra26. doi: 10.1126/scisignal.2002334.
Extracellular Ca2+ acts as a mediator of communication from neurons to glia. Torres A, Wang F, Xu Q, Fujita T, Dobrowolski R, Willecke K, Takano T, Nedergaard M. Science signaling. 2012 Jan 24; 5(208):ra8. Epub 2012 Jan 24.
Glial calcium and diseases of the nervous system. Nedergaard M, Rodríguez JJ, Verkhratsky A. Cell calcium. 2010 Feb 0; 47(2):140-9. Epub 2009 Dec 31.
Astrocytic calcium signaling: mechanism and implications for functional brain imaging. Wang X, Takano T, Nedergaard M. Methods in molecular biology (Clifton, N.J.). 2009 489:93-109.
Astrocytic Ca2+ signaling evoked by sensory stimulation in vivo. Wang X, Lou N, Xu Q, Tian GF, Peng WG, Han X, Kang J, Takano T, Nedergaard M. Nature neuroscience. 2006 Jun 0; 9(6):816-23. Epub 2006 May 14.
New roles for astrocytes: redefining the functional architecture of the brain. Nedergaard M, Ransom B, Goldman SA. Trends in neurosciences. 2003 Oct 0; 26(10):523-30.
Intercellular calcium signaling mediated by point-source burst release of ATP. Arcuino G, Lin JH, Takano T, Liu C, Jiang L, Gao Q, Kang J, Nedergaard M. Proceedings of the National Academy of Sciences of the United States of America. 2002 Jul 23; 99(15):9840-5. Epub 2002 Jul 03.
ATP-mediated glia signaling. Cotrina ML, Lin JH, López-García JC, Naus CC, Nedergaard M. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2000 Apr 15; 20(8):2835-44.
ATP as a messenger in astrocyte-neuronal communication. Cotrina, M.; Nedergaard, M. The Neuroscientist. 2000; 6(2): 120-126.
Connexins regulate calcium signaling by controlling ATP release. Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, Naus CC, Nedergaard M. Proceedings of the National Academy of Sciences of the United States of America. 1998 95(26):15735-40.
Astrocyte-mediated potentiation of inhibitory synaptic transmission. Kang J, Jiang L, Goldman SA, Nedergaard M. Nature neuroscience. 1998 1(8):683-92.
Direct signaling from astrocytes to neurons in cultures of mammalian brain cells. Nedergaard M. Science (New York, N.Y.). 1994 Mar 25; 263(5154):1768-71.