Astrocyte Signaling - A New Frontier in Neurobiology

Adam Zakheim

May 15, 2009

Bio202 – Prof. Grobstein

Web Paper #3

  Astrocyte Signaling - A New Frontier in Neurobiology 

            As we have discussed in class, the central doctrine of neurobiology attests to the primacy of neurons. This view, defined by the Neuron Doctrine, expounds the notion that neurons, the excitable cells in the central nervous system (CNS), constitute the core components of the brain. These cells process and transmit information using unidirectional electrochemical signaling pathways to induce a response. Neurons are connected to one another by the synaptic cleft, the gap formed between one neuron’s dendrites and another neuron’s branching terminal (1). Through this synaptic cleft, neurons sense certain neurotrophic factors released from neighboring neurons, which results in the regeneration of an action potential and the subseuqent propagation of electrochemical signals. In addition to neurons, the human CNS also contains glial cells.

           Previously, these non-neuronal cells were believed only to provide structural and nutritional support to neurons in the CNS. By surrounding neurons, glial cells hold these cells in place during neurogenesis, while also providing a permissive microenvironment which allows for the passage of nutrients and oxygen from the astrocyte to the immature neuron (2). Current research, however, has shown that astrocytes, a subpopulation of glial cells, do not just provide neurons with structural support. Rather, these cells communicate with neurons and play an active role in nerve signal transduction. In this paper, I will discuss how the discovery of the various, functional roles of astrocyte cells is altering our understanding of the human central nervous system (CNS).

            In the developing nervous system, astrocytes actively help to promote synapse formation and function (3). Essentially, the astrocytes located near the synapses, or perisynaptic astrocytes, engage in bi-directional signaling with neurons to facilitate the formation of neural networks (3). Although these cells are incapable of generating action potentials, astrocytes secrete a diverse array of “neuroactive ‘gliotransmitters,’” and also contain the “same channels, receptors and cell surface molecules” as neurons. (3). Due to the inherent structural similarity and the fact that these cells secrete synaptogenic factors, astrocytes provide instructive signals, controlling the formation and development of synapses. Astrocytes, for instance, secrete Thrombo-spondins (TSPs), a key astrocyte-derived signal promoting synaptogenesis in the CNS.

TSPs are a family of large oligiomeric extracellular matrix proteins that promote the structural formation of synapses (3). Furthermore, astrocytes also secrete other neurotrophic factors such as TNFα, a proinflammatory cytokine that increases synaptic strength, and cholesterol, which enhances synaptic efficiency (3). Taken together, these results indicate that astrocytes induce and maintain synaptogenesis through the release of these trophic factors, which allow for astrocyte to communicate with neurons and ensure the formation of active synapses.

            Asytrocytes can also respond to calcium-mediated neuronal signaling processes. With elevations in the intracellular Ca2+ concentration, cultured astrocytes were found to mediate the release of glutamate, “which triggers ionotropic glutamate receptor-mediated Ca2+ increases in nearby neurons.” (4). This finding proves astrocytes have the ability to respond to neurotransmitters by generating elevations in Ca2+ levels in the synapse. With this increase in calcium, astrocytes are activated and release glutamate molecules. The secretion of glutamate allows astrocytes to communicate with neighboring neurons through a Ca2+ dependent mechanism. In addition to glutamate, current research demonstrates that astrocytes respond to the synaptic release of various neurotransmitters, such as GABA, noradrenaline and acetylcholine in a Ca2+ dependent fashion (4). Following the elevation of Ca2+ levels at the synapse and the activation of calcium-dependent signaling pathways, neurons release these neurotransmitters which bind to astrocytes, activate them and thereby generate a positive-feedback loop in which astrocytes secrete additional neurotrophic factors inducing a response from nearby neurons. Hence, neurons and astrocytes communicate in a reciprocal fashion to facilitate the activation of different signaling pathways. This is striking revelation, considering a single astrocyte “can associate with multiple neurons, and over 100,000 synapses” (3). Therefore, astrocytes are involved in a wide range of signaling pathways with in the CNS.

            Interestingly, astrocytes are also involved in coordinating cerebral blood flow to deliver oxygen to activated neurons. Active neurons require an increased concentration of oxygen and glucose levels to meet the cells metabolic needs. Zonta et. al. have reported that astrocytes detect the level of glutamate-dependent synaptic activity and then signal to adjacent cerebral capillaries to cause vasodilation, increasing the blood flow to the active neuron (5). Astrocytes, as mentioned above, are sensitive to local changes in calcium concentrations. When a neuron is activated and releases Ca2+ ions causing an increased calcium concentration within the synapse, astrocytes “sense” this increase and release an unknown compound of the cyclooxygenase (COX) family of proteins (which function as anti-inflammatory agents). Although the nature of the astrocyte signal responsible for the mediation of vasodilation is currently unknown, Zonta et. al. believe a local increase in calcium levels in the astrocyte activates “phospholipase A2 to produce arachidonic acid, from which COX catalyzes the production of a range of products (such as prostaglandins and prostacyclin) that have vasoactive actions” (5). In the regulation of blood flow, astrocytes communicate with neurons to ensure proper function. Due to this distinct function, astrocytes are of critical importance to modern neuroscience.

            Functional magnetic resonance imagining (fMRI) relies on the blood flow generated by astrocytes to provide neurologists and neuroscientists with images of activated regions of the brain (6). The fMRI is the most commonly used diagnostic technique in neuroscience and so, ascertaining the various functional roles of astrocytes will aid researchers in their ability to refine and develop new methods of probing the brain.

            In reviewing the relationship between neurons and astrocytes, it is apparent our understanding of the CNS is fickle and continues to evolve. At the time of its creation, the Neuron Doctrine, one of the founding tenets of neurobiology, was a good theory. This Doctrine, however, must be adapted to include astrocytes – which form interconnected, communicative networks with neurons in our CNS. In terms of future research, it is essential to discover the exact mechanism by which astrocytes release neurotransmitters and how this mechanism is regulated. Such answers will provide contemporary neuroscience with a greater understanding of how astrocytes influence synaptic function. With the discovery of the functional capabilities of astrocytes, however, a new door has been opened in the field of neurobiology, which promises to deliver new advancements in the study of the CNS. 

 

 

Works Cited and References:

 

(1) Biology 202 Course Notes Page, on the Serendip web site, http://serendip.brynmawr.e du/exchange/courses/bio202/s09/notes; accessed 14 May 2009.

 

(2) Wikipedia, Astrocyte. http://en.wikipedia.org/wiki/Astrocyte; accessed 14 May 2009.

 

(3) Stevens, Beth. Neurone-Astrocyte Signaling in the Development and Plasticity of Neural Circuits. Neurosignals 2008, 16; 278-288.

 

(4) Fellin, Tommaso & Giorgio Carmignoto. Neurone-to-astrocyte signaling in the brain represents a distinct multifunctional unit. The Journal of Physiology 2004, 559.1; 3-15. 

 

(5) Rheinallt, Parri & Vincenzo Crunelli. An Astrocyte bridge from synapse to blood flow. Nature 2003, 6.1; 5-6.

 

(6) Saey, Tine Hesman. Astrocytes are Rising Stars. Science News 2008, 174.3. http://www.sciencenews.org/view/generic/id/34048/title/Astrocytes_are_rising_stars; accessed 14 May 2009.

 

(7) Carmignoto, Giorgio. Reciprocal communication systems between astrocytes and neurones. Progress in Neurobiology 2000, 62; 561-581.

 

(8) Jiao, Jianwei & Dong Feng Chen. Induction of Neurogenesis in Nonconventional Neurogenic Regions of the Adult Central Nervous System by Niche Astrocyte-Produced Signals. Stem Cells 2008, 26; 1221-1230.

 

(9) Allen, Nicola J. and Ben A. Barres. Signaling Between glia and neurons: focus on synaptic plasticity. Current Opinion in Neurobiology 2005, 15; 542-548.