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“Can neural circuits exist without astrocytes?”
To construct a viable answer, the technicalities of the question must first be explored. For the purposes of this essay, we will assume that “neural circuits existing” is relative to timeframe. We will explore if neural circuits can exist in the short term and long term without astrocytes, whether they can be formed in the first place, and whether they are efficient enough to be considered “true” neural circuits. Firstly, we will begin with some general information on the functions of the astrocyte, followed by the various specific roles that astrocytes undertake in the CNS.
Figure 1: Timescales of neural development, adapted from (Sauvageot and Stiles, 2002).
The generation of neural cells occurs in waves, with astrogenesis following neurogenesis (Fig1). Once astrocytes are established, they contribute to the development of CNS neural cells (Fig2) and act as homeostatic maintainers of the CNS: regulating ion concentrations (e.g sodium and potassium), neurotransmitter concentrations (e.g glutamate, GABA, glycine), releasing growth factors that promote neuronal growth (e.g BDNF), maintaining availability of glucose and H2O from nearby blood vessels, and performing many other roles that ensure the survival of neurons (Sfroniew and Vinters, 2010).
Figure 2: Schematic of developmental roles of astrocytes, adapted from (Reemst et al, 2016).
- Can neurons survive without astrocytes in a hypothetical organism?
Organisms typically suffer from three things: the inefficiencies of their biochemical systems that may produce harmful substances, disease caused by pathogenic organisms and injury caused by external events. We will explore these aspects with a hypothetical organism in mind to assess the viability of an in vivo neural circuit absent of astrocytes.
Oxidative stress could be classified as inefficiency regarding biochemical systems. Neurons generating ATP from metabolic reactions with glucose as a substrate could generate hydrogen peroxide, a source of free radicals that can damage cellular components. Astrocytes were found to have a protective role for neurons in metabolising H2O2; to simulate the effect of oxidative stress, one experimentexposed purely neuronal cultures to 100µM H2O2 for 30 minutes, with the authors finding that cell survival decreased by around 50% (exposures were done 24 times in triplicate). But when exposure occurred in the presence of astrocytes, survival was maintained at 97%, assuming a ratio of neurons to astrocytes of 1:4 (Desagher et al, 1996). This serves as ready evidence that if astrocytes were absent, the normal function of neurons would result in metabolic stress that would halve their numbers in a short time, through the action of H2O2 alone. Thus, the normal function of neurons would eventually lead to cell death in the short term, causing the breakdown of the neural circuit.
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In cases of disease (to be considered a long-term factor, assuming neurons could pass the short-term stage of survival), nitrous oxide (NO) is a neurotransmitter that can be produced excessively, leading to a neurotoxic environment. Like the regulation of hydrogen peroxide, astrocytes maintain regular levels of NO through “a glutathione-dependent mechanism” (Dawson and Dawson, 1998). As the astrocytes surround neurons with their processes, NO from the local environment gets trapped by glutathione stored inside the astrocytes before reaching the neurons, safeguarding them from the neurotoxic effects. This was proven in experiment by introducing NO donors to a sheet of neurons that had a sheet of astrocytes covering it; when the astrocyte sheet was removed, the neurons underneath would die within “3-4 hours”(Chen et al, 2001). Thus, we can reasonably conclude that a neural circuit absent of astrocytes would be compromised by NO toxicity if disease was ever to occur (which would be a matter of due course, as no recorded organism is immune to every disease).
In the case of injury, astrocytes perform a vital role in maintaining the function of neural circuits after a small section has been destroyed. By going through astrogliosis (becoming “reactive”), astrocytes perform a variety of roles in repairing and preventing further damage caused by neuronal degeneration, like “clearing up debris” and promoting proteins that remodel the extra cellular matrix (Eddleston and Mucke, 1993). One study found that even a relatively small injury to a neural circuit absent of astrocytes could cause “severe demyelination, neuronal and oligodendrocyte death, and pronounced motor deficits” (Faulkner et al, 2004). The study is effective in showing the importance of astrocytes being locally present, as these negative effects were observed when astrocytes that were local to the site of injury were thoroughly ablated, by using a retroviral method to make reactive astrocytes susceptible to an antiviral. Furthermore, without the recuperative actions of astrocytes the damaged area would spread (Fig3) due to the release of neurotoxic factors that dying neurons release. Without astrocytes providing an effective means of damage control to the neural circuit, a single injury could theoretically wipe out the entire circuit as part of a chain reaction.
Figure 3: Cell stain showing injury site (red arrow) and labelled neurons (boxed). A-B control, C-D transgenic mice. Note the lack of neurons in D compared to B, caused by the neurotoxic environment produced from dying neurons in absence of astrocytes. (Adapted from (Faulkner et al, 2004))
- Can neural circuits form without astrocytes?
As the astrocyte has such extensive functions in vivo, the best way to consider whether neural circuits can initially form without astrocytes is to investigate whether they can form in vitro. To form a synapse, one neuron must be able to find a target (another neuron) with its axon. Exploration of the environment is conducted by the neuronal growth cone, a structure containing actin bundles that rapidly increase and decrease in length randomly, producing filopodia and lamellipodia(Bray and Chapman, 1985). These structures of the growth cone explore the environment, looking for cues – guideposts – that will turn the growth cone (Kuhn et al, 1995). Laminin and fibronectin are components of the extracellular matrix (ECM) in vivo; producing a 3-dimensional path for neurons to chemically interact with and navigate would be difficult. However, the use of microstructures designed to obstruct axon growth with barbs (Fig4) has resulted in success with regards to directing an axon from one place to another(Le Feber et al, 2015). One chamber would have an “emitting” neuron, and the other a “receiving” neuron; it was shown that rudimentary neural circuits could be made in this way by verifying the unidirectionality of the signal. When the emitting chamber was stimulated, a slower response was recorded in the receiving chamber, but when the receiving chamber was stimulated, there was no response in the emitting chamber. This model could surely be expanded further to include more neurons connected in series, but it would be difficult from an engineering perspective to create a truly intricate neural network with multiple loops, let alone one that could rival the complexity of neurons in vivo. Furthermore, synapses generated in vitro without the presence of astrocytes are functionally immature (Ullian et al, 2001), suggesting that full efficiency of the neural circuit cannot be achieved with neurons alone. However, this system of guiding axons via obstruction is enough to show that basic neural circuits with directionality can be made following a design in vitro without astrocytes, a step further from a random circuit forming with no directionality.
Figure 4: Schematic showing neurons growing with respect to barbs. PDMS = polydimethylsiloxane. Adapted from (11).
- Can neural circuits achieve greater complexity without astrocytes?
We can consider the complexity of a neural circuit to be dependent on the number of synapses generated, which are the primary ways that signals are transduced from one neuron to another. But first, we must consider the ways in which astrocytes contribute to synaptogenesis in neural circuits.
Astrocytes release thrombospondins (TSPs) to form synapses that are “presynaptically active but postsynaptically silent” between neurons (Christopherson et al, 2005). Although synapses can form without astrocytes, the number of excitatory synapses is increased by “7-fold” when generated in the presence of astrocytes. This is evident from cell stains (fig 5) that show higher numbers of puncta (which mark functional synapses) in media conditioned by or containing astrocytes. Even though one could argue that neural circuits do not require astrocytes in the long term, merely for a short time to increase the number of synapses, the authors of the same study found that miniature excitatory postsynaptic currents were only higher than the control when a feeding layer of astrocytes was present, suggesting that astrocytes need to be present to increase the number of signals that pass across neurons, irrespective of the number of synapses. It was found in another study that astrocytes release glypicans 4 and 6 to make generated synapses postsynaptically active (Allen et al, 2012). The contribution of astrocytes is noted especially by the fact that when glypican 4 is introduced to pure neurons, the frequency and amplitude of synaptic events is increased. Both studies show that astrocytes fulfil a major role in establishing strength of signalling in a neural circuit and making it properly functional.
Figure 5: Cell stains showing labelled synapses on retinal ganglion cells. Control medium contains no astrocytes. ACM = Astrocyte Conditioned Medium, Astros = Astrocyte feeding layer. Adapted from (Christopherson et al, 2005).
The complexity of a neural circuit is also increased by astrocytes with regards to the generation of inhibitory synapses; astrocytes play a role in ensuring the diversity in the type of signal that a neuron receives or transmits. When astrocytes are absent, GABAergic neurons (which play an inhibitory role in the CNS) fail to extend their axons adequately, and the number and density of their synapses is also reduced compared to when astrocytes are present (Hughes et al, 2010). Naturally, to ensure complex processing signals must be modulated up and down in terms of amplitude to convey meaningful information through the neural circuit. Astrocytes maintain the integrity of signal transmission by surrounding synapses with their processes (Nedergaard et al, 2010), a factor that could play a large part in purely neuron-based neural circuits where neurotransmitters leaking between synapses could distort the quality of information passing through the circuit (Piet et al, 2004).
In conclusion, we have explored the various aspects in which astrocytes play fundamental roles within neural circuits. Knowing the importance of astrocytes in promoting neuronal survival, maintaining homeostasis, repairing and quarantining damage from disease and injury, and understanding their contributions to synaptogenesis, its efficacy and efficiency, as well as maintaining the integrity and diversity of action potentials, we can see why asking whether neural circuits can exist without astrocytes has an obvious answer; although some leeway can be found in technicalities, the neural circuits produced by astrocytes in conjunction with neurons vastly outmatch the rudimentary circuits built by pure neurons that struggle to function without their potent support cells.
Word count: 1784/2000
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