Astrocytes: Glutamate producers for neurons

Abstract

In order for the brain to use the common amino acid glutamate as a neurotransmitter, it has been necessary to introduce a series of innovations that greatly restrict the availability of glutamate, so that it cannot degrade the signal-to-noise ratio of glutamatergic neurons. The most far-reaching innovations have been: i) to exclude the brain from access to glutamate in the systemic circulation by the blood-brain barrier, thereby making the brain autonomous in the production and disposal of glutamate; ii) to surround glutamatergic synapses with glial cells and endow these cells with much more powerful glutamate uptake carriers than the neurons themselves, so that most released transmitter glutamate is rapidly inactivated by uptake in glial cells; iii) to restrict to glial cells a key enzyme (glutamine synthetase) that is involved in the return of accumulated glutamate to neurons by amidation to glutamine, which has no transmitter activity, and can be safely released to the extracellular space, returned to neurons and deaminated to glutamate; iv) to restrict to glial cells two key enzymes (pyruvate carboxylase and cytosolic malic enzyme) that are involved in, respectively, de novo synthesis (from glucose) of the carbon skeleton of glutamate, and the return of the carbon skeleton of excess glutamate to the metabolic pathway for glucose oxidation. As a consequence of these innovations, neurons constantly require new carbon skeletons from glial to sustain their TCA cycle. When these supplies are withdrawn, neurons are unable to generate amino acid transmitters and their rate of oxidative metabolism is impaired. Given the commensalism that exists between neurons and glia, it may be fruitful to view brain function not just as a series of interactions between neurons, but also as a series of interactions between neurons and their collaborating glial cells.

Primary Cultures of Astrocytes: Their Value in Understanding Astrocytes in Health and Disease

“…The observation that two such enzymes, GS and PC, are expressed only in astrocytes and not in neurons (24, 25, 77) was instrumental for our current view of the role of astrocytes in glucose and glutamate metabolism. Moreover, the use of primary cultures of astrocytes has been important for placing astrocytes as the cell in the brain providing the precursor glutamine for de novo biosynthesis of the main neurotransmitters, glutamate and GABA (78, 79). Interestingly, the transcriptomic analysis by Lovatt et al (66) provided evidence that the above mentioned enzymes are indeed exclusively found in astrocytes and not in neurons.…”

Pharmacological inhibitions of glutamate transporters EAAT1 and EAAT2 compromise glutamate transport in photoreceptor to ON-bipolar cell synapses

“…Therefore, it is suggested that they clear free synaptic GLU in a way resembling a buffer (Tong and Jahr 1994) instead of just a transporter. In the retina, glutamate not reabsorbed by the presynaptic EAATs is thought to be removed and recycled through a secondary process, which involves transporting into the Muller cell via its membrane EAAT1 and conversion into glutamine before transporting back to the photoreceptors (Hertz, Dringen et al 1999). …”

TRP Channels Coordinate Ion Signalling in Astroglia

“…Astrocytes, in particular, are fundamentally important for rapid regulation of extracellular ions (Kofuji and Newman 2004; Olsen and Sontheimer 2008) and neurotransmitters (Conti et al 2004; Danbolt 2001), that, to a large extent, shape neuronal excitability and synaptic transmission. Astrocytes are critical for providing glutamatergic and GABA-ergic neurones with glutamine, which is indispensable for maintaining releasable pool of these transmitters (Hertz et al 1999); similarly, astrocytes are mainly responsible for adenosine turnover (Boison et al 2010). Astrocytes, unlike neurones, can synthesise glutamate de novo owing to the entry of pyruvate to the citric acid cycle via astrocyte-specific mitochondrial enzyme pyruvate carboxylase (Hertz and Zielke 2004).…”