The Glutamatergic Synapse

Overview

• Introduction
• The Glutamatergic Tripartite Synapse
• De novo Synthesis of Glutamate
• The Glutamate-Glutamine Cycle
• Products
• Literature

Introduction

It is commonly known that neurons communicate via synapses. At the synapse the incoming electrical signal is converted into a chemical messenger, the neurotransmitter. Upon stimulation, the neurotransmitter is released from the presynapse of the transmitting neuron into the synaptic cleft and binds to postsynaptic receptors of the receiving neuron. Neurons can be excitatory or inhibitory depending on the neurotransmitter type. Nowadays, there are more than 100 neurotransmitters known, which allows a huge diversity in chemical signaling between neurons (Purves et al., 2008).

In the mammalian central nervous system (CNS), glutamate is the predominant excitatory neurotransmitter. It is estimated that more than half of all synapses release glutamate and that almost all excitatory neurons in the CNS are glutamatergic.

The Glutamatergic Tripartite Synapse

Astrocytes play a very important role at the glutamatergic synapse (Hertz, 1979, Schousboe et al., 2013 & 2014), and it was Alfonso Araque (Araque et al., 1999) who described the astrocyte as being the third element of the synapse. The so called ‘tripartite synapse’ consists of the pre- and postsynaptic nerve terminal and the perisynaptic astrocytic process (PAP). The neuron and the astrocyte can be viewed as a metabolic unit (Squire et al., 2002, Benarroch 2016). In case of the glutamatergic synapse, the astrocyte fulfills at least two specially important tasks for the neuron:

1. Uptake of glutamate from the synaptic cleft: Excessive activation of glutamate receptors is excitotoxic for the neuron, also known as glutamate excitotoxicity. To prevent toxicity, the astrocytes take up glutamate almost immediately after neuronal release.
2. Supply of glutamine as precursor of glutamate: The astrocyte is needed to maintain and to regulate neurotransmission at the glutamatergic nerve terminal (Perea et al., 2009), and it controls the biosynthesis and the turnover of glutamate. To this end, the astrocyte provides the neuron with the synaptically inert precursor glutamine. There are two pathways for glutamate/glutamine synthesis - de novo synthesis of glutamate/glutamine (figure 1) and recycling of glutamate/glutamine (figure 2).

Unbalanced glutamate metabolism in neurons and astrocytes is discussed to be involved in several neurological disorders (Rudy et al., 2014; Blanco-Suárez et al. 2017; Ferreira et al., 2021; Haroon & Miller 2016).

De novo Synthesis of Glutamate

Glutamate is a nonessential amino acid that does not cross the blood brain barrier and therefore has to be synthesized in the brain (Purves et al., 2008). De novo synthesis is possible by the citric acid cycle (TCA), which is not only a pathway to generate ATP but also provides intermediates for biosynthesis (Berg et al., 2003; Schousboe et al., 2013) (figure 1). Glutamate for example is derived from alpha-Ketoglutarate (figure 1 – step 1). Intermediates taken from the TCA for neurotransmitter biosynthesis have to be replenished immediately to ensure a continuous availability of metabolites. In mammals, oxaloacetate (OAA) is replenished by carboxylation of pyruvate catalyzed by pyruvate carboxylase (PC), an enzyme which is almost exclusively expressed in astrocytes but rarely in neurons (figure 1 – step 2). Consequently, most neuron are not able to synthesize glutamate de novo (Bak et al., 2006). That implicates that the glutamatergic neuron is dependent on astrocytes to refill the glutamate pool for transmission. Because glutamate itself is excitotoxic, it is converted into glutamine by glutamine synthetase (GS) before transfer from astrocyte to neuron (figure 1 – step 3, 4). The glutamatergic neuron expresses the enzyme glutaminase 1 (GLS1), also known as PAG (phosphate-activated glutaminase) and converts glutamine back into glutamate (figure 1 – step 5).

The Glutamate-Glutamine Cycle

Interestingly, the main part of glutamine is not built by de novo synthesis. The quantitative predominant metabolic pathway is the glutamate-glutamine cycle (figure 2), also known as glutamate-glutamine shuttle. This cycle is one example of the cooperation between neurons and astrocytes and describes the recycling of glutamate for neurotransmission. After release, glutamate binds to glutamate receptors located primarily in the postsynaptic membrane (figure 2 - step 1). There are two different types of glutamate receptors, ionotrophic receptors (AMPAR/GluA, KainateR/GluK, NMDAR/GluN receptors) and G-protein coupled metabotropic receptors (mGluRs). To prevent glutamate excitotoxicity caused by excessive activation of glutamate receptors, the astrocyte takes up glutamate almost immediately after its release via excitatory amino acid transporters (EAATs) (Malik & Willnow 2019), mostly by EAAT 1 (also known as GLAST - glutamate-aspartate transporter) and EAAT 2 (also known as GLT1 -glutamate transporter 1) (figure 2 - step 2). A minor part of glutamate is taken up by the neurons over EAAT 3 (also known as EAAC1 - excitatory amino acid carrier 1). The astrocyte converts the main part of glutamate into glutamine, catalyzed by glutamine synthetase (GS) (figure 2 - step 3). Glutamine is shuttled to the neuron via sodium-coupled neutral amino acid transporters (SNATs) (figure 2 - step 4). In the mitochondria of the neuron glutamine is deaminased to glutamate by the glutaminase 1 (GLS1) (figure 2 - step 5). The recycled glutamate is transferred into synaptic vesicles by vesiculary glutamate transporters (VGLUTs) and is prepared for the next round of transmission (figure 2 - step 6).

Products

Literature

Araque et al., 1999: Tripartite synapses: glia, the unacknowledged partner. PMID: 10322493

Bak et al., 2006: The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. PMID: 16787421

Benarroch 2016: Astrocyte signaling and synaptic homeostasis. PMID: 27335113

Blanco-Suárez et al. 2017: Role of astrocyte–synapse interactions in CNS disorders. PMID: 27381164

Ferreira et al., 2021: Rutin improves glutamate uptake and inhibits glutamate excitotoxicity in rat brain slices. PMID: 33492574

Haroon & Miller 2016: Inflammation Effects on Brain Glutamate in Depression: Mechanistic Considerations and Treatment Implications. PMID: 27830574

Hertz, 1979: Functional interactions between neurons and astrocytes I. Turnover and metabolism of putative amino acid transmitters. PMID: 42117

Malik & Willnow 2019: Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System. PMID: 31726793

Perea et al., 2009: Tripartite synapses: astrocytes process and control synaptic information. PMID: 19615761

Rudy et al., 2014: The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease. PMID: 25821641

Schousboe et al., 2013: Astrocytic Control of Biosynthesis and Turnover of the Neurotransmitters Glutamate and GABA. PMID: 23966981

Schousboe et al., 2014: Glutamate Metabolism in the Brain Focusing on Astrocytes. PMID: 25236722

Squire et al., 2002: Fundamental Neuroscience, 2nd Edition, ISBN: 9780080521800

Purves et al., 2008: Neuroscience, 4th Edition, ISBN: 9780878936977

Berg et al., 2002: Biochemistry, 5th Edition, ISBN: 9780716746843