Abstract
Synaptic plasticity is an extensively studied cellular correlate of learning and memory in which NMDARs play a starring role. One of the most interesting features of NMDARs is their ability to act as a co-incident detector. It is unique amongst neurotransmitter receptors in this respect. Co-incident detection is possible because the opening of NMDARs requires membrane depolarisation and the binding of glutamate. Opening of NMDARs also requires a co-agonist. Although the dynamic regulation of glutamate and membrane depolarization have been well studied in coincident detection, the role of the co-agonist site is unexplored. It turns out that non-neuronal glial cells, astrocytes, regulate co-agonist availability, giving them the ability to influence synaptic plasticity. The unique morphology and spatial arrangement of astrocytes at the synaptic level affords them the capacity to sample and integrate information originating from unrelated synapses, regardless of any pre-synaptic and post-synaptic commonality. As astrocytes are classically considered slow responders, their influence at the synapse is widely recognized as modulatory. The aim herein is to reconsider the potential of astrocytes to participate directly in ongoing synaptic NMDAR activity and co-incident detection.
Highlights
L-serine is the primary precursor of Dserine [47], residual production in the serine racemase (SR)-/- brain suggests an additional route for D-serine synthesis, albeit minor, possibly involving glycine cleavage system [63] or phosphoserine phosphatase [46]
Serine at a site apart from the synaptic cleft, potentially controlling the subunit composition of synaptic N-methyl-Daspartate receptors (NMDAR) in adult CA1 pyramidal neurons. These findings suggest that neuronal L-serine and SR are critical for long-term synaptic potentiation (LTP) but may not involve the co-agonism of synaptic NMDARs
In the context of the current review, addressing the role of astrocytes in co-incident detection, we focus on co-agonists released by astrocytes and direct interested readers to other reviews exploring neuronal release [101,102]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Hebb first hypothesized that synapses between neurons would be strengthened if they showed coincident activity [1]. This hypothesis has the potential to explain how associations between temporally linked events are formed. NMDARs materialized as critical molecules in LTP, learning and memory [4] are appreciated for their crucial role in coincidence detection and the ability to transform specific activity patterns into long-lasting changes in synapses. Understanding co-agonism at the subcellular level will be critical to understanding the physiological role(s) in circuit activity, learning and memory. The aim here is to review the current understanding of astrocyte-mediated co-agonism and explore its potential role in coincidence detection
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