Neurotransmission: The secret life of memory receptors

The canonical hippocampal NMDA memory receptor also controls the release of the transmitter glutamate and the growth factor BDNF.
  1. Hovy Ho-Wai Wong
  2. Olivier Camiré
  3. P Jesper Sjöström  Is a corresponding author
  1. Centre for Research in Neuroscience, Department of Medicine, The Research Institute of the McGill University Health Centre, Canada

The human brain contains around 86 billion neurons that communicate with each other through electrical and chemical signals. In the signaling neuron, an electrochemical event known as an action potential, or spike, triggers the release of molecular messengers into the synaptic cleft between two connected neurons. These neurotransmitters are then detected by postsynaptic receptors in the recipient cell. As information in the brain generally flows from the pre- to the postsynaptic neuron, it might seem unlikely to find any neurotransmitter receptors on the presynaptic, transmitting side (Figure 1A).

Presynaptic NMDA receptors regulate synapse-typespecific neurotransmission.

(A) In the textbook view of central neurotransmission, the presynaptic spike (lightning symbol) elicits the release of a neurotransmitter (e.g., glutamate; green), which binds to postsynaptic glutamate receptors such as NMDARs (blue). (B) However, Lituma et al. found that presynaptic NMDARs (red) in hippocampal mossy fibers facilitate the release of glutamate (green) and a growth factor called BDNF (purple), possibly through an influx of calcium ions (Ca2+; question marks). The released glutamate may further activate presynaptic NMDARs (red) in a form of loop.

Yet, early electron microscopy studies revealed that N-methyl-D-aspartate receptors (NMDARs) – which are glutamate receptors and ion channels – are present on both pre- and postsynaptic neurons (e.g., Siegel et al., 1994). NMDARs on postsynaptic cells play an important role in memory formation and Hebbian plasticity — that is, the strengthening of the connections between presynaptic and postsynaptic neurons that are activated together. However, their roles on the presynaptic side remain hotly debated (Wong et al., 2021). Now, in eLife, Pablo Castillo and colleagues at the Albert Einstein College of Medicine and the Universidad Castilla-La Mancha – including Pablo Lituma as first author – report how presynaptically located NMDARs (preNMDARs) are involved in regulating the release of the neurotransmitter glutamate (Figure 1B, Lituma et al., 2021).

Lituma et al. used electron microscopy to examine whether NMDARs are located on the axons of granule cells in the rat hippocampus, known as mossy fibers. These axons help to encode contextual and spatial memory by forming the main information pathway from the dentate gyrus to the CA3 region of the hippocampus, where they contact both excitatory pyramidal neurons and inhibitory neurons (Rebola et al., 2017). The electron microscopy results revealed that 32% of NMDARs were indeed present at the presynaptic sites of neurons.

To identify the purpose of these preNMDARs, the researchers explored low-frequency facilitation, a form of short-term plasticity specific to mossy fiber synapses. As expected, stimulation at 1 Hz temporarily strengthened the mossy fiber connections onto CA3 neurons in mouse brain tissue. However, pharmacologically blocking the receptors, or selectively deleting them through genetic engineering, reduced low-frequency facilitation, indicating an involvement of preNMDARs. Further experiments confirmed that this phenomenon was mediated by preNMDARs present in axons of the transmitting neurons, rather than NMDARs located in their cell bodies or dendrites.

Next, Lituma et al. wanted to test whether preNMDARs could contribute to synaptic facilitation due to high-frequency activity patterns that are more physiologically relevant. Therefore they stimulated mossy fibers using optogenetics and electrophysiological methods to mimic the brief bursts of action potentials seen in granule cells of the intact brain. Indeed, connections between mossy fibers and CA3 neurons were strengthened during these brief bursts. In contrast, removing or blocking preNMDARs reduced this burst-induced facilitation as well as the ability to evoke postsynaptic spiking responses. Thus, preNMDARs are pivotal for boosting synaptic information transfer.

It is possible that preNMDARs could contribute to glutamate release by boosting presynaptic calcium signals. To test this hypothesis, Lituma et al. monitored calcium levels using an imaging technique called 2-photon microscopy. This showed that upon burst firing, only neurons with intact preNMDARs saw boosted calcium signals in their mossy fibers. Additional experiments confirmed that a glutamate-induced rise of calcium ions only took place if NMDARs were present on the mossy fibers. This shows how preNMDARs promote calcium influx into mossy fibers, which could in turn enhance short-term facilitation.

Lituma et al. further speculated that the influx of calcium may additionally trigger the release of brain-derived neurotrophic factor, or BDNF — a growth factor involved in long-term plasticity and memory (Alonso et al., 2002; Kang and Schuman, 1995). Although a direct participation of preNMDAR-mediated calcium signaling remains to be confirmed, preNMDARs were found to be important for BDNF release.

In summary, Lituma et al. have provided compelling evidence that the preNMDARs present in mossy fibers contribute to synaptic information transfer. Interestingly, they also found that this role of preNMDARs was restricted to a subset of mossy fiber synapses, which was determined by the target neuron type: preNMDARs facilitated inputs to CA3 pyramidal neurons and to mossy cells, but not those to inhibitory neurons.

Still, some mysteries remain. For example, NMDARs have a well-known dual need for presynaptically released glutamate and postsynaptic depolarization to activate and elicit the calcium signals that in turn trigger long-term plasticity. This feature makes postsynaptic NMDARs ideal as coincidence detectors in Hebbian learning, which is triggered by simultaneous activity in connected cells. But when situated presynaptically, this dual need seems to make preNMDARs hard to activate — the spike that causes the glutamate release only lasts a millisecond, so the depolarization is long gone by the time preNMDARs become glutamate bound. So how are preNMDARs activated?

One possible answer is high-frequency presynaptic firing, during which subsequent spikes in a burst depolarize glutamate-bound preNMDARs (Abrahamsson et al., 2017). This, however, seems unlikely to happen during low-frequency facilitation at 1 Hz. Alternatively, these preNMDARs may also signal by changing conformation when binding glutamate – without the need for depolarization or calcium flux – similar to postsynaptic NMDARs in the hippocampus and preNMDARs in neocortex (Abrahamsson et al., 2017; Dore et al., 2016).

Intriguingly, flux-independent NMDAR signaling has been linked to Alzheimer’s disease while BDNF has been linked to epilepsy, which could make preNMDARs potential therapeutic targets (McNamara and Scharfman, 2012; Dore et al., 2021). Moreover, the synapse-type-specific regulation could potentially be leveraged for drug specificity. While many questions surrounding preNMDARs are yet to be answered, Lituma et al. provide exciting new evidence to unveil the secret life of NMDARs.

References

  1. Book
    1. McNamara JO
    2. Scharfman HE
    (2012) Temporal Lobe Epilepsy and the BDNF Receptor, TrkB
    In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's Basic Mechanisms of the Epilepsies. Wiley. pp. 1–46.
    https://doi.org/10.1111/j.1528-1167.2010.02832.x

Article and author information

Author details

  1. Hovy Ho-Wai Wong

    Hovy Ho-Wai Wong is in the Centre for Research in Neuroscience, Department of Medicine, The Research Institute of the McGill University Health Centre, Montréal, Canada

    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3317-478X
  2. Olivier Camiré

    Olivier Camiré is in the Centre for Research in Neuroscience, Department of Medicine, The Research Institute of the McGill University Health Centre, Montréal, Canada

    Competing interests
    No competing interests declared
  3. P Jesper Sjöström

    P Jesper Sjöström is in the Centre for Research in Neuroscience, Department of Medicine, The Research Institute of the McGill University Health Centre, Montréal, Canada

    For correspondence
    jesper.sjostrom@mcgill.ca
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7085-2223

Publication history

  1. Version of Record published: July 14, 2021 (version 1)

Copyright

© 2021, Wong et al.

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,678
    Page views
  • 147
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Hovy Ho-Wai Wong
  2. Olivier Camiré
  3. P Jesper Sjöström
(2021)
Neurotransmission: The secret life of memory receptors
eLife 10:e71178.
https://doi.org/10.7554/eLife.71178

Further reading

    1. Neuroscience
    William T Redman et al.
    Tools and Resources

    The hippocampus consists of a stereotyped neuronal circuit repeated along the septal-temporal axis. This transverse circuit contains distinct subfields with stereotyped connectivity that support crucial cognitive processes, including episodic and spatial memory. However, comprehensive measurements across the transverse hippocampal circuit in vivo are intractable with existing techniques. Here, we developed an approach for two-photon imaging of the transverse hippocampal plane in awake mice via implanted glass microperiscopes, allowing optical access to the major hippocampal subfields and to the dendritic arbor of pyramidal neurons. Using this approach, we tracked dendritic morphological dynamics on CA1 apical dendrites and characterized spine turnover. We then used calcium imaging to quantify the prevalence of place and speed cells across subfields. Finally, we measured the anatomical distribution of spatial information, finding a non-uniform distribution of spatial selectivity along the DG-to-CA1 axis. This approach extends the existing toolbox for structural and functional measurements of hippocampal circuitry.

    1. Neuroscience
    Liqiang Chen et al.
    Short Report

    The presynaptic protein α-synuclein (αSyn) has been suggested to be involved in the pathogenesis of Parkinson’s disease (PD). In PD, the amygdala is prone to develop insoluble αSyn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how αSyn aggregates affect amygdala function is unknown. In this study, we examined αSyn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that αSyn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in mouse BLA, which is consistent with higher levels of αSyn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that αSyn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble αSyn, which suggests that lower levels of soluble αSyn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in αSyn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of αSyn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.