INSIGHT

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.

HOVY HO-WAI WONG, OLIVIER CAMIRÉ AND P JESPER SJÖSTRÖM

(Wong et al., 2021). Now, in eLife, Pablo Cas-

Related research article Lituma PJ, Kwon tillo and colleagues at the Albert Einstein Col-
HB, Alviña K, Luján R, Castillo PE. 2021. lege of Medicine and the Universidad Castilla-La
Presynaptic NMDA receptors facilitate Mancha – including Pablo Lituma as first author
short-term plasticity and BDNF release at – report how presynaptically located NMDARs
hippocampal mossy fiber synapses. eLife (preNMDARs) are involved in regulating the
10:e66612. doi: 10.7554/eLife.66612 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,

T
he human brain contains around 86 bil- known as mossy fibers. These axons help to
lion neurons that communicate with each encode contextual and spatial memory by form-
other through electrical and chemical sig- ing the main information pathway from the den-
nals. In the signaling neuron, an electrochemical tate gyrus to the CA3 region of the
event known as an action potential, or spike, hippocampus, where they contact both excit-
triggers the release of molecular messengers atory pyramidal neurons and inhibitory neurons
into the synaptic cleft between two connected (Rebola et al., 2017). The electron microscopy
neurons. These neurotransmitters are then results revealed that 32% of NMDARs were
detected by postsynaptic receptors in the recipi- indeed present at the presynaptic sites of
ent cell. As information in the brain generally neurons.
flows from the pre- to the postsynaptic neuron, To identify the purpose of these pre-
it might seem unlikely to find any neurotransmit- NMDARs, the researchers explored low-fre-
ter receptors on the presynaptic, transmitting quency facilitation, a form of short-term
side (Figure 1A). plasticity specific to mossy fiber synapses. As
Yet, early electron microscopy studies
expected, stimulation at 1 Hz temporarily
revealed that N-methyl-D-aspartate receptors
strengthened the mossy fiber connections onto
(NMDARs) – which are glutamate receptors and
CA3 neurons in mouse brain tissue. However,
ion channels – are present on both pre- and
pharmacologically blocking the receptors, or
postsynaptic neurons (e.g., Siegel et al., 1994).
selectively deleting them through genetic engi-
Copyright Wong et al. This article NMDARs on postsynaptic cells play an important
neering, reduced low-frequency facilitation, indi-
is distributed under the terms of the role in memory formation and Hebbian plasticity
Creative Commons Attribution cating an involvement of preNMDARs. Further
— that is, the strengthening of the connections
License, which permits unrestricted experiments confirmed that this phenomenon
use and redistribution provided that
between presynaptic and postsynaptic neurons
that are activated together. However, their roles was mediated by preNMDARs present in axons
the original author and source are
credited. on the presynaptic side remain hotly debated of the transmitting neurons, rather than

Wong et al. eLife 2021;10:e71178. DOI: https://doi.org/10.7554/eLife.71178 1 of 3

 Insight Neurotransmission The secret life of memory receptors

Figure 1. 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.

NMDARs located in their cell bodies or present on the mossy fibers. This shows how
dendrites. preNMDARs promote calcium influx into mossy
Next, Lituma et al. wanted to test whether fibers, which could in turn enhance short-term
preNMDARs could contribute to synaptic facili- facilitation.
tation due to high-frequency activity patterns Lituma et al. further speculated that the influx
that are more physiologically relevant. Therefore of calcium may additionally trigger the release
they stimulated mossy fibers using optogenetics of brain-derived neurotrophic factor, or BDNF —
and electrophysiological methods to mimic the a growth factor involved in long-term plasticity
brief bursts of action potentials seen in granule and memory (Alonso et al., 2002; Kang and
cells of the intact brain. Indeed, connections Schuman, 1995). Although a direct participation
between mossy fibers and CA3 neurons were of preNMDAR-mediated calcium signaling
strengthened during these brief bursts. In con- remains to be confirmed, preNMDARs were
trast, removing or blocking preNMDARs found to be important for BDNF release.
reduced this burst-induced facilitation as well as In summary, Lituma et al. have provided com-
the ability to evoke postsynaptic spiking pelling evidence that the preNMDARs present in
responses. Thus, preNMDARs are pivotal for mossy fibers contribute to synaptic information
boosting synaptic information transfer. transfer. Interestingly, they also found that this
It is possible that preNMDARs could contrib- role of preNMDARs was restricted to a subset of
ute to glutamate release by boosting presynap- mossy fiber synapses, which was determined by
tic calcium signals. To test this hypothesis, the target neuron type: preNMDARs facilitated
Lituma et al. monitored calcium levels using an inputs to CA3 pyramidal neurons and to mossy
imaging technique called 2-photon microscopy. cells, but not those to inhibitory neurons.
This showed that upon burst firing, only neurons Still, some mysteries remain. For example,
with intact preNMDARs saw boosted calcium NMDARs have a well-known dual need for pre-
signals in their mossy fibers. Additional experi- synaptically released glutamate and postsynaptic
ments confirmed that a glutamate-induced rise depolarization to activate and elicit the calcium
of calcium ions only took place if NMDARs were signals that in turn trigger long-term plasticity.

Wong et al. eLife 2021;10:e71178. DOI: https://doi.org/10.7554/eLife.71178 2 of 3

 Insight Neurotransmission The secret life of memory receptors
Published 14 July 2021
This feature makes postsynaptic NMDARs ideal
as coincidence detectors in Hebbian learning,
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Competing interests: The authors declare that no

competing interests exist.

Wong et al. eLife 2021;10:e71178. DOI: https://doi.org/10.7554/eLife.71178 3 of 3