Presynaptic NMDARs in the Hippocampus Facilitate Transmitter Release at Theta Frequency

McGuinness, Lindsay; Taylor, C J; Taylor, Roger; Yau, Christopher; Langenhan, Tobias; Hart, Michael; Christian, Helen C.; Tynan, Patricia W.; Donnelly, Peter; Emptage, Nigel J.

doi:10.1016/j.neuron.2010.11.023

Cited by 110 publications

(132 citation statements)

References 82 publications

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“…S2). This observation was consistent with presynaptic expression of plasticity that had been previously reported for hippocampal synapses (28,30,33,(35)(36)(37). Importantly, EPSC amplitude change in the stimulated input was often accompanied by a stable EPSC amplitude change in the unstimulated input (referred as "heterosynapses"), suggesting that the expression of synaptic plasticity was not confined to the stimulated input (Fig.…”

Section: Activity-dependent Coordinated Modulation Of Presynaptic Strsupporting

confidence: 90%

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Letellier

Park

Chater

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

117

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Dendrites are neuronal structures specialized for receiving and processing information through their many synaptic inputs. How input strengths are modified across dendrites in ways that are crucial for synaptic integration and plasticity remains unclear. We examined in single hippocampal neurons the mechanism of heterosynaptic interactions and the heterogeneity of synaptic strengths of pyramidal cell inputs. Heterosynaptic presynaptic plasticity that counterbalances input strengths requires N-methyl-D-aspartate receptors (NMDARs) and astrocytes. Importantly, this mechanism is shared with the mechanism for maintaining highly heterogeneous basal presynaptic strengths, which requires astrocyte Ca 2+ signaling involving NMDAR activation, astrocyte membrane depolarization, and L-type Ca 2+ channels. Intracellular infusion of NMDARs or Ca 2+-channel blockers into astrocytes, conditionally ablating the GluN1 NMDAR subunit, or optogenetically hyperpolarizing astrocytes with archaerhodopsin promotes homogenization of convergent presynaptic inputs. Our findings support the presence of an astrocytedependent cellular mechanism that enhances the heterogeneity of presynaptic strengths of convergent connections, which may help boost the computational power of dendrites.synapse heterogeneity | synaptic strength | astrocyte | hippocampal neuron | heterosynaptic plasticity A n enduring challenge in neurobiology is to understand how neurons set the strengths of their numerous synapses to efficiently process and store different information while maintaining network homeostasis. Electrophysiology and imaging approaches have revealed that synapses display a high degree of functional heterogeneity, even for those sharing the same axon or dendrite (1-3). The observation that synaptic strengths are heterogeneous, in turn, suggests that synapses can operate independently from one another. Accordingly, many studies have demonstrated the input-specificity of Hebbian and also of homeostatic forms of synaptic plasticity, where synaptic changes are restricted to inputs whose activity is altered (4-6). Nevertheless, such a synapse-autonomous behavior could potentially compromise the global network homeostasis by biasing the overall activity toward excitation or depression, and to overcome this issue, it has been proposed that distinct inputs cooperate by coordinating their relative strengths through heterosynaptic interactions (7-9). In support of the idea that synapses behave as interdependent rather than isolated functional units, the restriction of synaptic strength changes to active inputs has been demonstrated to break down at times, with the induction of synaptic plasticity in the stimulated input accompanying either synaptic depression or potentiation of the nonstimulated inputs (10-13). In a highly studied plasticity paradigm of long-term potentiation (LTP) at hippocampal Schaffer collateral-CA1 synapses, tetanic stimulation that induces LTP is often accompanied by presynaptic long-term depression (LTD) of nonstimulated Schaffer collat...

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Section: Activity-dependent Coordinated Modulation Of Presynaptic Strsupporting

confidence: 90%

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Letellier

Park

Chater

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

117

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“…the soma of the primary afferents) (64) and the enhanced NMDA receptor activities by IL-1␤ in postsynaptic neurons in different nervous systems (21,52). It is conceivable to speculate that activation of presynaptic NMDA receptors causes influx of Ca 2ϩ through the NMDA receptors into the central terminals of primary afferents and subsequent increase of glutamate release, as shown in hippocampal slices (75). The influx of Ca 2ϩ could come directly from the opening of NMDA receptors (76) and/or from voltage-gated calcium channels in response to depolarization due to the opening of NMDA receptors (77,78).…”

Section: Discussionmentioning

confidence: 99%

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

Yan

严

Weng

et al. 2013

Journal of Biological Chemistry

106

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Background: Excessive activation of glutamate receptors is crucial to the genesis of neuropathic pain. Results: Endogenous IL-1␤ in neuropathic rats enhances glutamate release by increasing presynaptic NMDA receptor activities via sphingomyelinase signaling. Conclusion: Coupling between IL-1␤ receptors and presynaptic NMDA receptors contributes to the genesis of neuropathic pain. Significance: Interruption of such coupling could be an effective approach for the treatment of neuropathic pain.

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“…At least in certain developing neurons, the responsible receptors are found in the presynaptic rather than in the postsynaptic neuron. Recently, several studies have provided convincing functional evidence that the relevant receptors are localized to axons (Buchanan et al, 2012;McGuinness et al, 2010;Rodríguez-Moreno et al, 2011). However, it remained unclear whether these receptors were distributed throughout the axon, concentrated at presynaptic terminals or located in microdomains near synapses.…”

Section: Presynaptic Nmdarsmentioning

confidence: 99%

“…Although dendritic NMDARs might contribute to presynaptic plasticity (Christie and Jahr, 2008;Christie and Jahr, 2009), axonal NMDARs are necessary for tLTD (Rodríguez-Moreno et al, 2011). In addition, Ca 2+ transients are observed in presynaptic boutons upon focal uncaging of NMDA or glutamate (Buchanan et al, 2012;McGuinness et al, 2010). However, it is not clear whether the responsible axonal receptors are distributed throughout the axon or whether they are enriched at nerve terminals (Buchanan et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Presynaptic NMDA receptors: dynamics and distribution in developing axons in vitro and in vivo

Gill

Droubi

Giovedì

et al. 2014

Journal of Cell Science

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BSTRACTDuring cortical development, N-methyl-D-aspartate (NMDA) receptors (NMDARs) facilitate presynaptic terminal formation, enhance neurotransmitter release and are required in presynaptic neurons for spike-timing-dependent long-term depression (tLTD). However, the extent to which NMDARs are found within cortical presynaptic terminals has remained controversial, and the subsynaptic localization and dynamics of axonal NMDARs are unknown. Here, using live confocal imaging and biochemical purification of presynaptic membranes, we provide strong evidence that NMDARs localize to presynaptic terminals in vitro and in vivo in a developmentally regulated manner. The NR1 and NR2B subunits (also known as GRIN1 and GRIN2B, respectively) were found within the active zone membrane, where they could respond to synaptic glutamate release. Surprisingly, NR1 also appeared in glutamatergic and GABAergic synaptic vesicles. During synaptogenesis, NR1 was mobile throughout axons -including growth cones and filopodia, structures that are involved in synaptogenesis. Upon synaptogenic contact, NMDA receptors were quickly recruited to terminals by neuroligin-1 signaling. Unlike dendrites, the trafficking and distribution of axonal NR1 were insensitive to activity changes, including NMDA exposure, local glutamate uncaging or action potential blockade. These results support the idea that presynaptic NMDARs play an early role in presynaptic development.

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Presynaptic NMDARs in the Hippocampus Facilitate Transmitter Release at Theta Frequency

Cited by 110 publications

References 82 publications

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Astrocytes regulate heterogeneity of presynaptic strengths in hippocampal networks

Endogenous Interleukin-1β in Neuropathic Rats Enhances Glutamate Release from the Primary Afferents in the Spinal Dorsal Horn through Coupling with Presynaptic N-Methyl-d-aspartic Acid Receptors*

Presynaptic NMDA receptors: dynamics and distribution in developing axons in vitro and in vivo

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