Ionotropic NMDA Receptor Signaling Is Required for the Induction of Long-Term Depression in the Mouse Hippocampal CA1 Region

Babiec, Walter E.; Guglietta, Ryan; Jami, Shekib A.; Morishita, Wade; Malenka, Robert C.; O’Dell, Thomas J.

doi:10.1523/jneurosci.5419-13.2014

Cited by 72 publications

(64 citation statements)

References 34 publications

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“…This approach allowed us to assess the synapse-specific contributions of preNMDARs to tLTD and to overcome the possibility that channel-blocking NMDAR antagonists may not always block LTD induction (Nabavi et al, 2013; but see Babiec et al, 2014). While our genetic approach demonstrated a role for preNMDARs in L4-L2/3 tLTD and avoided the potential confound of using an open-channel NMDAR antagonist, we also found that reducing ion flux through NMDARs with MK-801 blocked tLTD mediated by preNMDARs at L4-L2/3 synapses (Figure 2) as well as tLTD mediated by postsynaptic NMDARs at L2/3-L2/3 synapses (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Synapse-Specific Control of Experience-Dependent Plasticity by Presynaptic NMDA Receptors

Larsen

Smith

Miriyala

et al. 2014

Neuron

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SUMMARY Sensory experience orchestrates the development of cortical circuitry by adaptively modifying neuro-transmission and synaptic connectivity. However, the mechanisms underlying these experience-dependent modifications remain elusive. Here we demonstrate that visual experience suppresses a presynaptic NMDA receptor (preNMDAR)-mediated form of timing-dependent long-term depression (tLTD) at visual cortex layer (L) 4-2/3 synapses. This tLTD can be maintained during development, or reinstated in adulthood, by sensory deprivation. The changes in tLTD are mirrored by changes in glutamate release; visual deprivation enhances both tLTD and glutamate release. These effects require the GluN3A NMDAR subunit, the levels of which are increased by visual deprivation. Further, by coupling the pathway-specific optogenetic induction of tLTD with cell-type-specific NMDAR deletion, we find that visual experience modifies preNMDAR-mediated plasticity specifically at L4-L2/3 synapses.

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Section: Discussionmentioning

confidence: 99%

Synapse-Specific Control of Experience-Dependent Plasticity by Presynaptic NMDA Receptors

Larsen

Smith

Miriyala

et al. 2014

Neuron

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“…This shift to LTD does not occur when the NMDAR is blocked by an antagonist blocking the glutamate binding site, suggesting that the induction of NMDAR-dependent LTD relies on metabotropic NMDAR function, rather than on ionotropic NMDAR function with calcium influx through the channel [46,47]. Provided that metobotropic NMDA-dependent LTD exists in mature dentate granule cells, it is thus a likely scenario that this LTD is unmasked when the inhibitory control of the ionotropic NMDAR function is strong, and newborn granule cells are depleted.…”

Section: Discussionmentioning

confidence: 99%

Irradiation of the Juvenile Brain Provokes a Shift from Long-Term Potentiation to Long-Term Depression

Zanni

Zhou²,

Riebe

et al. 2015

Dev Neurosci

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Radiotherapy is common in the treatment of brain tumors in children but often causes deleterious, late-appearing sequelae, including cognitive decline. This is thought to be caused, at least partly, by the suppression of hippocampal neurogenesis. However, the changes in neuronal network properties in the dentate gyrus (DG) following the irradiation of the young, growing brain are still poorly understood. We characterized the long-lasting effects of irradiation on the electrophysiological properties of the DG after a single dose of 6-Gy whole-brain irradiation on postnatal day 11 in male Wistar rats. The assessment of the basal excitatory transmission in the medial perforant pathway (MPP) by an examination of the field excitatory postsynaptic potential/volley ratio showed an increase of the synaptic efficacy per axon in irradiated animals compared to sham controls. The paired-pulse ratio at the MPP granule cell synapses was not affected by irradiation, suggesting that the release probability of neurotransmitters was not altered. Surprisingly, the induction of long-term synaptic plasticity in the DG by applying 4 trains of high-frequency stimulation provoked a shift from long-term potentiation (LTP) to long-term depression (LTD) in irradiated animals compared to sham controls. The morphological changes consisted in a virtually complete ablation of neurogenesis following irradiation, as judged by doublecortin immunostaining, while the inhibitory network of parvalbumin interneurons was intact. These data suggest that the irradiation of the juvenile brain caused permanent changes in synaptic plasticity that would seem consistent with an impairment of declarative learning. Unlike in our previous study in mice, lithium treatment did unfortunately not ameliorate any of the studied parameters. For the first time, we show that the effects of cranial irradiation on long-term synaptic plasticity is different in the juvenile compared with the adult brain, such that while irradiation of the adult brain will only cause a reduction in LTP, irradiation of the juvenile brain goes further and causes LTD. Although the mechanisms underlying the synaptic alterations need to be elucidated, these findings provide a better understanding of the effects of irradiation in the developing brain and the cognitive deficits observed in young patients who have been subjected to cranial radiotherapy.

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“…Studies supporting an ion-flow-independent role for NMDARs in LTD (4-7) and other processes (7-13) stand in contrast to studies proposing that flow of Ca 2+ through NMDAR is required for LTD (14) (see ref. 15 for additional references). An important test of an ion-flow-independent model would be to measure directly signaling actions by NMDARs in the absence of ion flow.…”

Section: Long-term Depression | Ltd | Nmdar-pp1 Fret | Nmdar-camkii Imentioning

confidence: 99%

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

Aow

Doré

Malinow

2015

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

112

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The NMDA receptor (NMDAR) is known to transmit important information by conducting calcium ions. However, some recent studies suggest that activation of NMDARs can trigger synaptic plasticity in the absence of ion flow. Does ligand binding transmit information to signaling molecules that mediate synaptic plasticity? Using Förster resonance energy transfer (FRET) imaging of fluorescently tagged proteins expressed in neurons, conformational signaling is identified within the NMDAR complex that is essential for downstream actions. Ligand binding transiently reduces FRET between the NMDAR cytoplasmic domain (cd) and the associated protein phosphatase 1 (PP1), requiring NMDARcd movement, and persistently reduces FRET between the NMDARcd and calcium/calmodulin-dependent protein kinase II (CaMKII), a process requiring PP1 activity. These studies directly monitor agonist-driven conformational signaling at the NMDAR complex required for synaptic plasticity.A gonist binding to the NMDAR is required for two major forms of synaptic plasticity: long-term potentiation (LTP) and longterm depression (LTD) (1). Surprisingly, activation of NMDARs can produce plasticity in opposite directions, with LTP enhancing transmission and LTD reducing transmission. A model was developed (2, 3) to explain how activation of NMDAR could produce these opposing phenomena: strong stimuli during LTP induction drive a large flux of Ca 2+ through NMDARs, leading to a large increase in intracellular calcium ion concentration ([Ca 2+ ] i ) that activates one series of biochemical steps leading to synaptic potentiation; a weaker stimulus during LTD induction drives a more reduced flux of Ca 2+ through NMDARs, producing a modest increase in [Ca 2+ ] i that activates a different series of biochemical steps, leading to synaptic depression. However, this model is not consistent with recent studies suggesting that no change in [Ca 2+ ] i is required for LTD, and instead invokes metabotropic signaling by the NMDAR (4). Studies supporting an ion-flow-independent role for NMDARs in LTD (4-7) and other processes (7-13) stand in contrast to studies proposing that flow of Ca 2+ through NMDAR is required for LTD (14) Results Transient NMDAR Agonist Binding Without Ion Flux DepressesSpontaneous Excitatory Postsynaptic Currents. In the accompanying study (16), Förster resonance energy transfer (FRET)-fluorescence lifetime imaging microscopy (FLIM) imaging was used to show that agonist binding to the NMDAR produces conformational movement of the NMDARcd. This effect displayed the same pharmacological profile as the electrically induced LTD recently published (4) and independently confirmed (7), suggesting that the conformational changes measured in the NMDARcd are associated with LTD induction. To test whether the stimulation protocol that drives conformational changes in the NMDARcd produces changes in synaptic function, spontaneous synaptic activity was recorded in primary hippocampal neurons, and NMDA was transiently applied in the presence of 7CK, a noncompetit...

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Ionotropic NMDA Receptor Signaling Is Required for the Induction of Long-Term Depression in the Mouse Hippocampal CA1 Region

Cited by 72 publications

References 34 publications

Synapse-Specific Control of Experience-Dependent Plasticity by Presynaptic NMDA Receptors

Synapse-Specific Control of Experience-Dependent Plasticity by Presynaptic NMDA Receptors

Irradiation of the Juvenile Brain Provokes a Shift from Long-Term Potentiation to Long-Term Depression

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

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