Multiple roles of GluN2B-containing NMDA receptors in synaptic plasticity in juvenile hippocampus

Fernández-Fernández, Diego; Burnell, Erica S.; Irvine, Mark W.; Monaghan, Daniel T.; Jane, David E.; Bortolotto, Zuner A.; Collingridge, Graham L.; Volianskis, Arturas

doi:10.1016/j.neuropharm.2016.08.010

Cited by 38 publications

(37 citation statements)

References 48 publications

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“…Indeed our data demonstrate that GluN2B subunits are critical for LTD induction by LFS, consistent with previous in vivo 38 , 65 , and many in vitro studies, e.g. 66 , 67 , reviewed in 40 but see 68 – 70 . Similarly, although an apparent resistance of LTD to inhibition by NMDAR antagonists, including D-AP5 and CPP, in vitro has been attributed to a preferential involvement of GluN2C/D subunit-containing NMDARs in juvenile rat hippocampus 71 , 72 the present data strongly indicate a requirement for GluN2B in LTD in the adult rat in vivo .…”

Section: Discussionsupporting

confidence: 92%

Physiological activation of mGlu5 receptors supports the ion channel function of NMDA receptors in hippocampal LTD induction in vivo

O’Riordan

Rowan

2018

Sci Rep

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Synaptic long-term depression (LTD) is believed to underlie critical mnemonic processes in the adult hippocampus. The roles of the metabotropic and ionotropic actions of glutamate in the induction of synaptic LTD by electrical low-frequency stimulation (LFS) in the living adult animal is poorly understood. Here we examined the requirement for metabotropic glutamate (mGlu) and NMDA receptors in LTD induction in anaesthetized adult rats. LTD induction was primarily dependent on NMDA receptors and required the involvement of both the ion channel function and GluN2B subunit of the receptor. Endogenous mGlu5 receptor activation necessitated the local application of relatively high doses of either competitive or non-competitive NMDA receptor antagonists to block LTD induction. Moreover, boosting endogenous glutamate activation of mGlu5 receptors with a positive allosteric modulator lowered the threshold for NMDA receptor-dependent LTD induction by weak LFS. The present data provide support in the living animal that NMDA receptor-dependent LTD is boosted by endogenously released glutamate activation of mGlu5 receptors. Given the predominant perisynaptic location of mGlu5 receptors, the present findings emphasize the need to further evaluate the contribution and mechanisms of these receptors in NMDA receptor-dependent synaptic plasticity in the adult hippocampus in vivo.

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Section: Discussionsupporting

confidence: 92%

Physiological activation of mGlu5 receptors supports the ion channel function of NMDA receptors in hippocampal LTD induction in vivo

O’Riordan

Rowan

2018

Sci Rep

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“…The calcium channels of NMDARs containing NR2B, NR2C, or NR2D subunits have a lower probability of being open than those of NR2A-containing NMDARs. Thus, NR2B-containing NMDARs exhibit slower kinetics 52 and make larger contributions to synaptic LTD, whereas NR2A/2B-containing NMDARs mostly mediate synaptic LTP 53 54 . GSK3β also plays an essential role in establishing this synaptic plasticity.…”

Section: Discussionmentioning

confidence: 99%

Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces

Garzón

Rodríguez-Muñoz

Cortés-Montero

et al. 2017

Sci Rep

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Mice with histidine triad nucleotide-binding protein 1 (HINT1) deletion exhibit manic-like symptoms that evolve into depressive-like behavior in response to stressful paradigms. Molecular and electrophysiological studies have indicated that HINT1−/− mice exhibit increased PKC, PKA, and GSK3β activities, as well as glutamate N-methyl-D-aspartate receptor (NMDAR)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor (AMPAR) and NR2B/NR2A subunit ratios. Pharmacological interventions stabilized their behavior but through different mechanisms. GSK3β inhibitors and valproate directly attenuated the expression of the manic-like symptoms, whereas PKC inhibition, lamotrigine, or risperidone promoted NMDAR-mediated depressive-like behaviors that counterbalanced the preexisting manic-like symptoms. Naïve HINT1−/− mice exposed to stressful paradigms rapidly manifested depressive-like behaviors in subsequent stressful situations, a capacity that persisted for a couple of weeks thereafter. During the depressive-like phase, citalopram, amitriptyline and MK801 precipitated manic-like behaviors in stressed HINT1−/− mice. Notably, the antagonism of NMDARs prevented HINT1−/− mice from alternating behaviors in response to stress. A comparison with “manic” Black Swiss mice indicated that in HINT1−/− mice, PKC supports manic-like symptoms and reduces the expression of depressive-like behaviors via activation of GSK3β and regulation of NR2B-enriched NMDARs. HINT1−/− mice represent a suitable model for studying human BPD and may facilitate the identification of novel targets and drugs to treat this mental disorder.

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“…However, as 2 distinct inhibitors of GluN2B subunits failed to reduce the magnitude of leptin-induced LTD at TA-CA1 synapses, activation of GluN2B subunits is unlikely to be required for leptin to induce LTD. This contrasts with activity-dependent LTD at hippocampal SC-CA1 synapses that is reported to involve activation of GluN2B-containing NMDA receptors ( Bartlett et al., 2007 , Liu et al., 2004 ) and more recently GluN2B di-heretromers ( France et al., 2017 ).…”

Section: Discussionmentioning

confidence: 75%

Age-dependent regulation of excitatory synaptic transmission at hippocampal temporoammonic-CA1 synapses by leptin

McGregor

Clements

Farah

et al. 2018

Neurobiology of Aging

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The hippocampus is a key target for the hormone leptin and leptin regulation of excitatory synaptic transmission at Schaffer-collateral–CA1 synapses during aging are well documented. However, little is known about the age-dependent actions of leptin at the temporoammonic (TA) input to CA1 neurons. Here we show that leptin induces a novel form of N-methyl-D-aspartate receptor–dependent long-term depression (LTD) at adult (12–24 weeks old) TA-CA1 synapses. Leptin-induced LTD requires activation of canonical Janus tyrosine kinase 2- signal transducer and activator of transcription signaling and removal of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors from synapses. Moreover, leptin-induced LTD is occluded by activity-dependent LTD at TA-CA1 synapses. By contrast, leptin has no effect on excitatory synaptic transmission at aged (12–14 months old) TA-CA1 synapses, and low-frequency stimulation also fails to induce LTD at this age. These findings demonstrate clear age-related alterations in the leptin sensitivity of TA-CA1 synapses and provide valuable information on how the leptin system alters with age. As leptin has been linked to Alzheimer's disease, these findings have important implications for understanding of age-related disorders such as Alzheimer's disease.

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Multiple roles of GluN2B-containing NMDA receptors in synaptic plasticity in juvenile hippocampus

Cited by 38 publications

References 48 publications

Physiological activation of mGlu5 receptors supports the ion channel function of NMDA receptors in hippocampal LTD induction in vivo

Physiological activation of mGlu5 receptors supports the ion channel function of NMDA receptors in hippocampal LTD induction in vivo

Increased PKC activity and altered GSK3β/NMDAR function drive behavior cycling in HINT1-deficient mice: bipolarity or opposing forces

Age-dependent regulation of excitatory synaptic transmission at hippocampal temporoammonic-CA1 synapses by leptin

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