GluN2D Subunit-Containing NMDA Receptors Control Tissue Plasminogen Activator-Mediated Spatial Memory

Obiang, Pauline; Macrez, Richard; Jullienne, A.; Bertrand, Thomas; Lesept, Flavie; Ali, Carine; Maubert, Eric; Vivien, Denis; Agin, Véronique

doi:10.1523/jneurosci.6202-11.2012

Cited by 26 publications

(16 citation statements)

References 47 publications

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“…By increasing the surface dynamics of a fraction of extrasynaptic NMDAR, we can propose that cumulative effects in the whole population of NMDARs are responsible for the potentiating effect of tPA on NMDARs signaling. These observations fit with our previous finding that tPA-promoted neurotoxicity through a mechanism that involved extrasynaptic and possibly GluN2D-containing NMDARs, 35, 44 a phenomenon also associated with an activation of the ERK(½) pathway. 35 In this study, we show that Glunomab is also capable to prevent the tPA-dependent increase of neuronal ERK(½) activation.…”

Section: Discussionsupporting

confidence: 92%

Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors

et al. 2016

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N-methyl-d-aspartate receptors (NMDARs) are ion channels whose synaptic versus extrasynaptic localization critically influences their functions. This distribution of NMDARs is highly dependent on their lateral diffusion at the cell membrane. Each obligatory subunit of NMDARs (GluN1 and GluN2) contains two extracellular clamshell-like domains with an agonist-binding domain and a distal N-terminal domain (NTD). To date, the roles and dynamics of the NTD of the GluN1 subunit in NMDAR allosteric signaling remain poorly understood. Using single nanoparticle tracking in mouse neurons, we demonstrate that the extracellular neuronal protease tissue-type plasminogen activator (tPA), well known to have a role in the synaptic plasticity and neuronal survival, leads to a selective increase of the surface dynamics and subsequent diffusion of extrasynaptic NMDARs. This process explains the previously reported ability of tPA to promote NMDAR-mediated calcium influx. In parallel, we developed a monoclonal antibody capable of specifically blocking the interaction of tPA with the NTD of the GluN1 subunit of NMDAR. Using this original approach, we demonstrate that the tPA binds the NTD of the GluN1 subunit at a lysine in position 178. Accordingly, when applied to mouse neurons, our selected antibody (named Glunomab) leads to a selective reduction of the tPA-mediated surface dynamics of extrasynaptic NMDARs, subsequent signaling and neurotoxicity, both in vitro and in vivo. Altogether, we demonstrate that the tPA is a ligand of the NTD of the obligatory GluN1 subunit of NMDAR acting as a modulator of their dynamic distribution at the neuronal surface and subsequent signaling.

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Section: Discussionsupporting

confidence: 92%

Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors

et al. 2016

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“…GluN2C and GluN2D) in the frontal cortex and hippocampus of eNRG1-treated mice, which can be involved in the hypersensitivity to MK-801. The specificity of the anti-GluN2D antibody, but not that for the anti-GluN2C antibody, has been verified with the use of knockout mice [ 39 , 40 ] Although the molecular nature of the present GluN2C-like immunoreactivity required further validation, the above arguments are in agreement with the observation that NMDA receptor-hypomorphic mutant mice show hypersensitivity to an NMDA receptor blocker [ 24 , 41 ]. Recently, Belforte et al (2010) also provide supportive evidence that the psychomimetric activity of MK-801 is ascribed to a decrease in the NMDA receptor sensitivity of parvalbumin-positive GABA neurons during postnatal development [ 42 ].…”

Section: Discussionmentioning

confidence: 73%

Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801

Kato¹,

Abe²,

Hirokawa³

et al. 2015

CMM

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Neuregulin-1 (NRG1) is a well-recognized risk gene for schizophrenia and is often implicated in the neurodevelopmental hypothesis of this illness. Alternative splicing and proteolytic processing of the NRG1 gene produce more than 30 structural variants; however, the neuropathological roles of individual variants remain to be characterized. On the basis of the neurodevelopmental hypothesis of schizophrenia, we administered eNRG1 (0.1~1.0 µg/g), a core epidermal growth factor-like (EGF) domain common for all splicing NRG1 variants, to neonatal mice and compared their behavioral performance with mice challenged with a full mature form of type 1 NRG1 variant. During the neonatal stage, recombinant eNRG1 protein administrated from the periphery passed the blood-brain barrier and activated its receptor (ErbB4) in the brain. In adults, the mice receiving the highest dose exhibited lower locomotor activity and deficits in prepulse inhibition and tonedependent fear learning, although the hearing reduction of the eNRG1-treated mice may explain these behavioral deficits. Neonatal eNRG1 treatment also significantly potentiated MK-801-driven locomotor activity in an eNRG1 dose-dependent manner. In parallel eNRG1 treatment enhanced MK-801-driven c-Fos induction and decreased immunoreactivity for NMDA receptor subunits in adult brain. In contrast, mice that had been treated with the same molar dose of a full mature form of type 1 NRG1 as neonates did not exhibit hypersensitivity to MK-801. However, both animal models exhibited similar hypersensitivity to methamphetamine. Collectively, our findings suggest that aberrant peripheral NRG1 signals during neurodevelopment alter later behavioral traits and auditory functions in the NRG1 subtype-dependent manner.

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“…Grin2c but not Grin2d or Grin2b subunits mediated both mPFC-evoked HA-NMDAR currents in vitro and quinine-resistant alcohol intake. Little is otherwise known about the behavioral functions of Grin2c and Grin2d, although alcohol intake decreases Grin2c striatal mRNA 47 and Grin2d is implicated in acute drug responses 48 and spatial memory 49 . Adult striatum has very little Grin2c and Grin2d 50 , and these subunits have not been detectable in total brain tissue (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake

et al. 2013

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Compulsive drinking despite serious adverse medical, social and economic consequences is a characteristic of alcohol use disorders in humans. Although frontal cortical areas have been implicated in alcohol use disorders, little is known about the molecular mechanisms and pathways that sustain aversion-resistant intake. Here, we show that nucleus accumbens core (NAcore) NMDA-type glutamate receptors and medial prefrontal (mPFC) and insula glutamatergic inputs to the NAcore are necessary for aversion-resistant alcohol consumption in rats. Aversion-resistant intake was associated with a new type of NMDA receptor adaptation, in which hyperpolarization-active NMDA receptors were present at mPFC and insula but not amygdalar inputs in the NAcore. Accordingly, inhibition of Grin2c NMDA receptor subunits in the NAcore reduced aversion-resistant alcohol intake. None of these manipulations altered intake when alcohol was not paired with an aversive consequence. Our results identify a mechanism by which hyperpolarization-active NMDA receptors under mPFC- and insula-to-NAcore inputs sustain aversion-resistant alcohol intake.

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GluN2D Subunit-Containing NMDA Receptors Control Tissue Plasminogen Activator-Mediated Spatial Memory

Cited by 26 publications

References 47 publications

Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors

Tissue-type plasminogen activator controls neuronal death by raising surface dynamics of extrasynaptic NMDA receptors

Neurobehavioral Differences Between Mice Receiving Distinct Neuregulin Variants as Neonates; Impact on Sensitivity to MK-801

Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake

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