Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

Franchini, Luca; Carrano, Nicolò; Luca, Monica Di; Gardoni, Fabrizio

doi:10.3390/ijms21041538

Cited by 73 publications

(52 citation statements)

References 256 publications

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“…The decline in GluN2A subunit in adult rats may infer a decreased efficacy of synaptic transmission during synaptic plasticity processes. Published data suggests that the GluN2A subunit of NMDA receptor is not necessary for long-term memory tasks but seems to affect short-term memory and the rapid acquisition of spatial information [ 96 ]. Although GluN2B subunit also affects short-term memory, it may make a greater contribution to learning when information must be retained after a longer delay or there is incremental task acquisition across a number of days [ 93 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Mephedrone and Amphetamine Exposure during Adolescence on Spatial Memory in Adulthood: Behavioral and Neurochemical Analysis

Grochecki

Smaga

Łopatyńska-Mazurek

et al. 2021

IJMS

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A synthetic cathinone, mephedrone is widely abused by adolescents and young adults. Despite its widespread use, little is known regarding its long-term effects on cognitive function. Therefore, we assessed, for the first time, whether (A) repeated mephedrone (30 mg/kg, i.p., 10 days, once a day) exposure during adolescence (PND 40) induces deleterious effects on spatial memory and reversal learning (Barnes maze task) in adult (PND 71–84) rats and whether (B) these effects were comparable to amphetamine (2.5 mg/kg, i.p.). Furthermore, the influence of these drugs on MMP-9, NMDA receptor subunits (GluN1, GluN2A/2B) and PSD-95 protein expression were assessed in adult rats. The drug effects were evaluated at doses that per se induce rewarding/reinforcing effects in rats. Our results showed deficits in spatial memory (delayed effect of amphetamine) and reversal learning in adult rats that received mephedrone/amphetamine in adolescence. However, the reversal learning impairment may actually have been due to spatial learning rather than cognitive flexibility impairments. Furthermore, mephedrone, but not amphetamine, enhanced with delayed onset, MMP-9 levels in the prefrontal cortex and the hippocampus. Mephedrone given during adolescence induced changes in MMP-9 level and up-regulation of the GluN2B-containing NMDA receptor (prefrontal cortex and hippocampus) in young adult (PND 63) and adult (PND 87) rats. Finally, in adult rats, PSD-95 expression was increased in the prefrontal cortex and decreased in the hippocampus. In contrast, in adult rats exposed to amphetamine in adolescence, GluN2A subunit and PSD-95 expression were decreased (down-regulated) in the hippocampus. Thus, in mephedrone—but not amphetamine-treated rats, the deleterious effects on spatial memory were associated with changes in MMP-9 level. Because the GluN2B-containing NMDA receptor dominates in adolescence, mephedrone seems to induce more harmful effects on cognition than amphetamine does during this period of life.

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Section: Discussionmentioning

confidence: 99%

Effects of Mephedrone and Amphetamine Exposure during Adolescence on Spatial Memory in Adulthood: Behavioral and Neurochemical Analysis

Grochecki

Smaga

Łopatyńska-Mazurek

et al. 2021

IJMS

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“…There is controversy about GluN2A silencing and memory processes. There is evidence that GluN2A KO does not alter spatial long-term memory acquired after several training sessions over days (Bannerman et al, 2008;Bannerman, 2009;Franchini et al, 2020). However, other studies described an impairment in a fear-conditioning task both in a GluN2A knockdown model (de Solis et al, 2015) and after blocking GluN2A-NMDAR in the amygdala (Dalton et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Reduced Expression of Hippocampal GluN2A-NMDAR Increases Seizure Susceptibility and Causes Deficits in Contextual Memory

et al. 2021

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N-methyl-D-aspartate receptors are heterotetramers composed of two GluN1 obligatory subunits and two regulatory subunits. In cognitive-related brain structures, GluN2A and GluN2B are the most abundant regulatory subunits, and their expression is subjected to tight regulation. During development, GluN2B expression is characteristic of immature synapses, whereas GluN2A is present in mature ones. This change in expression induces a shift in GluN2A/GluN2B ratio known as developmental switch. Moreover, modifications in this relationship have been associated with learning and memory, as well as different pathologies. In this work, we used a specific shRNA to induce a reduction in GluN2A expression after the developmental switch, both in vitro in primary cultured hippocampal neurons and in vivo in adult male Wistar rats. After in vitro characterization, we performed a cognitive profile and evaluated seizure susceptibility in vivo. Our in vitro results showed that the decrease in the expression of GluN2A changes GluN2A/GluN2B ratio without altering the expression of other regulatory subunits. Moreover, rats expressing the anti-GluN2A shRNA in vivo displayed an impaired contextual fear-conditioning memory. In addition, these animals showed increased seizure susceptibility, in terms of both time and intensity, which led us to conclude that deregulation in GluN2A expression at the hippocampus is associated with seizure susceptibility and learning–memory mechanisms.

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“…Calcium influx resulting from NMDAR activation is a significant step for the formation of a CaMKII/NR2B complex and, by extension, synaptic connections [ 12 , 59 ]. CaMKII is abundantly found at the glutaminergic postsynaptic density and is activated by Ca 2+ -calmodulin deriving from NMDAR opening, effects that last long after the stimulus has subsidized [ 60 ]. Prior studies have shown that a bond between CaMKII and the NR2B subunit is necessary for LTP induction, and disruption of the NR2B/CaMKII complex can lead to the downregulation of LTP as well as CaMK2A autophosphorylation in the hippocampus [ 61 – 63 ].…”

Section: Discussionmentioning

confidence: 99%

Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model

Abdoulaye

Chibaatar

et al. 2021

Neural Plasticity

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Background. Ketamine has been shown to possess lasting antidepressant properties. However, studies of the mechanisms involved in its effects on poststroke depression are nonexistent. Methods. To investigate these mechanisms, Sprague-Dawley rats were treated with a single local dose of ketamine after middle cerebral artery occlusion and chronic unpredicted mild stress. The effects on the hippocampal dentate gyrus were analyzed through assessment of the N-methyl-D-aspartate receptor/calcium/calmodulin-dependent protein kinase II (NMDAR/CaMKII) pathway, synaptic plasticity, and behavioral tests. Results. Ketamine administration rapidly exerted significant and lasting improvements of depressive symptoms. The biochemical analysis showed rapid, selective upregulation and downregulation of the NMDAR2-β and NMDAR2-α subtypes as well as their downstream signaling proteins β-CaMKII and α-phosphorylation in the dentate gyrus, respectively. Furthermore, the colocalization analysis indicated a significant and selectively increased conjunction of β-CaMKII and postsynaptic density protein 95 (PSD95) coupled with a notable decrease in NMDAR2-β association with PSD95 after ketamine treatment. These changes translated into significant and extended synaptic plasticity in the dentate gyrus. Conclusions. These findings not only suggest that ketamine represents a viable candidate for the treatment of poststroke depression but also that ketamine’s lasting antidepressant effects might be achieved through modulation of NMDAR/CaMKII-induced synaptic plasticity in key brain regions.

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Synaptic GluN2A-Containing NMDA Receptors: From Physiology to Pathological Synaptic Plasticity

Cited by 73 publications

References 256 publications

Effects of Mephedrone and Amphetamine Exposure during Adolescence on Spatial Memory in Adulthood: Behavioral and Neurochemical Analysis

Effects of Mephedrone and Amphetamine Exposure during Adolescence on Spatial Memory in Adulthood: Behavioral and Neurochemical Analysis

Reduced Expression of Hippocampal GluN2A-NMDAR Increases Seizure Susceptibility and Causes Deficits in Contextual Memory

Ketamine Induces Lasting Antidepressant Effects by Modulating the NMDAR/CaMKII-Mediated Synaptic Plasticity of the Hippocampal Dentate Gyrus in Depressive Stroke Model

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