GluN2D-mediated excitatory drive onto medial prefrontal cortical PV+ fast-spiking inhibitory interneurons

Garst-Orozco, Jonathan; Malik, Ruchi; Lanz, Thomas A.; Weber, Mark L.; Xi, Hualin Simon; Arion, Dominique; Enwright, John F.; Lewis, David A.; O’Donnell, Patricio; Buhl, Derek L.

doi:10.1371/journal.pone.0233895

Cited by 29 publications

(33 citation statements)

References 42 publications

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“…Unexpectedly in PV-INs, the lack of effect was associated with a reduced sensitivity of postsynaptic NMDARs to exogenous zinc application (Figure S2I-J). The underlying cellular mechanism behind such a difference in zinc sensitivity is at present unclear but is likely associated with variation in the subunit composition of synaptic NMDARs that can affect the sensitivity of synaptic NMDARs to zinc inhibition (Garst-Orozco et al, 2020; Paoletti, 2011).…”

Section: Resultsmentioning

confidence: 99%

Activity-dependent modulation of NMDA receptors by endogenous zinc shapes dendritic function in cortical neurons

Morabito

Zerlaut

Serraz

et al. 2021

Preprint

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Activation of NMDA receptors (NMDARs) has been proposed to be a key component of single neuron computations in vivo. However is unknown if specific mechanisms control the function of such receptors and modulate input-output transformations performed by cortical neurons under in vivo-like conditions. Here we found that in layer 2/3 pyramidal neurons (L2/3 PNs), repeated synaptic stimulation results in an activity-dependent decrease in NMDARs activity by vesicular zinc. Such a mechanism shifted the threshold for dendritic non-linearities and strongly reduced LTP induction. Modulation of NMDARs was cell- and pathway-specific, being present selectively in L2/3-L2/3 connections but absent in ascending bottom-up inputs originating from L4 neurons. Numerical simulations highlighted that activity-dependent modulation of NMDARs has an important influence in dendritic computations endowing L2/3 PN dendrites with the ability to sustain dendritic non-linear integrations constant across different regimes of synaptic activity like those found in vivo. The present results therefore provide a new perspective on the action of vesicular zinc in cortical circuits by highlighting the role of this endogenous ion in normalizing dendritic integration of PNs during a constantly changing synaptic input pattern.

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Section: Resultsmentioning

confidence: 99%

Activity-dependent modulation of NMDA receptors by endogenous zinc shapes dendritic function in cortical neurons

Morabito

Zerlaut

Serraz

et al. 2021

Preprint

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“…During early brain development, GluN2B and GluN2D are the dominant isoforms in the hippocampus ( Monyer et al, 1994 ; Flint et al, 1997 ; Martel et al, 2009 ; McKay et al, 2012 ). In mature principal hippocampal neurons GluN2A and GluN2B subunits predominate while GluN2D subunits have been reported in some IN populations ( Engelhardt et al, 2015 ; Perszyk et al, 2016 ; Garst-Orozco et al, 2020 ). Native NMDARs can exist as either diheteromers (i.e., GluN1/GluN2A) or as triheteromeric assemblies (i.e., GluN1/2A/2B) with ligand binding, receptor kinetics and ion channel conductance being conferred by the identity of the nature of the GluN2 subunits present ( Stern et al, 1992 ; Wyllie et al, 1996 ; Gielen et al, 2009 ; Hansen et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…During early brain development, GluN2B and GluN2D are the dominant isoforms in the hippocampus (Flint et al, 1997;Martel et al, 2009;McKay et al, 2012;Monyer et al, 1994). In mature principal hippocampal neurons GluN2A and GluN2B subunits predominate while GluN2D subunits have been reported in some IN populations (Engelhardt et al, 2015;Garst-Orozco et al, 2020;Perszyk et al, 2016). Native NMDARs can exist as either diheteromers (i.e.…”

Section: Introductionmentioning

confidence: 99%

Contribution of NMDA Receptors to Synaptic Function in Rat Hippocampal Interneurons

Booker

Sumera

Kind

et al. 2021

eNeuro

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The ability of neurons to produce behaviorally relevant activity in the absence of pathology relies on the fine balance of synaptic inhibition to excitation. In the hippocampal CA1 microcircuit, this balance is maintained by a diverse population of inhibitory interneurons that receive largely similar glutamatergic afferents as their target pyramidal cells, with EPSCs generated by both AMPA receptors (AMPARs) and NMDA receptors (NMDARs). In this study, we take advantage of a recently generated GluN2A-null rat model to assess the contribution of GluN2A subunits to glutamatergic synaptic currents in three subclasses of interneuron found in the CA1 region of the hippocampus. For both parvalbumin-positive and somatostatin-positive interneurons, the GluN2A subunit is expressed at glutamatergic synapses and contributes to the EPSC. In contrast, in cholecystokinin (CCK)-positive interneurons, the contribution of GluN2A to the EPSC is negligible. Furthermore, synaptic potentiation at glutamatergic synapses on CCK-positive interneurons does not require the activation of GluN2A-containing NMDARs but does rely on the activation of NMDARs containing GluN2B and GluN2D subunits.

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“…GluN2C/2D-contaning NMDARs could allow selective modification of circuit function in regions expressing GluN2C/2D subunits[ 4 – 7 ]. The expression of GluN2C/2D has been reported in adult cerebral cortices [ 8 – 13 ]. GluN2D subunits were reported to play roles in synaptic transmission of hippocampal neurons[ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

NMDA GluN2C/2D receptors contribute to synaptic regulation and plasticity in the anterior cingulate cortex of adult mice

Chen

et al. 2021

Mol Brain

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Introduction N-Methyl-D-aspartate receptors (NMDARs) play a critical role in different forms of plasticity in the central nervous system. NMDARs are always assembled in tetrameric form, in which two GluN1 subunits and two GluN2 and/or GluN3 subunits combine together. Previous studies focused mainly on the hippocampus. The anterior cingulate cortex (ACC) is a key cortical region for sensory and emotional functions. NMDAR GluN2A and GluN2B subunits have been previously investigated, however much less is known about the GluN2C/2D subunits. Results In the present study, we found that the GluN2C/2D subunits are expressed in the pyramidal cells of ACC of adult mice. Application of a selective antagonist of GluN2C/2D, (2R*,3S*)-1-(9-bromophenanthrene-3-carbonyl) piperazine-2,3-dicarboxylic acid (UBP145), significantly reduced NMDAR-mediated currents, while synaptically evoked EPSCs were not affected. UBP145 affected neither the postsynaptic long-term potentiation (post-LTP) nor the presynaptic LTP (pre-LTP). Furthermore, the long-term depression (LTD) was also not affected by UBP145. Finally, both UBP145 decreased the frequency of the miniature EPSCs (mEPSCs) while the amplitude remained intact, suggesting that the GluN2C/2D may be involved in presynaptic regulation of spontaneous glutamate release. Conclusions Our results provide direct evidence that the GluN2C/2D contributes to evoked NMDAR mediated currents and mEPSCs in the ACC, which may have significant physiological implications.

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GluN2D-mediated excitatory drive onto medial prefrontal cortical PV+ fast-spiking inhibitory interneurons

Cited by 29 publications

References 42 publications

Activity-dependent modulation of NMDA receptors by endogenous zinc shapes dendritic function in cortical neurons

Activity-dependent modulation of NMDA receptors by endogenous zinc shapes dendritic function in cortical neurons

Contribution of NMDA Receptors to Synaptic Function in Rat Hippocampal Interneurons

NMDA GluN2C/2D receptors contribute to synaptic regulation and plasticity in the anterior cingulate cortex of adult mice

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