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Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity.

ABSTRACT: Selective disruption of synaptic drive to inhibitory neurons could contribute to the pathophysiology of various brain disorders. We have previously identified a GluN2A-selective positive allosteric modulator, GNE-8324, that selectively enhances N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in inhibitory but not excitatory neurons. Here, we demonstrate that differences in NMDAR subunit composition do not underlie this selective potentiation. Rather, a higher ambient glutamate level in the synaptic cleft of excitatory synapses on inhibitory neurons is a key factor. We show that increasing expression of glutamate transporter 1 (GLT-1) eliminates GNE-8324 potentiation in inhibitory neurons, while decreasing GLT-1 activity enables potentiation in excitatory neurons. Our results reveal an unsuspected difference between excitatory synapses onto different neuronal types, and a more prominent activation of synaptic NMDARs by ambient glutamate in inhibitory than excitatory neurons. This difference has implications for tonic NMDAR activity/signaling and the selective modulation of inhibitory neuron activity to treat brain disorders.

SUBMITTER: Yao L

PROVIDER: S-EPMC6167324 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity.

Yao Lulu L Grand Teddy T Hanson Jesse E JE Paoletti Pierre P Zhou Qiang Q

Nature communications 20181001 1

Selective disruption of synaptic drive to inhibitory neurons could contribute to the pathophysiology of various brain disorders. We have previously identified a GluN2A-selective positive allosteric modulator, GNE-8324, that selectively enhances N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic responses in inhibitory but not excitatory neurons. Here, we demonstrate that differences in NMDAR subunit composition do not underlie this selective potentiation. Rather, a higher ambient glutamate ...[more]

PMID: 30275542

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Project description:Excitatory signaling mediated by NMDARs has been shown to regulate mood disorders. However, current treatments targeting NMDAR subtypes have shown limited success in treating patients, highlighting a need for alternative therapeutic targets. Here, we identify a role for GluN2D-containing NMDARs in modulating emotional behaviors and neural activity in the bed nucleus of the stria terminalis (BNST). Using a GluN2D KO mouse line (GluN2D-/-), we assessed behavioral phenotypes across tasks modeling emotional behavior. We then used a combination of ex vivo electrophysiology and in vivo fiber photometry to assess changes in BNST plasticity, cell-specific physiology, and cellular activity profiles. GluN2D-/- male mice exhibit evidence of exacerbated negative emotional behavior, and a deficit in BNST synaptic potentiation. We also found that GluN2D is functionally expressed on corticotropin-releasing factor (CRF)-positive BNST cells implicated in driving negative emotional states, and recordings in mice of both sexes revealed increased excitatory and reduced inhibitory drive onto GluN2D-/- BNST-CRF cells ex vivo and increased activity in vivo Using a GluN2D conditional KO line (GluN2Dflx/flx) to selectively delete the subunit from the BNST, we find that BNST-GluN2Dflx/flx male mice exhibit increased depressive-like behaviors, as well as altered NMDAR function and increased excitatory drive onto BNST-CRF neurons. Together, this study supports a role for GluN2D-NMDARs in regulating emotional behavior through their influence on excitatory signaling in a region-specific manner, and suggests that these NMDARs may serve as a novel target for selectively modulating glutamate signaling in stress-responsive structures and cell populations.SIGNIFICANCE STATEMENT Excitatory signaling mediated through NMDARs plays an important role in shaping emotional behavior; however, the receptor subtypes/brain regions through which this occurs are poorly understood. Here, we demonstrate that loss of GluN2D-containing NMDARs produces an increase in anxiety- and depressive-like behaviors in mice, deficits in BNST synaptic potentiation, and increased activity in BNST-CRF neurons known to drive negative emotional behavior. Further, we determine that deleting GluN2D in the BNST leads to increased depressive-like behaviors and increased excitatory drive onto BNST-CRF cells. Collectively, these results demonstrate a role for GluN2D-NMDARs in regulating the activity of stress-responsive structures and neuronal populations in the adult brain, suggesting them as a potential target for treating negative emotional states in mood-related disorders.

Project description:A key feature of excitatory synapses is the existence of subsynaptic protein nanoclusters whose precise alignment across the cleft in a trans-synaptic nanocolumn influences the strength of synaptic transmission. However, whether nanocolumn properties vary between excitatory synapses functioning in different cellular contexts is unknown. We used a combination of confocal and DNA-PAINT super-resolution microscopy to directly compare the organization of shared scaffold proteins at two important excitatory synapses - those forming onto excitatory principal neurons (Ex→Ex synapses) and those forming onto parvalbumin-expressing interneurons (Ex→PV synapses). As in Ex→Ex synapses, we find that in Ex→PV synapses presynaptic Munc13-1 and postsynaptic PSD-95 both form nanoclusters that demonstrate alignment, underscoring synaptic nanostructure and the trans-synaptic nanocolumn as conserved organizational principles of excitatory synapses. Despite the general conservation of these features, we observed specific differences in the characteristics of pre- and postsynaptic Ex→PV nanostructure. Ex→PV synapses contained larger PSDs with fewer PSD-95 NCs when accounting for size than Ex→Ex synapses. Furthermore, the PSD-95 NCs were larger and denser. The identity of the postsynaptic cell also had a retrograde impact on Munc13-1 organization, as Ex→PV synapses hosted larger Munc13-1 puncta that contained less dense but larger and more numerous Munc13-1 NCs. Moreover, we measured the spatial variability of transsynaptic alignment in these synapse types, revealing protein alignment in Ex→PV synapses over a distinct range of distances compared to Ex→Ex synapses. We conclude that while general principles of nanostructure and alignment are shared, cell-specific elements of nanodomain organization likely contribute to functional diversity of excitatory synapses. Understanding the rules of synapse nanodomain assembly, which themselves are cell-type specific, will be essential for illuminating brain network dynamics.

Project description:Background and purposePerampanel is a newly approved anticonvulsant uniquely targeting AMPA receptors, which mediate the most abundant form of excitatory synaptic transmission in the brain. However, the network mechanism underlying the anti-epileptic effect of the AMPAergic inhibition remains to be explored.Experimental approachThe mechanism of perampanel action was studied with the basolateral amygdala network containing pyramidal-inhibitory neuronal resonators in seizure models of 4-aminopyridine (4-AP) and electrical kindling.Key resultsApplication of either 4-AP or electrical kindling to the basolateral amygdala readily induces AMPAergic transmission-dependent reverberating activities between pyramidal-inhibitory neuronal resonators, which are chiefly characterized by burst discharges in inhibitory neurons and corresponding recurrent inhibitory postsynaptic potentials in pyramidal neurons. Perampanel reduces post-kindling "paroxysmal depolarizing shift" especially in pyramidal neurons and, counterintuitively, eliminates burst activities in inhibitory neurons and inhibitory synaptic inputs onto excitatory pyramidal neurons to result in prevention of epileptiform discharges and seizure behaviours. Intriguingly, similar effects can be obtained with not only the AMPA receptor antagonist CNQX but also the GABAA receptor antagonist bicuculline, which is usually considered as a proconvulsant.Conclusion and implicationsIctogenesis depends on the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations tuned by dynamic glutamatergic and GABAergic transmission. The anticonvulsant effect of perampanel then stems from disruption of the coordinated network activities rather than simply decreased neuronal excitability or excitatory transmission. Positive or negative modulation of epileptic network reverberations may be pro-ictogenic or anti-ictogenic, respectively, constituting a more applicable rationale for the therapy against seizures.

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Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity.

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Higher ambient synaptic glutamate at inhibitory versus excitatory neurons differentially impacts NMDA receptor activity.

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