Author: Li, Yuanxi ; Song, Yingcai ; Li, Tianyu ; Zhang, Bing ; Guo, Fei ; Cao, Hang ; Zhou, Xianjin ; Li, Qian ; Du, Weijia ; Zhu, Shujia ; Zheng, Yinli ; Li, Yang ; Zhang, Yongmei ; Liu, Wei ; Shen, Fuyi ; Liu, Zhiqiang

Background and PurposeSevoflurane, a commonly used inhaled anaesthetic known for its favourable safety profile and rapid onset and offset, has not been thoroughly investigated as a potential treatment for depression. In this study, we reveal the mechanism through which sevoflurane delivers enduring antidepressant effects.Experimental ApproachTo assess the antidepressant effects of sevoflurane, behavioural tests were conducted, along with in vitro and ex vivo whole‐cell patch‐clamp recordings, to examine the effects on GluN1–GluN2 incorporated N‐methyl‐d‐aspartate (NMDA) receptors (NMDARs) and neuronal circuitry in the medial prefrontal cortex (mPFC). Multiple‐channel electrophysiology in freely moving mice was performed to evaluate sevoflurane's effects on neuronal activity, and GluN2D knockout (grin2d−/−) mice were used to confirm the requirement of GluN2D for the antidepressant effects.Key ResultsRepeated exposure to subanaesthetic doses of sevoflurane produced sustained antidepressant effects lasting up to 2 weeks. Sevoflurane preferentially inhibited GluN2C‐ and GluN2D‐containing NMDARs, causing a reduction in interneuron activity. In contrast, sevoflurane increased action potentials (AP) firing and decreased spontaneous inhibitory postsynaptic current (sIPSC) in mPFC pyramidal neurons, demonstrating a disinhibitory effect. These effects were absent in grin2d−/− mice, and both pharmacological blockade and genetic knockout of GluN2D abolished sevoflurane's antidepressant actions, suggesting that GluN2D is essential for its antidepressant effect.Conclusion and ImplicationsSevoflurane directly targets GluN2D, leading to a specific decrease in interneuron activity and subsequent disinhibition of pyramidal neurons, which may underpin its antidepressant effects. Targeting the GluN2D subunit could hold promise as a potential therapeutic strategy for treating depression.

01 Feb 2024·eneuro

Tonic NMDAR Currents of NR2A-Containing NMDARs Represent Altered Ambient Glutamate Concentration in the Supraoptic Nucleus

Article

Author: Park, Su Eun ; Shin, Hyunjin ; Bae, Young Min ; Stern, Javier E ; Park, Jin Bong ; Kim, Hyun-Woo ; Pham, Thuy Linh ; Lee, So Yeong ; Sharma, Ramesh ; Neupane, Chiranjivi

NMDA receptors (NMDARs) modulate glutamatergic excitatory tone in the brain via two complementary modalities: a phasic excitatory postsynaptic current and a tonic extrasynaptic modality. Here, we demonstrated that the tonic NMDAR-current (INMDA) mediated by NR2A-containing NMDARs is an efficient biosensor detecting the altered ambient glutamate level in the supraoptic nucleus (SON).INMDAof magnocellular neurosecretory cells (MNCs) measured by nonselective NMDARs antagonist, AP5, at holding potential (Vholding) −70 mV in low concentration of ECF Mg2+([Mg2+]o) was transiently but significantly increased 1-week post induction of a DOCA salt hypertensive model rat which was compatible with that induced by a NR2A-selective antagonist, PEAQX (IPEAQX) in both DOCA-H2O and DOCA-salt groups. In agreement, NR2B antagonist, ifenprodil, or NR2C/D antagonist, PPDA, did not affect the holding current (Iholding) atVholding−70 mV. Increased ambient glutamate by exogenous glutamate (10 mM) or excitatory amino acid transporters (EAATs) antagonist (TBOA, 50 mM) abolished theIPEAQXdifference between two groups, suggesting that attenuated EAATs activity increased ambient glutamate concentration, leading to the largerIPEAQXin DOCA-salt rats. In contrast, only ifenprodil but not PEAQX and PPDA uncoveredINMDAatVholding+40 mV under 1.2 mM [Mg2+]ocondition.Iifenprodilwas not different in DOCA-H2O and DOCA-salt groups. Finally, NR2A, NR2B, and NR2D protein expression were not different in the SON of the two groups. Taken together, NR2A-containing NMDARs efficiently detected the increased ambient glutamate concentration in the SON of DOCA-salt hypertensive rats due to attenuated EAATs activity.

06 Sep 2023·ACS chemical neuroscience

Development of a Dihydroquinoline-Pyrazoline GluN2C/2D-Selective Negative Allosteric Modulator of the N-Methyl-d-aspartate Receptor.

Article

Author: Jing, Yao ; Kim, Sukhan ; Fritzemeier, Russell G ; Acker, Timothy M ; Allen, James P ; D'Erasmo, Michael P ; Liotta, Dennis C ; Ullman, Elijah Z ; Pons-Bennaceur, Alexandre ; Bui, Thi-Thien ; Arcoria, Paul J ; Swanger, Sharon A ; Perszyk, Riley E ; Ma, Peipei ; Nocilla, Kelsey A ; Traynelis, Stephen F ; Taz, Azmain ; Menaldino, David S ; Bartsch, Perry W ; Le, Phuong ; Sharma, Savita K ; Zhang, Jing ; Burton, Samantha L ; Coe, Kevin ; Yuan, Hongjie ; Akins, Nicholas S ; Burnashev, Nail

Subunit-selective inhibition of N-methyl-d-aspartate receptors (NMDARs) is a promising therapeutic strategy for several neurological disorders, including epilepsy, Alzheimer's and Parkinson's disease, depression, and acute brain injury. We previously described the dihydroquinoline-pyrazoline (DQP) analogue 2a (DQP-26) as a potent NMDAR negative allosteric modulator with selectivity for GluN2C/D over GluN2A/B. However, moderate (<100-fold) subunit selectivity, inadequate cell-membrane permeability, and poor brain penetration complicated the use of 2a as an in vivo probe. In an effort to improve selectivity and the pharmacokinetic profile of the series, we performed additional structure-activity relationship studies of the succinate side chain and investigated the use of prodrugs to mask the pendant carboxylic acid. These efforts led to discovery of the analogue (S)-(-)-2i, also referred to as (S)-(-)-DQP-997-74, which exhibits >100- and >300-fold selectivity for GluN2C- and GluN2D-containing NMDARs (IC₅₀ 0.069 and 0.035 μM, respectively) compared to GluN2A- and GluN2B-containing receptors (IC₅₀ 5.2 and 16 μM, respectively) and has no effects on AMPA, kainate, or GluN1/GluN3 receptors. Compound (S)-(-)-2i is 5-fold more potent than (S)-2a. In addition, compound 2i shows a time-dependent enhancement of inhibitory actions at GluN2C- and GluN2D-containing NMDARs in the presence of the agonist glutamate, which could attenuate hypersynchronous activity driven by high-frequency excitatory synaptic transmission. Consistent with this finding, compound 2i significantly reduced the number of epileptic events in a murine model of tuberous sclerosis complex (TSC)-induced epilepsy that is associated with upregulation of the GluN2C subunit. Thus, 2i represents a robust tool for the GluN2C/D target validation. Esterification of the succinate carboxylate improved brain penetration, suggesting a strategy for therapeutic development of this series for NMDAR-associated neurological conditions.

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