Molecular Psychiatry, Год журнала: 2024, Номер unknown
Опубликована: Авг. 30, 2024
Язык: Английский
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Июль 9, 2024
In the mammalian neocortex, GABAergic interneurons (INs) inhibit cortical networks in profoundly different ways. The extent to which this depends on how INs process excitatory signals along their dendrites is poorly understood. Here, we reveal that functional specialization of two major populations determined by unique association dendritic integration modes with distinct synaptic organization motifs. We found somatostatin (SST)-INs exhibit NMDAR-dependent and uniform synapse density tree. contrast, parvalbumin (PV)-INs passive coupled proximally enriched distributions. Theoretical analysis shows these configurations result strategies optimize efficacy thin structures. Yet, lead temporal engagement each IN during network activity. confirmed predictions
Язык: Английский
Процитировано
4
Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(31)
Опубликована: Июль 25, 2024
Delta receptors (GluD1 and GluD2), members of the large ionotropic glutamate receptor (iGluR) family, play a central role in numerous neurodevelopmental psychiatric disorders. The amino-terminal domain (ATD) GluD orchestrates synapse formation maturation processes through its interaction with Cbln family synaptic organizers neurexin (Nrxn). transsynaptic triad Nrxn–Cbln–GluD also serves as potent regulator plasticity, at both excitatory inhibitory synapses. Despite these recognized functions, there is still debate to whether functions "canonical" ion channel, similar other iGluRs. A recent report proposes that ATD GluD2 imposes conformational constraints on channel activity; removal this constraint by binding Cbln1 Nrxn, or ATD, reveals activity upon administration glycine (Gly) d -serine ( -Ser), two ligands. We were able reproduce currents when Gly -Ser was administered clusters heterologous human embryonic kidney 293 (HEK293) cells expressing Cbln1, (or GluD1), Nrxn. However, -Ser, but l -glutamate -Glu), evoked naive (i.e., untransfected) HEK293 GluD2-null Purkinje neurons. Furthermore, no current detected isolated lacking Gly. Taken together, results cast doubt previously proposed hypothesis extracellular ligands directly gate wild-type channels.
Язык: Английский
Процитировано
4
Journal of Neurochemistry, Год журнала: 2024, Номер 168(11), С. 3663 - 3684
Опубликована: Июль 29, 2024
The neurotransmitter glycine is an agonist at the strychnine-sensitive receptors. In addition, it has recently been discovered to act two new receptors, excitatory receptor and metabotropic receptor. Glycine's roles have most extensively investigated in spinal cord, where known play essential pain, itch, motor function. contrast, less about supraspinal glycinergic functions, their contributions pain circuits are largely unrecognized. As neurons absent from cortical regions, a clearer understanding of how modulates could reveal pharmacological targets. This review aims synthesize published research on glycine's role adult brain, highlighting regions signaling may modulate responses. was achieved through scoping methodology identifying several key circuitry involved. Therefore, this unveils critical gaps for potential pain-associated responses, encouraging researchers consider neurotransmission more widely when investigating neural mechanisms pain.
Язык: Английский
Процитировано
4
Neurochemical Research, Год журнала: 2025, Номер 50(2)
Опубликована: Март 3, 2025
Язык: Английский
Процитировано
0
Channels, Год журнала: 2025, Номер 19(1)
Опубликована: Апрель 16, 2025
N-methyl-D-aspartate receptors (NMDARs) are heterotetrameric ion channels that play crucial roles in brain function. Among all the NMDAR subtypes, GluN1-N3 exhibit unique agonist binding and gating properties. Unlike "conventional" GluN1-N2 receptors, which require both glycine glutamate for activation, activated solely by glycine. Furthermore, display faster desensitization, reduced Ca2+ permeability, lower sensitivity to Mg2+ blockage compared receptors. Due these characteristics, thought critical eliminating redundant synapses pruning spines early stages of development. Recent studies have advanced pharmacological tools specifically targeting provided direct evidence glycine-activated excitatory native tissue. The structural basis has also been elucidated through cryo-EM artificial intelligence. These findings highlight not only involved essential functions but present potential targets drug
Язык: Английский
Процитировано
0
The Journal of General Physiology, Год журнала: 2023, Номер 155(6)
Опубликована: Апрель 20, 2023
NMDA-type ionotropic glutamate receptors are critical for normal brain function and implicated in central nervous system disorders. Structure of NMDA composed GluN1 GluN3 subunits less understood compared to those GluN2 subunits. GluN1/3 display unusual activation properties which binding glycine elicits strong desensitization, while alone is sufficient activation. Here, we explore mechanisms by GluN1-selective competitive antagonists, CGP-78608 L-689,560, potentiate GluN1/3A GluN1/3B preventing GluN1. We show that both L-689,560 prevent desensitization receptors, but CGP-78608-bound higher potency efficacy at L-689,560-bound receptors. Furthermore, demonstrate a potent antagonist GluN1FA+TL/3A mutated abolish GluN1, this inhibition mediated non-competitive mechanism involving the agonist domain (ABD) negatively modulate GluN3A. Molecular dynamics simulations reveal or mutations site promote distinct conformations ABD, suggesting ABD conformation influences These results uncover enables native application presence CGP-78608, not intra-subunit allosteric interactions may be relevant neuronal signaling disease.
Язык: Английский
Процитировано
7
Cell Reports, Год журнала: 2023, Номер 42(5), С. 112477 - 112477
Опубликована: Май 1, 2023
Signaling via N-methyl-d-aspartate receptors (NMDARs) is critical for the maturation of glutamatergic synapses, partly through a developmental switch from immature synapses expressing primarily GluN2B- and GluN3A-containing subtypes to GluN2A-rich mature ones. This subunit thought underlie synaptic stabilization NMDARs necessary neural network consolidation. However, cellular mechanisms controlling NMDAR exchange remain unclear. Using combination single-molecule confocal imaging biochemical electrophysiological approaches, we show that surface GluN3A-NMDARs form highly diffusive receptor pool loosely anchored synapses. Remarkably, changes in GluN3A expression selectively alter diffusion anchoring GluN2A- but not GluN2B-NMDARs, possibly altered interactions with cell receptors. The effects on are restricted an early time window postnatal development rodents, allowing subunits control timing signaling neuronal refinements.
Язык: Английский
Процитировано
7
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Июнь 23, 2024
ABSTRACT Cocaine use disorder is characterized by persistent drug-seeking behavior and a high risk of relapse, driven lasting molecular circuit adaptations in the nucleus accumbens. To explore transcriptomic changes underlying these alterations, we employed fluorescence-activated sorting coupled with single-nucleus RNA sequencing to analyze D1 D2 medium spiny neurons this brain region male mice subjected acute cocaine exposure or prolonged withdrawal from repeated without an rechallenge. This approach allowed us precisely delineate contrast transcriptionally distinct neuronal subpopulations─or ensembles – across various treatment conditions. We identified significant heterogeneity within both MSNs, revealing clusters unique transcriptional profiles. Notably, discrete MSN population upregulation immediate early genes, as well another group MSNs linked withdrawal, uncovering novel regulators withdrawal-related transcriptome dynamics. Our findings provide high-resolution map illustrating dynamic induced withdrawal. These insights into mechanisms highlight potential targets for therapeutic intervention aimed at preventing relapse.
Язык: Английский
Процитировано
2
Frontiers in Physiology, Год журнала: 2024, Номер 15
Опубликована: Авг. 20, 2024
N -methyl- D -aspartate (NMDA) receptors are heterotetrametric ion channels composed of two obligatory GluN1 subunits and alternative GluN2 or GluN3 subunits, forming GluN1-N2, GluN1-N3, GluN1-N2-N3 type NMDA receptors. Extensive research has focused on the functional structural properties conventional GluN1–GluN2 due to their early discovery high expression levels. However, knowledge unconventional GluN1-N3 remains limited. In this study, we modeled GluN1-N3A, GluN1-N3B, GluN1-N3A-N3B using deep-learned protein-language predication algorithms AlphaFold RoseTTAFold All-Atom. We then compared these structures with GluN1-N2 GluN1-N3A receptor cryo-EM found that have distinct in subunit arrangement, domain swap, interaction. Furthermore, predicted agonist- antagonist-bound structures, highlighting key molecular–residue interactions. Our findings shed new light diversity provide a direction for drug development. This study uses advanced AI model receptors, revealing unique interactions By predicting ligand-bound our enhances understanding offers insights targeted
Язык: Английский
Процитировано
2
Epilepsia, Год журнала: 2023, Номер 64(12), С. 3377 - 3388
Опубликована: Сен. 22, 2023
N-methyl-d-aspartate (NMDA) receptors are expressed at synaptic sites, where they mediate fast excitatory neurotransmission. NMDA critical to brain development and cognitive function. Natural variants the GRIN1 gene, which encodes obligatory GluN1 subunit of receptor, associated with severe neurological disorders that include epilepsy, intellectual disability, developmental delay. Here, we investigated pathogenicity three missense p. Ile148Val (GluN1-3b[I481V]), p.Ala666Ser (GluN1-3b[A666S]), p.Tyr668His (GluN1-3b[Y668H]).
Язык: Английский
Процитировано
5