Topic: NMDARs

Mammalian babies are “sensory traps” for parents. Various sensory cues from the newborn are tremendously efficient in triggering parental responses in caregivers. We recently showed that core aspects of maternal behavior such as pup retrieval in response to infant vocalizations rely on active learning of auditory cues from pups facilitated by the neurohormone oxytocin (OT). Release of OT from the hypothalamus might thus help induce recognition of different infant cues but it is unknown what sensory stimuli can activate OT neurons. I performed unprecedented in vivo whole-cell and cell-attached

Synaptonuclear signalling pathways have been implicated in long term plasticity events. Nonetheless, their role in regulating cognitive behavior remains to be clarified. Here, we demonstrated that RNF10-mediated synapse-to-nucleus signaling, linking activation of synaptic NMDARs to specific transcriptional programmes in the dorsal CA1, is necessary for cognitive flexibility. In vivo RNF10 downregulation, through gene deletion and silencing, induced, specifically in CA1, alterations of both long-term potentiation and dendritic spines’ structure. At behavioral level, RNF10 downregulation suppres

During development, critical periods of synaptic plasticity facilitate the reordering and refinement of neural connections, allowing the definitive synaptic circuits responsible for correct adult physiology to be established. The L4-L2/3 synapses in the somatosensory cortex (S1) exhibit a presynaptic form of spike timing-dependent long-term depression (t-LTD) that probably fulfills a role in synaptic refinement. This t-LTD persists until the 4rd postnatal week in mice, disappearing thereafter. When we investigated the mechanisms underlying this maturation-related loss of t-LTD in mouse slices,

Calcium, an important secondary messenger, lies at the hub of multiple signaling pathways. The increase in cytosolic calcium contributed by different calcium-permeable channels can create transient high-calcium microenvironments and activate distinct signaling cascades in neurons. The spatio-temporal calcium changes, and calcium-mediated signaling pathways act as critical regulators of synaptic plasticity. Here, we have studied the regulation of activity-mediated protein synthesis by calcium response generated on NMDAR or mGluR stimulation in rat primary cortical neurons. Using calcium imaging

AIMS:Investigate whether the endoplasmic reticulum (ER) quality control machinery verifies the structure of ligand-binding domains (LBDs) of NMDARs or controls the functionality of NMDARs.METHODS:HEK293 cells were used to express wild-type (WT) or mutation forms of GluN1/GluN2A and GluN1/GluN2B receptors. Surface expressions were observed using fluorescence confocal microscopy. Electrophysiological properties of NMDARs were assessed via the whole-cell patch-clamp technique.RESULTS:Using alanine substitutions combined with microscopy and electrophysiology, we found that surface expression of Gl

Dopamine (DA) neurons in the substantia nigra are vital for the control of movement. This fundamental function is encoded by the output signal of DA neurons which switches from spontaneous firing to bursts of action potentials. The latter produces an increase of DA release in targeted areas which is associated to locomotion initiation. The impairment of this process, such as DA neurons degeneration, leads to the motor symptoms of Parkinson’s disease. The activation of the N-methyl-D-aspartate receptors (NMDARs), by the simultaneous binding of glutamate and a co-agonist, is indispensable for th

NMDA receptors (NMDARs) are ionotropic receptors crucial for brain information processing. Yet, evidence also supports an ion flux-independent signaling mode mediating synaptic long-term depression (LTD) and spine shrinkage. How these different modes of NMDAR activity are controlled remains unknown. Here, we identify AETA (Aη), an amyloid-β precursor protein (APP) cleavage product, as an NMDAR modulator with the unique dual regulatory capacity to impact both signaling modes. AETA inhibits ionotropic NMDAR activity, principally of GluN2A containing heteromers, by competing with the co-agonist a

The anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder characterized by specific autoantibodies targeting the GluN1 subunit of postsynaptic NMDARs. Here, we investigated the effects of patient monoclonal anti-GluN1 antibodies on the synaptic signalling and plasticity molecules CaMKII and DAPK1 and their related pathways.We incubated primary hippocampal cell cultures (div 14-21) with patient-derived monoclonal anti-GluN1 or control antibodies. Thereafter, we induced chemical LTP and/or treated cells with the DAPK1 inhibitor TC-DAPK6. We then analysed NMDARs GluN1

Early life aversive experiences influence brain development, contributing to the emergence of psychiatric diseases, such as schizophrenia and major depression. Most of the inhibitory neurons in the thalamus are parvalbumin-expressing (PV+) cells located in the thalamic reticular nucleus (TRN). Alterations of PV+ interneurons, some of them mediated by perineuronal nets (PNNs), have been related to these psychiatric diseases. We have developed two models of early life aversive experiences on the TRN of adult mice. We have used a double-hit (DH) model in male mice combining an injection of the NM

N-acetyl spermine (NASPM) is known from in vitro and in vivo animal models for its action as calcium permeable AMPA receptors (CP-AMPARs) antagonist. Our study aim to investigate the impact of NASPM on an ex vivo human brain slice neocortex model, focusing on its ability to suppress epileptic activity. While AMPA receptors play a central role in neocortical signaling and neuronal activity, the contribution of CP-AMPARs, particularly in the context of seizure-induced inhibition/excitation imbalance, remains unknown. By applying NASPM to ex vivo human cortex slices, we aimed to investigate its a

Cortical spreading depression (CSD) is the neurophysiological correlate of migraine aura and a trigger of migraine pain mechanisms. The mechanisms of initiation of CSD in migraineurs are unknown. Insights into these mechanisms can be obtained by studying the mechanisms of facilitation of CSD initiation in genetic mouse models of the disease. Here, we investigated these mechanisms in knock-in mice carrying a mutation in cacna1a causing familial hemiplegic migraine (FHM1 mice). High KCl puffs of increasing duration up to the threshold duration eliciting a CSD were applied on layer 2/3 of cerebra

While neuronal activity is important for synapse refinement and maintenance, its contribution to synapse formation and dendritic arborization remains unclear. Our previous work in dissociated hippocampal neurons identified a timeframe prior to the establishment of synapses during which spontaneous glutamate release facilitates the branching of dissociated hippocampal neurons by targeting NMDA receptors (NMDARs). We now demonstrate the role of NMDARs in synapse formation and dendritic maturation in hippocampal CA1 pyramidal neurons in cultured slices and in vivo. To test whether NMDARs guide sy

Rabphilin 3A (Rph3A) is a synaptic protein crucial for regulating exo- and endocytosis processes at presynaptic terminals and dendritic spines. The protein promotes the stabilization of the NMDA-type glutamate receptors (NMDARs) at the cell surface, forming a ternary complex with the PSD-95 and GluN2A subunit of the receptor. This complex is needed for long-term potentiation induction and NMDAR-dependent hippocampal behaviors, such as spatial learning. Rph3A overexpression increases dendritic spine density and GluN2A-containing NMDARs at synaptic membranes. Overall, these results suggest that

AIMS: Investigate the impact of disrupting specific disulfide bonds in the GluN1 subunit on the early trafficking and functional properties of conventional NMDARs.METHODS:HEK293 cells were utilized to express wild-type (WT) or mutant forms of GluN1/GluN2A and GluN1/GluN2B receptors. Surface expression and colocalization of NMDAR with the Golgi apparatus were observed using fluorescence confocal microscopy. Electrophysiological properties of NMDARs were assessed via the whole-cell patch-clamp technique. In addition, NMDA-induced excitotoxicity in rat hippocampal neurons was examined specificall

N-methyl-D-aspartate receptors (NMDARs) are a family of ionotropic glutamate receptors that mediate excitatory neurotransmission in the CNS. Native NMDARs are assembled as heterotetramers composed of two obligatory GluN1 and two GluN2A-D/GluN3A-B subunits at various combinations. The opening of the ion channel is a central feature of NMDAR function and is controlled by binding of two co-agonists (glutamate/glycine) to the agonist binding domains (ABD). In our previous work, using molecular dynamics simulations, we proposed functionally important residues in this process of channel opening, Glu