TopicNeuroscience

NMDA receptors

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29Total items

26ePosters

3Seminars

Latest

SeminarNeuroscience

Decoding ketamine: Neurobiological mechanisms underlying its rapid antidepressant efficacy

Zanos Panos

Translational Neuropharmacology Lab, University of Cyprus, Center for Applied Neurosience & Department of Psychology, Nicosia, Cyprus

Apr 4, 2025

Unlike traditional monoamine-based antidepressants that require weeks to exert effects, ketamine alleviates depression within hours, though its clinical use is limited by side effects. While ketamine was initially thought to work primarily through NMDA receptor (NMDAR) inhibition, our research reveals a more complex mechanism. We demonstrate that NMDAR inhibition alone cannot explain ketamine's sustained antidepressant effects, as other NMDAR antagonists like MK-801 lack similar efficacy. Instead, the (2R,6R)-hydroxynorketamine (HNK) metabolite appears critical, exhibiting antidepressant effects without ketamine's side effects. Paradoxically, our findings suggest an inverted U-shaped dose-response relationship where excessive NMDAR inhibition may actually impede antidepressant efficacy, while some level of NMDAR activation is necessary. The antidepressant actions of ketamine and (2R,6R)-HNK require AMPA receptor activation, leading to synaptic potentiation and upregulation of AMPA receptor subunits GluA1 and GluA2. Furthermore, NMDAR subunit GluN2A appears necessary and possibly sufficient for these effects. This research establishes NMDAR-GluN2A activation as a common downstream effector for rapid-acting antidepressants, regardless of their initial targets, offering promising directions for developing next-generation antidepressants with improved efficacy and reduced side effects.

SeminarNeuroscience

Imaging neuronal morphology and activity pattern in developing cerebral cortex layer 4

Hidenobu Mizuno

Kumamoto University, Japan

Oct 27, 2021

Establishment of precise neuronal connectivity in the neocortex relies on activity-dependent circuit reorganization during postnatal development. In the mouse somatosensory cortex layer 4, barrels are arranged in one-to-one correspondence to whiskers on the face. Thalamocortical axon termini are clustered in the center of each barrel. The layer 4 spiny stellate neurons are located around the barrel edge, extend their dendrites primarily toward the barrel center, and make synapses with thalamocortical axons corresponding to a single whisker. These organized circuits are established during the first postnatal week through activity-dependent refinement processes. However, activity pattern regulating the circuit formation is still elusive. Using two-photon calcium imaging in living neonatal mice, we found that layer 4 neurons within the same barrel fire synchronously in the absence of peripheral stimulation, creating a ''patchwork'' pattern of spontaneous activity corresponding to the barrel map. We also found that disruption of GluN1, an obligatory subunit of the N-methyl-D-aspartate (NMDA) receptor, in a sparse population of layer 4 neurons reduced activity correlation between GluN1 knockout neuron pairs within a barrel. Our results provide evidence for the involvement of layer 4 neuron NMDA receptors in spatial organization of the spontaneous firing activity of layer 4 neurons in the neonatal barrel cortex. In the talk I will introduce our strategy to analyze the role of NMDA receptor-dependent correlated activity in the layer 4 circuit formation.

SeminarNeuroscienceRecording

Playing fast and loose with glutamate builds healthy circuits in the developing cortex

Chris Dulla

Tufts University

Feb 17, 2021

The construction of cortical circuits requires the precise formation of connections between excitatory and inhibitory neurons during early development. Multiple factors, including neurotransmitters, neuronal activity, and neuronal-glial interactions, shape how these critical circuits form. Disruptions of these early processes can disrupt circuit formation, leading to epilepsy and other neurodevelopmental disorders. Here, I will describe our work into understanding how prolonged post-natal astrocyte development in the cortex creates a permissive window for glutamate signaling that provides tonic activation of developing interneurons through Grin2D NMDA receptors. Experimental disruption of this pathway results in hyperexcitable cortical circuits and human mutations in the Grin2D gene, as well as other related molecules that regulate early life glutamate signaling, are associated with devastating epileptic encephalopathies. We will explore fundamental mechanisms linking early life glutamate signaling and later circuit hyperexcitability, with an emphasis on potential therapeutic interventions aimed at reducing epilepsy and other neurological dysfunction.

NMDA receptors

Latest

Decoding ketamine: Neurobiological mechanisms underlying its rapid antidepressant efficacy

Imaging neuronal morphology and activity pattern in developing cerebral cortex layer 4

Playing fast and loose with glutamate builds healthy circuits in the developing cortex

Excitatory drive of cortical fast-spiking GABAergic interneurons is set by D-serine acting on NMDA receptors

Alteration of NMDA receptors in different excitatory synapses in the hippocampus of APP/PS1 transgenic mice

Modulation of Spike-timing-dependent Plasticity via the Interaction of Astrocyte-regulated D-serine with NMDA Receptors

Age-dependent role of NMDA receptors in experimental autoimmune encephalomyelitis

Developmental and adult memory capacity control via interplay between non-conventional GluN3A-NMDA receptors and mTOR signaling

Fragile X Mental Retardation protein mediates BDNF-induced increase of synaptic NMDA receptors content

Implication of medial prefrontal cortex and nucleus accumbens dopamine transmission in goal-directed behaviors: a role for dopamine and NMDA receptors heteromers ?

Molecular mechanisms of unconventional NMDA receptors containing GluN3A subunits

NMDA receptors shape sensory processing in the piriform cortex

Oligodendroglial NMDA receptors containing GluN3A subunits: roles in activity-dependent myelination

Optical control of GluN2B-NMDA receptors

Optical manipulation and interrogation of GluN2B-NMDA receptors in the brain

Pathogenic mutation GluN1-N650K in combination with GluN2A subunit changes kinetic parameters and conductance of NMDA receptors

Photocontrol of NMDA receptors with subunit stoichiometry resolution

Regulation of CRTC1-mediated synapse-to-nucleus communication by excitotoxic activation of NMDA receptors

Sex dimorphic role of NMDA receptors in hippocampal-dependent spatial memory and plasticity during juvenility

The effects of disease-associated mutations on the conformational dynamics of NMDA receptors

Endoplasmic reticulum quality control machinery validates structural changes, not functionality, of NMDA receptors

Estimating the effect of NMDA receptors on network-level oscillations and information processing

Fragile-X-messenger ribonucleoprotein mediates BDNF-induced upregulation of GluN2B-containing NMDA receptors: Role in LTP of CA1 synapses

APP fragment controls both ionotropic and non-ionotropic signaling of NMDA receptors

Modified synaptic and extrasynaptic distribution of NMDA receptors in cortex of Alzheimer’s disease individuals

Myelin plasticity requires the expression in oligodendrocyte progenitors of NMDA receptors containing GluN3A subunits

The role of disulfide bonds in GluN1 in the regulation of the early trafficking and functional properties of GluN1/GluN2 subtypes of NMDA receptors

The role of disulfide bonds in GluN1 in the regulation of the early trafficking and functional properties of GluN1/GluN3A subtypes of NMDA receptors

The role of neocortical and hippocampal presynaptic NMDA receptors in the induction of spike timing-dependent long-term depression