NMDA receptor

Decoding ketamine: Neurobiological mechanisms underlying its rapid antidepressant efficacy

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.

The GluN2A Subunit of the NMDA Receptor and Parvalbumin Interneurons: A Possible Role in Interneuron Development

N-methyl-D-aspartate receptors (NMDARs) are excitatory glutamate-gated ion channels that are expressed throughout the central nervous system. NMDARs mediate calcium entry into cells, and are involved in a host of neurological functions. The GluN2A subunit, encoded by the GRIN2A gene, is expressed by both excitatory and inhibitory neurons, with well described roles in pyramidal cells. By using Grin2a knockout mice, we show that the loss of GluN2A signaling impacts parvalbumin-positive (PV) GABAergic interneuron function in hippocampus. Grin2a knockout mice have 33% more PV cells in CA1 compared to wild type but similar cholecystokinin-positive cell density. Immunohistochemistry and electrophysiological recordings show that excess PV cells do eventually incorporate into the hippocampal network and participate in phasic inhibition. Although the morphology of Grin2a knockout PV cells is unaffected, excitability and action-potential firing properties show age-dependent alterations. Preadolescent (P20-25) PV cells have an increased input resistance, longer membrane time constant, longer action-potential half-width, a lower current threshold for depolarization-induced block of action-potential firing, and a decrease in peak action-potential firing rate. Each of these measures are corrected in adulthood, reaching wild type levels, suggesting a potential delay of electrophysiological maturation. The circuit and behavioral implications of this age-dependent PV interneuron malfunction are unknown. However, neonatal Grin2a knockout mice are more susceptible to lipopolysaccharide and febrile-induced seizures, consistent with a critical role for early GluN2A signaling in development and maintenance of excitatory-inhibitory balance. These results could provide insights into how loss-of-function GRIN2A human variants generate an epileptic phenotypes.

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

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.

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

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.

EXPRESSION OF NEOCORTICAL SPIKE TIMING-DEPENDENT LONG-TERM DEPRESSION BY MODULATION OF PRESYNAPTIC NMDA RECEPTOR TONE

FENS Forum 2026

IMPACTS OF <EM>GRIN1</EM> MUTATIONS ON NMDA RECEPTOR LOCALIZATION AND CORTICAL DEVELOPMENT

FENS Forum 2026

TAU CONTROLS THE HOMEOSTASIS OF SYNAPTIC NMDA RECEPTORS IN NEURONS

FENS Forum 2026

TARGETING NMDA RECEPTORS THROUGH D-SERINE SUPPLEMENTATION IN A RAT MODEL OF PARKINSON’S DISEASE

FENS Forum 2026

COMPARATIVE ASSESSMENT OF SELECTIVE AND PAN-NMDA RECEPTOR SUBTYPE INHIBITION ON FUNCTIONAL CONNECTIVITY IN THE PREFRONTAL CORTEX BY USING AN NR2B NAM AND S-KETAMINE

FENS Forum 2026

DEVELOPMENT OF A NOVEL OPEN-CHANNEL BLOCKER FOR GLUN1/GLUN2 NMDA RECEPTORS: MECHANISM AND PHARMACOLOGY

FENS Forum 2026

THE INTERPLAY BETWEEN CB<SUB >2</SUB> AND NMDA RECEPTORS IN PARKINSON’S DISEASE

FENS Forum 2026

ASTROCYTES REGULATE PHASIC ACTIVATION OF LOCUS COERULEUS NOREPINEPHRINE NEURONS VIA NMDA RECEPTOR-DEPENDENT PLASTICITY

FENS Forum 2026

GLUN2D‑CONTAINING NMDA RECEPTORS IN HIPPOCAMPAL INTERNEURONS REGULATE INHIBITORY FEEDBACK CIRCUITS AND RESTORE PLASTICITY IN DEPRESSION MODELS

FENS Forum 2026

DISTINCT PRE- AND POSTSYNAPTIC NMDA RECEPTOR POOLS GOVERN DIVERSE FORMS OF CORTICAL PLASTICITY

FENS Forum 2026

IMPACT ON TRANSCALLOSAL, LONG RANGE AND LOCAL MPFC EXCITATORY INPUTS BY EARLY POSTNATAL NMDA RECEPTOR ABLATION

FENS Forum 2026

NON-IONOTROPIC NMDA RECEPTOR FUNCTIONS OF GLUN2B SHAPE EARLY CORTICAL DEVELOPMENT

FENS Forum 2026

MYELIN PLASTICITY MEDIATED BY NMDA RECEPTORS CONTAINING GLUN3A SUBUNITS OLIGODENDROCYTE PROGENITOR CELLS

FENS Forum 2026

DIZOCILPINE (MK-801) DERIVATIVES AS NEUROPROTECTIVE NMDA RECEPTOR ANTAGONISTS WITHOUT PSYCHOMIMETIC SIDE EFFECTS

FENS Forum 2026

A GLUN2A-N615S PORE MUTATION MODEL REVEALS HOW MG²⁺ CONTROLS KETAMINE INHIBITION OF NMDA RECEPTORS

FENS Forum 2026

LOSS OF MG²⁺ BLOCK IN GLUN2A-N615S NMDA RECEPTORS RESHAPES INHIBITION BY MEMANTINE AND K2060

FENS Forum 2026

EAR-20: A NOVEL PEPTIDE ENHANCING NMDA RECEPTOR FUNCTION

FENS Forum 2026

NMDA RECEPTOR ACTIVITY REGULATED BY DOCK4 DRIVES VLO TO ACTIVATE VLPAG FOR ANTINOCICEPTION

FENS Forum 2026

HIPPOCALCIN SIGNALING WITHIN THE SPINES IN RESPONSE TO NMDA RECEPTORS ACTIVATION

FENS Forum 2026

ANTIBODY FC GLYCAN SIGNATURES TRACK WITH COMPARTMENTS, ETIOLOGY AND ONE-YEAR OUTCOMES IN ANTI-NMDA RECEPTOR ENCEPHALITIS

FENS Forum 2026

DISRUPTED SPATIAL REPRESENTATION RETRIEVAL AND ENCODING IN LARGE NEURONAL POPULATIONS IN HIPPOCAMPAL CA1 UNDER NMDA RECEPTOR BLOCKADE

FENS Forum 2026

ALTERED INHIBITORY MOTIF ORGANIZATION IN MOUSE MODELS OF ALZHEIMER’S DISEASE AND NMDA RECEPTOR HYPOFUNCTION

FENS Forum 2026

EFFECTS OF PRENATAL EXPOSURE TO PATIENT-DERIVED NMDA RECEPTOR AUTOANTIBODIES ON THE DEVELOPING MOUSE STRIATUM

FENS Forum 2026

LOOKING FOR THE ENGRAM UNDERLYING PTSD-LIKE MEMORY: FOCUS ON THE ROLE OF THE ANTERIOR CINGULATE CORTEX AND NMDA RECEPTORS IN TRAUMATIC MEMORY MAINTENANCE

FENS Forum 2026

PREDICTION ERROR ENGAGES NMDA RECEPTORS IN THE BASOLATERAL AMYGDALA COMPLEX FOR PAVLOVIAN FEAR CONDITIONING

FENS Forum 2026

Endogenous NMDA receptor modulators alter dendritic arbor complexity in cultured cortical neurons

NMDA receptor-related mechanisms of dopaminergic modulation of tDCS-induced neuroplasticity

The NMDA receptor triggers neuronal autophagy during Oxygen and Glucose Deprivation

NMDA receptors shape sensory processing in the piriform cortex

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

Electrophysiological Characterisation of Hippocampal Networks in Anti-NMDA Receptor Encephalitis: From Synapse to Circuit

The constitutive activity of the histamine H1 receptor, interaction with the NMDA receptor: consequences in epilepsy

The NMDA receptor modulator zelquistinel durably relieves behavioral deficits in three mouse models of autism

NMDA receptor hypofunction during adolescence reduces GABAergic efficacy and adult neurogenesis in the dorsal dentate gyrus of adult mice

Effects of a novel positive NMDA receptor modulator in a mouse model of impaired fear extinction

Molecular mechanisms of unconventional NMDA receptors containing GluN3A subunits

Mechanism of NMDA receptor potentiation by lactate

Dopamine System, NMDA Receptor and EGF Family Expressions in Brain Structures of Bl6 and 129Sv Strains Displaying Different Behavioral Adaptation

Comprehensive delineation and precision medicine of GRIN-related neurodevelopmental disorders, a primary disturbance of the NMDA receptor

Age-dependent role of NMDA receptors in experimental autoimmune encephalomyelitis