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.

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

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

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

FENS Forum 2024

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

Bernstein Conference 2024

Adenosine A2A Receptor Antagonists block NMDA Receptor Function in APPSW/Ind mice model of Alzheimer's disease

Age-dependent role of NMDA receptors in experimental autoimmune encephalomyelitis

Analysis of rat dopaminergic neuron NMDA receptor dose-response relation and potentiation effects of the positive allosteric modulator, PTC-174

Astrocytic EphB3 receptors control NMDA receptor functions and memory

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

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

Different modes of synaptic and extrasynaptic NMDA receptor alteration in the hippocampus of P301S tau transgenic mice

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

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

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

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

Endothelial NMDA receptor impairs the differentiation of oligodendrocytes

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

The heterogeneity of synaptic NMDA receptor responses within individual lamina I pain processing neurons is conserved across sex and species

The hippocampal CA2 subregion in the NMDA receptor hypofunction pathology of psychiatric disorders

The impact of NMDA receptor subunit GluN3A deletion on the brain activity of young and adult mice

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

Investigation of NMDA receptor function in a rodent model of early life stress

Mechanism of NMDA receptor potentiation by lactate

Molecular mechanisms of unconventional NMDA receptors containing GluN3A subunits

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

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

The NMDA receptor triggers neuronal autophagy during Oxygen and Glucose Deprivation

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

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

Regulation of NMDA receptor dynamics by brain-derived neurotrophic factor in hippocampal neurons

RNF10: a synaptonuclear messenger linking NMDA receptor synaptic activity at CA1 synapses to cognitive flexibility

Zinc Modulates Fronto-Striatal Glutamatergic Transmission and Implementation of Proactive Inhibitory Control through high-affinity binding at NMDA receptor GluN2A subunit

Brief application of (S)-ketamine causes long-term depression of NMDA receptor-mediated synaptic transmission in the mouse hippocampus

FENS Forum 2024

Characterization of zebrafish larvae with knockouts in the NMDA receptor subunit genes grin2Aa and grin2Ab

FENS Forum 2024