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Ketamine alleviates NMDA receptor hypofunction through synaptic trapping
Frédéric Villéga1, Alexandra Fernandes2, Julie Jézéquel2
1University of Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS UMR 5297, 33000 Bordeaux, France; Department of Pediatric Neurology, CIC-1401, University Children's Hospital of Bordeaux, Bordeaux, France.
Neuron
|July 24, 2024
Summary
Ketamine enhances N-methyl-D-aspartate glutamate receptor (NMDAR) trapping at synapses, which can counteract receptor loss caused by anti-NMDAR encephalitis and improve cognitive functions.
Area of Science:
- Neuroscience
- Neuropharmacology
- Synaptic Plasticity
Background:
- N-methyl-D-aspartate glutamate receptor (NMDAR) synaptic trapping is crucial for regulating excitatory neurotransmission and cognitive functions.
- NMDAR synaptic destabilization is linked to neurological and psychiatric disorders, but therapeutic modulation of synaptic trapping remains challenging.
Purpose of the Study:
- To investigate how ketamine (KET) and other NMDAR open channel blockers (OCBs) affect NMDAR synaptic trapping.
- To determine if enhanced NMDAR trapping can mitigate deficits caused by autoantibodies in anti-NMDAR encephalitis.
Main Methods:
- Examined the interaction between NMDAR and PDZ-domain scaffolding proteins upon OCB treatment.
- Assessed the impact of KET-induced trapping enhancement on synaptic receptor levels in an anti-NMDAR encephalitis model.
- Evaluated NMDAR-mediated CaMKII signaling and behavioral outcomes, including anxiety and sensorimotor gating.
Main Results:
- Ketamine and other OCBs promote NMDAR interactions with PDZ-domain proteins, enhancing synaptic trapping.
- KET-enhanced trapping counteracted synaptic receptor depletion induced by anti-NMDAR encephalitis autoantibodies.
- Preventing synaptic depletion restored NMDAR-mediated CaMKII signaling and ameliorated behavioral deficits.
Conclusions:
- OCBs exert an unexpected effect by enhancing NMDAR synaptic anchoring.
- Targeting NMDAR receptor anchoring presents a potential therapeutic strategy for NMDAR-related synaptopathies.
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