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A key requirement for synaptic Reelin signaling in ketamine-mediated behavioral and synaptic action
- Source :
- Proc Natl Acad Sci U S A
- Publication Year :
- 2021
-
Abstract
- Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant action in some patients with treatment-resistant depression. However, recent data suggest that ∼50% of patients with treatment-resistant depression do not respond to ketamine. The factors that contribute to the nonresponsiveness to ketamine's antidepressant action remain unclear. Recent studies have reported a role for secreted glycoprotein Reelin in regulating pre- and postsynaptic function, which suggests that Reelin may be involved in ketamine's antidepressant action, although the premise has not been tested. Here, we investigated whether the disruption of Reelin-mediated synaptic signaling alters ketamine-triggered synaptic plasticity and behavioral effects. To this end, we used mouse models with genetic deletion of Reelin or apolipoprotein E receptor 2 (Apoer2), as well as pharmacological inhibition of their downstream effectors, Src family kinases (SFKs) or phosphoinositide 3-kinase. We found that disruption of Reelin, Apoer2, or SFKs blocks ketamine-driven behavioral changes and synaptic plasticity in the hippocampal CA1 region. Although ketamine administration did not affect tyrosine phosphorylation of DAB1, an adaptor protein linked to downstream signaling of Reelin, disruption of Apoer2 or SFKs impaired baseline NMDA receptor-mediated neurotransmission. These results suggest that maintenance of baseline NMDA receptor function by Reelin signaling may be a key permissive factor required for ketamine's antidepressant effects. Taken together, our results suggest that impairments in Reelin-Apoer2-SFK pathway components may in part underlie nonresponsiveness to ketamine's antidepressant action.
- Subjects :
- Male
Low-density lipoprotein receptor-related protein 8
Neurotransmission
Receptors, N-Methyl-D-Aspartate
Mice
Phosphatidylinositol 3-Kinases
Postsynaptic potential
Animals
Reelin
LDL-Receptor Related Proteins
Multidisciplinary
Neuronal Plasticity
biology
Behavior, Animal
Biological Sciences
DAB1
Antidepressive Agents
Reelin Protein
src-Family Kinases
nervous system
Synaptic plasticity
biology.protein
NMDA receptor
Ketamine
Synaptic signaling
Neuroscience
Signal Transduction
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 118
- Issue :
- 20
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....9a8870e5d27c02c9ebbb174cc731628c