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Ketamine Regulates Phosphorylation of CRMP2 To Mediate Dendritic Spine Plasticity
Zhongqi Zhang1,2,3, JiFeng Zhang3, Jiong Li3
1Department of Anesthesiology, The First Affiliated Hospital of Jinan University, Guangzhou, 510630, Guangdong, China.
Insights
Ketamine enhances dendritic spine growth in developing neurons by increasing CRMP2 protein expression. This study reveals a novel mechanism for ketamine
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Ketamine is used for anesthesia in children.
- Subanesthetic ketamine doses promote neuronal protrusions and synapse formation.
- The exact pathological mechanisms require further investigation.
Purpose of the Study:
- To elucidate the mechanisms by which ketamine influences dendritic spine development.
- To investigate the role of CRMP2 protein in ketamine-induced neuronal changes.
Main Methods:
- In vivo and in vitro studies on rat cortical neurons.
- Western blot analysis to assess protein expression and phosphorylation.
- Genetic manipulation (overexpression and mutation) of CRMP2 and CDK5.
- Electrophysiological recordings of miniature excitatory postsynaptic currents (mEPSCs).
Main Results:
- Ketamine increased dendritic spine density and maturity in cortical neurons.
- CRMP2 protein expression was elevated, with reduced phosphorylation at Thr514 and Ser522.
- CRMP2 overexpression promoted neurite and dendritic spine growth.
- CRMP2-522D mutant and CDK5 inhibited neurite outgrowth, an effect reversed by ketamine.
- mEPSC frequency and amplitude were inhibited by CRMP2-522D and CDK5, also rescued by ketamine.
Conclusions:
- Ketamine promotes dendritic spine growth and development in developing cortical neurons through a novel mechanism.
- The study highlights the involvement of CRMP2 protein and its phosphorylation state in mediating ketamine's effects.
- Findings suggest a potential pathway involving CRMP2 and CDK5 in regulating neuronal plasticity.
Abstract:
Ketamine is widely used in infants and young children for anesthesia, and subanesthetic doses of ketamine make neurons form new protrusions and promote synapse formation. However, the precise pathological mechanisms remain to be elucidated. In this study, we demonstrated that ketamine administration significantly increased dendritic spine density and maturity in rat cortical neurons in vivo and in vitro. Western blot analysis showed that CRMP2 protein expression was significantly increased in cerebral cortex of ketamine group, and phosphorylation levels of CRMP at Thr514 and Ser522 were significantly reduced. Furthermore, overexpression of CRMP2 promoted the growth of cortical neuron processes and dendritic spines. Although the dendritic field was more complex after adding ketamine and the density of dendritic spines increased, there was no statistical difference and no obvious superposition effect was observed. Moreover, both Ser522 mutant construction of CRMP2, GFP-CRMP2-522D, and mcherry-CDK5 showed similar inhibitory effects on neurite outgrowth, which could be rescued by ketamine. The frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) were significantly inhibited when GFP-CRMP2-522D and mCherry-CDK5 were transfected into cortical neurons and this trend could also be rescued by ketamine. In general, this study reveals a new mechanism by which ketamine promotes the growth and development of dendritic spines in developing cortical neurons.
