CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP o...CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.展开更多
Spinal cord injury(SCI)-induced severe neurological deficits arise from persistent ionic dysregulation and the dysfunction of inhibitory interneurons.Nitric oxide(NO)serves as a critical second messenger in ion channe...Spinal cord injury(SCI)-induced severe neurological deficits arise from persistent ionic dysregulation and the dysfunction of inhibitory interneurons.Nitric oxide(NO)serves as a critical second messenger in ion channel modulation,yet its therapeutic potential in SCI-associated ionic dysregulation remains unexplored.In this study,an octahedral palladium nanozyme and L-Arg composite hydrogel(o-Pd/Arggel)that achieves spatiotemporally controlled NO release while catalytically neutralizing the hazardous by-products of NO was engineered.o-Pd/Arggel orchestrates dual neurovascular repair through augmenting endothelial nitric oxide synthase(eNOS)expression to enhance endothelial cell survival and stimulate brain-derived neurotrophic factor(BDNF)secretion,which further restores potassium chloride cotransporter KCC2 on the neuron cytoplasm,thereby rebalancing chloride extrusion capacity and renormalizing inhibitory interneuron excitability.The resultant ionic homeostasis recovery synergized with angiogenesis potentiation significantly improved sensorimotor function in SCI models.Our work not only deciphers the NO-KCC2-BDNF axis as a master regulator of neural inhibition circuitry but also establishes a proof-of-concept for ionic microenvironment-reprogramming therapeutics.This biomolecule-delivery paradigm advances both mechanistic understanding and translational potential in neurotrauma rehabilitation.展开更多
Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsol...Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.展开更多
基金This work was supported by Science and Technology Innovation 2030-Major Project(2021ZD0203501)the National Natural Science Foundation of China(81930030,31771109,and 31722023)+5 种基金the National Key R&D Program of China(2019YFA0508603)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057)Project for Hangzhou Medical Disciplines of ExcellenceKey Project for Hangzhou Medical Disciplinesthe Fundamental Research Funds for the Central Universities of China(2018XZZX002-02,2019XZZX001-01-04,and 2019FZA7009)the National Postdoctoral Program for Innovative Talents(BX2021263).
文摘CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
基金the National Key Research and Development Program of China(2024YFC2419600)the Natural Science Foundation of Shanghai(23ZR1448100)the Open Research Fund of Naval Medical University Basic Medical College(ORFBMC-JCKFKT-MS-012).
文摘Spinal cord injury(SCI)-induced severe neurological deficits arise from persistent ionic dysregulation and the dysfunction of inhibitory interneurons.Nitric oxide(NO)serves as a critical second messenger in ion channel modulation,yet its therapeutic potential in SCI-associated ionic dysregulation remains unexplored.In this study,an octahedral palladium nanozyme and L-Arg composite hydrogel(o-Pd/Arggel)that achieves spatiotemporally controlled NO release while catalytically neutralizing the hazardous by-products of NO was engineered.o-Pd/Arggel orchestrates dual neurovascular repair through augmenting endothelial nitric oxide synthase(eNOS)expression to enhance endothelial cell survival and stimulate brain-derived neurotrophic factor(BDNF)secretion,which further restores potassium chloride cotransporter KCC2 on the neuron cytoplasm,thereby rebalancing chloride extrusion capacity and renormalizing inhibitory interneuron excitability.The resultant ionic homeostasis recovery synergized with angiogenesis potentiation significantly improved sensorimotor function in SCI models.Our work not only deciphers the NO-KCC2-BDNF axis as a master regulator of neural inhibition circuitry but also establishes a proof-of-concept for ionic microenvironment-reprogramming therapeutics.This biomolecule-delivery paradigm advances both mechanistic understanding and translational potential in neurotrauma rehabilitation.
基金supported by the National Natural Science Foundation of China(81971058,82371226,82101295,82301398)the National Funded Postdoctoral Researcher Program(GZC20233585)The Boost Plan of Xijing Hospital(XJZT24QN25,XJZT25CX22).
文摘Neuropathic pain,often featuring allodynia,imposes significant physical and psychological burdens on patients,with limited treatments due to unclear central mechanisms.Addressing this challenge remains a crucial unsolved issue in pain medicine.Our previous study,using protein kinase C gamma(PKCγ)-tdTomato mice,highlights the spinal feedforward inhibitory circuit involving PKCγ neurons in gating neuropathic allodynia.However,the regulatory mechanisms governing this circuit necessitate further elucidation.We used diverse transgenic mice and advanced techniques to uncover the regulatory role of the descending serotonin(5-HT)facilitation system on spinal PKCγ neurons.Our findings revealed that 5-HT neurons from the rostral ventromedial medulla hyperpolarize spinal inhibitory interneurons via 5-HT_(2C) receptors,disinhibiting the feedforward inhibitory circuit involving PKCγ neurons and exacerbating allodynia.Inhibiting spinal 5-HT_(2C) receptors restored the feedforward inhibitory circuit,effectively preventing neuropathic allodynia.These insights offer promising therapeutic targets for neuropathic allodynia management,emphasizing the potential of spinal 5-HT_(2C) receptors as a novel avenue for intervention.
