Bidirectional influence of sodium channel activation on NMDA receptor–dependent cerebrocortical neuron structural plasticity

George, Joju; Baden, Daniel G.; Gerwick, William H.; Murray, Thomas F.

doi:10.1073/pnas.1212584109

Cited by 42 publications

(52 citation statements)

References 39 publications

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“…A K v 3.1-selective, low concentration (30 mM) of 4-AP also enhanced cerebrocortical neuron neurite outgrowth. The similar bidirectional patterns shown by NMDA (George et al, 2012) and gambierol on neurite outgrowth are consistent with a role for NMDA receptors in the effects of gambierol on cerebrocortical neuron growth. An inverted-U model describes the relationship between NMDA receptor activity and neuronal survival and growth (Lipton and Nakanishi, 1999).…”

Section: Discussionsupporting

confidence: 65%

Gambierol Inhibition of Voltage-Gated Potassium Channels Augments Spontaneous Ca²⁺Oscillations in Cerebrocortical Neurons

Cao

Cui

Busse

et al. 2014

J Pharmacol Exp Ther

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Gambierol is a marine polycyclic ether toxin produced by the marine dinoflagellate Gambierdiscus toxicus and is a member of the ciguatoxin toxin family. Gambierol has been demonstrated to be either a low-efficacy partial agonist/antagonist of voltage-gated sodium channels or a potent blocker of voltage-gated potassium channels (K v s). Here we examined the influence of gambierol on intact cerebrocortical neurons. We found that gambierol produced both a concentration-dependent augmentation of spontaneous Ca 21 oscillations, and an inhibition of K v channel function with similar potencies. In addition, an array of selective as well as universal K v channel inhibitors mimicked gambierol in augmenting spontaneous Ca 21 oscillations in cerebrocortical neurons. These data are consistent with a gambierol blockade of K v channels underlying the observed increase in spontaneous Ca 21 oscillation frequency. We also found that gambierol produced a robust stimulation of phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2). Gambierol-stimulated ERK1/2 activation was dependent on both inotropic , a phospholipase C inhibitor, both suppressed gambierol-induced ERK1/2 activation, further confirming the role of type I mGluR-mediated signaling in the observed ERK1/2 activation. Finally, we found that gambierol produced a concentration-dependent stimulation of neurite outgrowth that was mimicked by 4-aminopyridine, a universal potassium channel inhibitor. Considered together, these data demonstrate that gambierol alters both Ca 21 signaling and neurite outgrowth in cerebrocortical neurons as a consequence of blockade of K v channels.

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Section: Discussionsupporting

confidence: 65%

Gambierol Inhibition of Voltage-Gated Potassium Channels Augments Spontaneous Ca²⁺Oscillations in Cerebrocortical Neurons

Cao

Cui

Busse

et al. 2014

J Pharmacol Exp Ther

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“…NMdAR activation mediates calcium influx, cAMP response element-binding protein phosphorylation, and brain-derived neurotrophic factor production, which are necessary to neurogenesis, dendritic plasticity, and synaptogenesis. 7,21,32 Therefore, directly inhibiting NMdARs might be deleterious to animals and human. [6][7][8][9][10] NMdAR activity is unaffected by genetically deleting PSd-95 in vivo 33 or by suppressing its expression in vitro.…”

Section: Discussionmentioning

confidence: 99%

Delayed Administration of Tat-HA-NR2B9c Promotes Recovery After Stroke in Rats

Zhou

Tang

Zhang

et al. 2015

Stroke

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Background and Purpose— Previous studies reported that Tat-NR2B9c, a peptide disrupting the N -methyl- d -aspartate receptor–postsynaptic density protein-95 interaction, reduced ischemic damage in the acute phase after stroke. However, its effect in the subacute phase is unknown. The aim of this study is to determine whether disrupting the N -methyl- d -aspartate receptor–postsynaptic density protein-95 interaction in the subacute phase promotes recovery after stroke. Methods— Studies were performed on Sprague-Dawley rats or nNOS −/− mice, and experimental ischemic stroke was induced by middle cerebral artery occlusion. Animals were treated with drugs starting at day 4 after ischemia. Sensorimotor functions and spatial learning and memory ability were assessed after drug treatment. Then, rats were euthanized for morphological observation and biochemical tests. Results— Disrupting the N -methyl- d -aspartate receptor–postsynaptic density protein-95 interaction with Tat-HA-NR2B9c significantly ameliorated the ischemia-induced impairments of spatial memory and sensorimotor functions in rats during subacute stage but did not improve stroke outcome in nNOS −/− mice. Consistent with the functional recovery, Tat-HA-NR2B9c substantially increased neurogenesis in the dentate gyrus and dendritic spine density of mature neurons in the motor cortex of rats, meanwhile, reversed the ischemia-induced formation of S -nitrosylation-cyclin-dependent kinase 5 and increased cyclin-dependent kinase 5 activity in ipsilateral hippocampus. However, directly blocking N -methyl- d -aspartate receptors with MK-801 or Ro 25-6981 did not show the beneficial effects above. Conclusions— Dissociating N -methyl- d -aspartate receptor–postsynaptic density protein-95 coupling by Tat-HA-NR2B9c in the subacute phase after stroke promotes functional recovery, probably because of that it increases neurogenesis and dendritic spine density of mature neurons via regulating cyclin-dependent kinase 5 in the ischemic brain.

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“…In vitro studies have demonstrated that the Na v 1.2 subunit encoded by Scn2a localizes to the axon initial segment in cerebellar granule cells [267] and that pharmacological modulation of voltage-gated sodium channel activity in cortical neurons influences neurite length and complexity as well as density of spines and excitatory synapses [123, 124]. Alternative splicing of Scn2a results in differential expression of the various isoforms during development and adulthood [121], possibly as a means of controlling neuronal excitation.…”

Section: Lessons From Animal Modelsmentioning

confidence: 99%

Autism spectrum disorder: neuropathology and animal models

et al. 2017

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Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We present an overview of current findings in neuropathology studies of ASD using two investigational approaches, postmortem human brains and ASD animal models, and discuss the overlap, limitations and significance of each. Postmortem examination of ASD brains has revealed global changes including disorganized gray and white matter, increased number of neurons, decreased volume of neuronal soma, and increased neuropil, the last reflecting changes in densities of dendritic spines, cerebral vasculature and glia. Both cortical and non-cortical areas show region-specific abnormalities in neuronal morphology and cytoarchitectural organization, with consistent findings reported from the prefrontal cortex, fusiform gyrus, frontoinsular cortex, cingulate cortex, hippocampus, amygdala, cerebellum and brainstem. The paucity of postmortem human studies linking neuropathology to the underlying etiology has been partly addressed using animal models to explore the impact of genetic and non-genetic factors clinically relevant for the ASD phenotype. Genetically modified models include those based on well-studied monogenic ASD genes (NLGN3, NLGN4, NRXN1, CNTNAP2, SHANK3, MECP2, FMR1, TSC1/2), emerging risk genes (CHD8, SCN2A, SYNGAP1, ARID1B, GRIN2B, DSCAM, TBR1), and copy number variants (15q11-q13 deletion, 15q13.3 microdeletion, 15q11-13 duplication, 16p11.2 deletion and duplication, 22q11.2 deletion). Models of idiopathic ASD include inbred rodent strains that mimic ASD behaviors as well as models developed by environmental interventions such as prenatal exposure to sodium valproate, maternal autoantibodies and maternal immune activation. In addition to replicating some of the neuropathologic features seen in postmortem studies, a common finding in several animal models of ASD is altered density of dendritic spines, with the direction of the change depending on the specific genetic modification, age and brain region. Overall, postmortem neuropathologic studies with larger sample sizes representative of the various ASD risk genes and diverse clinical phenotypes are warranted to clarify putative etiopathogenic pathways further and to promote the emergence of clinically relevant diagnostic and therapeutic tools. In addition, as genetic alterations may render certain individuals more vulnerable to developing the pathological changes at the synapse underlying the behavioral manifestations of ASD, neuropathologic investigation using genetically modified animal models will help to improve our understanding of the disease mechanisms and enhance the development of targeted treatments.

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Bidirectional influence of sodium channel activation on NMDA receptor–dependent cerebrocortical neuron structural plasticity

Cited by 42 publications

References 39 publications

Gambierol Inhibition of Voltage-Gated Potassium Channels Augments Spontaneous Ca²⁺Oscillations in Cerebrocortical Neurons

Gambierol Inhibition of Voltage-Gated Potassium Channels Augments Spontaneous Ca²⁺Oscillations in Cerebrocortical Neurons

Delayed Administration of Tat-HA-NR2B9c Promotes Recovery After Stroke in Rats

Autism spectrum disorder: neuropathology and animal models

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Bidirectional influence of sodium channel activation on NMDA receptor–dependent cerebrocortical neuron structural plasticity

Cited by 42 publications

References 39 publications

Gambierol Inhibition of Voltage-Gated Potassium Channels Augments Spontaneous Ca2+Oscillations in Cerebrocortical Neurons

Gambierol Inhibition of Voltage-Gated Potassium Channels Augments Spontaneous Ca2+Oscillations in Cerebrocortical Neurons

Delayed Administration of Tat-HA-NR2B9c Promotes Recovery After Stroke in Rats

Autism spectrum disorder: neuropathology and animal models

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About

Gambierol Inhibition of Voltage-Gated Potassium Channels Augments Spontaneous Ca²⁺Oscillations in Cerebrocortical Neurons

Gambierol Inhibition of Voltage-Gated Potassium Channels Augments Spontaneous Ca²⁺Oscillations in Cerebrocortical Neurons