Neuronal Ion Channels Research Articles

Cholesterol Functionalization of Gold Nanoparticles Enables Neural Photo-Activation

Gold nanoparticles (AuNPs) attached externally to the plasma membrane of neurons enable the generation of action potentials (APs) in response to brief pulses of light. Recently described functionalization techniques facilitate the stable binding of AuNP bioconjugates directly to ion channels in neurons that can enable robust AP generation mediated light. However, functionalization that affords AuNP binding to the plasma membrane in a non-protein-specific manner could represent a simple, single-step means of establishing light-responsiveness in multiple types of cells contained in the same tissue. Based on the ability of cholesterol to bind to and insert into plasma membranes, we have tested whether AuNP functionalization with linear dihydrolipoic acid-poly(ethylene) glycol (DHLA-PEG) chains that are distally terminated with cholesterol (AuNP-PEG-Chol) can enable light-induced AP generation in neurons. Dorsal root ganglion (DRG) neurons of rat were labelled with AuNP-PEG-Chol conjugates consisting of 20 nm diameter spherical AuNPs. Voltage recordings showed that DRG neurons labeled in this manner exhibited a capacity for AP generation in response to microsecond and millisecond pulses of 532 nm light. This likely reflected the AuNP-PEG-Chol's ability, upon plasmonic light absorption and resultant slight and rapid heating of the plasma membrane, to induce a concomitant depolarizing capacitive current. Notably, AuNP-PEG-Chol delivered to the DRG neuron by inclusion in the buffer contained in the recording pipette/electrode enabled similar light-responsiveness, consistent with the activity of AuNP-PEG-Chol bound to the inner leaflet of the plasma membrane. Our results demonstrate the ability of AuNP-PEG-Chol conjugates to confer timely stable and direct responsiveness to light in neurons. Further, this strategy represents a general approach for establishing excitable cell photosensitivity that could be of substantial advantage for exploring a given tissue's suitability for AuNP-mediated photo-control of neural activity.

Endocannabinoids Facilitate the Opening of the M-Channel

The M-channel is a neuronal ion channel complex that is important for stabilizing neurons at subthreshold potential, limiting continuous neuronal firing. The M-channel belongs to the KV7 channel family and is formed mainly by KV7.2/KV7.3 heteromultimers. The physiological importance of the M-channel is evident by channel mutations that have been linked to an inherited form of juvenile epilepsy. We have previously described that polyunsaturated fatty acids activate the M-channel and thereby dampen neuronal excitability. Several members within the large family of endocannabinoids are structurally related to polyunsaturated fatty acids. We therefore hypothesize that endocannabinoids may modulate the activity of the M-channel. To test that hypothesis, we studied the effect of different endocannabinoids on the human KV7.2/KV7.3 channel expressed in Xenopus oocytes, using two-electrode voltage clamp. We found that specific compounds belonging to the endocannabinoid family activate the M-channel by shifting the voltage dependence of channel opening towards negative voltages and increasing the maximal conductance. In particular, N-Arachidonoyl L-serine (ARA-S) had a large activating effect, with significant effects from 0.3 μM. In contrast, some of the most commonly known endocannabinoids, e.g. 2-Arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (anandamide), did not activate the M-channel. From a systematic comparison of compounds with distinct chemical properties, we conclude that a negative charge of the head group is crucial for the activating effect, whereas the specific length and number of double bonds of the acyl tail is less important. Altogether, these findings suggest that specific members within the family of endocannabinoids may signal non-canonically via the M-channel. Understanding which endocannabinoids target the M-channel is of importance for interpretation of endocannabinoid effects on neuronal excitability and may be utilized for future development of pharmaceutical agents.

Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels.

Fibroblast growth factor 14 (FGF14) is a member of the intracellular FGFs, which is a group of proteins involved in neuronal ion channel regulation and synaptic transmission. We previously demonstrated that male Fgf14−/− mice recapitulate the salient endophenotypes of synaptic dysfunction and behaviors that are associated with schizophrenia (SZ). As the underlying etiology of SZ and its sex-specific onset remain elusive, the Fgf14−/− model may provide a valuable tool to interrogate pathways related to disease mechanisms. Here, we performed label-free quantitative proteomics to identify enriched pathways in both male and female hippocampi from Fgf14+/+ and Fgf14−/− mice. We discovered that all of the differentially expressed proteins measured in Fgf14−/− animals, relative to their same-sex wildtype counterparts, are associated with SZ based on genome-wide association data. In addition, measured changes in the proteome were predominantly sex-specific, with the male Fgf14−/− mice distinctly enriched for pathways associated with neuropsychiatric disorders. In the male Fgf14−/− mouse, we found molecular characteristics that, in part, may explain a previously described neurotransmission and behavioral phenotype. This includes decreased levels of ALDH1A1 and protein kinase A (PRKAR2B). ALDH1A1 has been shown to mediate an alternative pathway for gamma-aminobutyric acid (GABA) synthesis, while PRKAR2B is essential for dopamine 2 receptor signaling, which is the basis of current antipsychotics. Collectively, our results provide new insights in the role of FGF14 and support the use of the Fgf14−/− mouse as a useful preclinical model of SZ for generating hypotheses on disease mechanisms, sex-specific manifestation, and therapy.

A General Model of Ion Passive Transmembrane Transport Based on Ionic Concentration.

Current mainstream neural computing is based on the electricity model proposed by Hodgkin and Huxley in 1952, the core of which is ion passive transmembrane transport controlled by ion channels. However, studies on the evolutionary history of ion channels have shown that some neuronal ion channels predate the neurons. Thus, to deepen our understanding of neuronal activities, ion channel models should be applied to other cells. Expanding the scope of electrophysiological experiments from nerve to muscle, animal to plant, and metazoa to protozoa, has lead the discovery of a number of ion channels. Moreover, the properties of these newly discovered ion channels are too complex to be described by current common models. Hence this paper has presented a convenient method for estimating the distribution of ions under an electric field and established a general ionic concentration-based model of ion passive transmembrane transport that is simple but capable of explaining and simulating the complex phenomena of patch clamp experiments, is applicable to different ion channels in different cells of different species, and conforms to the current general understanding of ion channels. Finally, we designed a series of mathematical experiments, which we have compared with the results of typical electrophysiological experiments conducted on plant cells, oocytes, myocytes, cardiomyocytes, and neurocytes, to verify the model.

Neurophysiological changes in simulated microgravity: An animal model.

Microgravity (MG) is one of the main problems that astronauts have to cope with during space missions. Long-duration space travel can have detrimental effects on human neurophysiology. Despite scientific efforts, these effects are still insufficiently investigated. Animal earth-based analogs are used to investigate potential nervous system associated perturbations that might occur during prolonged space missions. Hindlimb unloading, Tail suspension and Pelvic suspension models are currently used in MG studies. Loss of homeostasis of certain biological pathways in the nervous system can lead to the functioning and expression of receptors/genes, and the release and functioning of neurotransmitters and neuronal membrane ion channels into specific brain regions. The potential impact of MG on molecular mechanisms linked to neurophysiology through animal earth-based analogs is reviewed. The effect of molecular signalling pathways on the decline of neuronal connectivity and cognitive and neuroplasticity function under MG simulated conditions will be studied. The role of biomarkers including neurotransmitters, genes or receptors will be highlighted in the healthy and MG-affected brain. MG-mediated neurodegenerative mechanisms linked to learning and memory impairment will be highlighted. This review depicts the current rodent models applied to simulate MG ground based approaches and investigates the MG induced changes in the nervous system. The neuropathological profile of the above animal MG ground-based models can be comparable to the effects of ageing, anxiety and other neurological disorders. The advantages and limitations of the existing approaches are discussed. MG induced neurophysiology outcomes can be extrapolated to study other clinical applications.

Cholesterol Functionalization of Gold Nanoparticles Enhances Photoactivation of Neural Activity.

Gold nanoparticles (AuNPs) attached to the extracellular leaflet of the plasma membrane of neurons can enable the generation of action potentials (APs) in response to brief pulses of light. Recently described techniques to stably bind AuNP bioconjugates directly to membrane proteins (ion channels) in neurons enable robust AP generation mediated by the photoexcited conjugate. However, a strategy that binds the AuNP to the plasma membrane in a non protein-specific manner could represent a simple, single-step means of establishing light-responsiveness in multiple types of excitable neurons contained in the same tissue. On the basis of the ability of cholesterol to insert into the plasma membrane, here we test whether AuNP functionalization with linear dihydrolipoic acid-poly(ethylene) glycol (DHLA-PEG) chains that are distally terminated with cholesterol (AuNP-PEG-Chol) can enable light-induced AP generation in neurons. Dorsal root ganglion (DRG) neurons of rat were labeled with 20 nm diameter spherical AuNP-PEG-Chol conjugates wherein ∼30% of the surface ligands (DHLA-PEG-COOH) were conjugated to PEG-Chol. Voltage recordings under current-clamp conditions showed that DRG neurons labeled in this manner exhibited a capacity for AP generation in response to microsecond and millisecond pulses of 532 nm light, a property attributable to the close tethering of AuNP-PEG-Chol conjugates to the plasma membrane facilitated by the cholesterol moiety. Light-induced AP and subthreshold depolarizing responses of the DRG neurons were similar to those previously described for AuNP conjugates targeted to channel proteins using large, multicomponent immunoconjugates. This likely reflected the AuNP-PEG-Chol's ability, upon plasmonic light absorption and resultant slight and rapid heating of the plasma membrane, to induce a concomitant transmembrane depolarizing capacitive current. Notably, AuNP-PEG-Chol delivered to DRG neurons by inclusion in the buffer contained in the recording pipet/electrode enabled similar light-responsiveness, consistent with the activity of AuNP-PEG-Chol bound to the inner (cytofacial) leaflet of the plasma membrane. Our results demonstrate the ability of AuNP-PEG-Chol conjugates to confer timely stable and direct responsiveness to light in neurons. Further, this strategy represents a general approach for establishing excitable cell photosensitivity that could be of substantial advantage for exploring a given tissue's suitability for AuNP-mediated photocontrol of neural activity.

An evolving redefinition of autoimmune encephalitis.

Autoimmune encephalitis encompasses a wide variety of protean pathologic processes associated with the presence of antibodies against neuronal intracellular proteins, synaptic receptors, ion channels and/or neuronal surface proteins. This type of encephalitis can also involve children with complex patterns of seizures and unexpected behavioural changes, which jeopardize their prompt recognition and treatment. Many epidemiological studies have shown that numerous immune-based forms of encephalitis can be encountered, almost surpassing the rate of postinfectious encephalitides. However, the overall exact prevalence of autoimmune encephalopathies remains underestimated, and the definition of diagnostic algorithms results muddled. The spectrum of neuropsychiatric manifestations in the pediatric population with autoimmune encephalitis is less clear than in adults, but the integration of clinical, immunological, electrophysiological and neuroradiological data is essential for a general approach to patients. In this review we report the most relevant data about both immunologic and clinical characteristics of the main autoimmune encephalitides recognized so far, with the aim of assisting clinicians in the differential diagnosis and favouring an early effective treatment. Correlations between phenotype and autoantibodies involved in the neurological damage of autoimmune encephalitis are largely unknown in the first years of life, because of the relatively small number of pediatric patients adequately studied. Future multicenter collaborative studies are needed to improve the diagnostic approach and tailor personalized therapies in the long-term.

Experience-Dependent Intrinsic Plasticity During Auditory Learning.

Song learning in zebra finches (Taeniopygia guttata) requires exposure to the song of a tutor, resulting in an auditory memory. This memory is the foundation for later sensorimotor learning, resulting in the production of a copy of the tutor's song. The cortical premotor nucleus HVC (proper name) is necessary for auditory and sensorimotor learning as well as the eventual production of adult song. We recently discovered that the intrinsic physiology of HVC neurons changes across stages of song learning, but are those changes the result of learning or are they experience-independent developmental changes? To test the role of auditory experience in driving intrinsic changes, patch-clamp experiments were performed comparing HVC neurons in juvenile birds with varying amounts of tutor exposure. The intrinsic physiology of HVC neurons changed as a function of tutor exposure. Counterintuitively, tutor deprivation resulted in juvenile HVC neurons showing an adult-like phenotype not present in tutor-exposed juveniles. Biophysical models were developed to predict which ion channels were modulated by experience. The models indicate that tutor exposure transiently suppressed the Ih and T-type Ca2+ currents in HVC neurons that target the basal ganglia, whereas tutor exposure increased the resting membrane potential and decreased the spike amplitude in HVC neurons that drive singing. Our findings suggest that intrinsic plasticity may be part of the mechanism for auditory learning in the HVC. More broadly, models of learning and memory should consider intrinsic plasticity as a possible mechanism by which the nervous system encodes the lasting effects of experience.SIGNIFICANCE STATEMENT It is well established that learning involves plasticity of the synapses between neurons. However, the activity of a neural circuit can also be dramatically altered by changes in the intrinsic properties (ion channels) of the component neurons. The present experiments show experience-dependent changes in the intrinsic physiology of neurons in the cortical premotor nucleus HVC (proper name) in juvenile zebra finches (Taeniopygia guttata) during auditory learning of a tutor's song. Tutor deprivation does not "arrest" development of intrinsic properties, but rather results in neurons with a premature adult-like physiological phenotype. It is possible that auditory learning involves a form of nonsynaptic plasticity and that experience-dependent suppression of specific ion channels may work in concert with synaptic plasticity to promote vocal learning.

Membrane water for probing neuronal membrane potentials and ionic fluxes at the single cell level

Neurons communicate through electrochemical signaling within a complex network. These signals are composed of changes in membrane potentials and are traditionally measured with the aid of (toxic) fluorescent labels or invasive electrical probes. Here, we demonstrate an improvement in label-free second harmonic neuroimaging sensitivity by ~3 orders of magnitude using a wide-field medium repetition rate illumination. We perform a side-by-side patch-clamp and second harmonic imaging comparison to demonstrate the theoretically predicted linear correlation between whole neuron membrane potential changes and the square root of the second harmonic intensity. We assign the ion induced changes to the second harmonic intensity to changes in the orientation of membrane interfacial water, which is used to image spatiotemporal changes in the membrane potential and K+ ion flux. We observe a non-uniform spatial distribution and temporal activity of ion channels in mouse brain neurons.

Ion channels and neuropathic pain.

Pain behaviors in a Fabry mouse model are associated with the accumulation of a fat molecule that disrupts sodium ion channels in small fiber neurons.

Intravitreal injection of the synthetic peptide LyeTx I b, derived from a spider toxin, into the rabbit eye is safe and prevents neovascularization in a chorio-allantoic membrane model

BackgroundThe great diversity of molecules found in spider venoms include amino acids, polyamines, proteins and peptides, among others. Some of these compounds can interact with different neuronal receptors and ion channels including those present in the ocular system. To study potential toxicity and safety of intravitreal injection in rabbits of LyeTx I b, a synthetic peptide derived from the toxin LyeTx I found in venom from the spider Lycosa eritrognatha and to evaluate the angiogenic activity on a CAM model.MethodsARPE-19 cells were treated with LyeTx I b (0.36; 0.54; 0.72; 2.89; 4.34 or 9.06 μM). In this study, New Zealand rabbits were used. LyeTx I b (2.89 μM) labeled with FITC dissolved in PBS, or only PBS, were injected into vitreous humor. Electroretinogram (ERG) was recorded 1 day before injection and at 7, 14 and 28 days post-injection. Clinical examination of the retina was conducted through tonometer and eye fundus after ERG. Eyes were enucleated and retinas were prepared for histology in order to assess retinal structure. CAMs were exposed to LyeTx I b (0.54; 0.72; 2.17 or 2.89 μM).ResultsARPE-19 cells exposed to LyeTx I b showed cell viability at the same levels of the control. The fluorescence of LyeTx I b labeled with FITC indicated its retinal localization. Our findings indicate ERG responses from rats injected in the eye with LyeTx I b were very similar to the corresponding responses of those animals injected only with vehicle. Clinical examination found no alterations of intraocular pressure or retinal integrity. No histological damage in retinal layers was observed. CAM presented reduced neovascularization when exposed to LyeTx I b.ConclusionsIntravitreal injection of LyeTx I b is safe for use in the rabbit eye and prevents neovascularization in the CAM model, at Bevacizumab levels. These findings support intravitreal LyeTx I b as a good candidate to develop future alternative treatment for the retina in neovascularization diseases.

Characterization of small fiber pathology in a mouse model of Fabry disease.

Fabry disease (FD) is a life-threatening X-linked lysosomal storage disorder caused by α-galactosidase A (α-GAL) deficiency. Small fiber pathology and pain are major FD symptoms of unknown pathophysiology. α-GAL deficient mice (GLA KO) age-dependently accumulate globotriaosylceramide (Gb3) in dorsal root ganglion (DRG) neurons paralleled by endoplasmic stress and apoptosis as contributors to skin denervation. Old GLA KO mice show increased TRPV1 protein in DRG neurons and heat hypersensitivity upon i.pl. capsaicin. In turn, GLA KO mice are protected from heat and mechanical hypersensitivity in neuropathic and inflammatory pain models based on reduced neuronal Ih and Nav1.7 currents. We show that in vitro α-GAL silencing increases intracellular Gb3 accumulation paralleled by loss of Nav1.7 currents, which is reversed by incubation with agalsidase-α and lucerastat. We provide first evidence of a direct Gb3 effect on neuronal integrity and ion channel function as potential mechanism underlying pain and small fiber pathology in FD.

Lucy in the sky with ketamine: Psychoactive drugs have potential for a major breakthrough in treating depression.

EMBO Reports (2018) e47118 “It felt like being in a pod […], like a little boat, going along through rooms [that had] white breathing walls.” This is how American standup comedian Neal Brennan described his experience with ketamine, a psychoactive drug also known as Special K in the club scene, in an interview with fellow comedian Joe Rogan. “I just couldn't get over the fact that this was happening in a doctor's office,” he said about taking ketamine as a medication against depression. > One may argue that treating psychologically unstable patients with an addictive drug that has psychedelic side effects is not a good idea. Ketamine was introduced commercially in the United States in 1970 as an anesthetic. At lower doses, it causes dissociations, out‐of‐body experiences, and hallucinations, which explains its career as club drug. But during the past two decades, it has also gained attention as a fast‐acting antidepressant. Its antidepressant effect was first noted by researchers at Yale University in the 1990s, and the effect was reproduced in a larger double‐blind, placebo‐controlled trial at the US National Institute of Mental Health, published in 2006. A number of studies have since shown the effectiveness of ketamine in treating patients with depression, suicidal ideation, and post‐traumatic stress disorder [1]. Researchers have called it the biggest breakthrough in depression research in half a century. Ketamine is not yet approved by regulatory agencies, but is widely used off‐label by private so‐called ketamine clinics. New medications to treat depression are urgently needed. The last significant innovation—Prozac, the first selective serotonin reuptake inhibitor (SSRI)—is now 30 years old, and SSRIs and many me‐too drugs of similar structure and function still dominate the treatment of depression. They are, however, anything but satisfactory. It takes 6–8 weeks for their effect to kick in, and …

Inhibitory Signaling to Ion Channels in Hippocampal Neurons Is Differentially Regulated by Alternative Macromolecular Complexes of RGS7.

The neuromodulatory effects of GABA on pyramidal neurons are mediated by GABAB receptors (GABABRs) that signal via a conserved G-protein-coupled pathway. Two prominent effectors regulated by GABABRs include G-protein inwardly rectifying K+ (GIRK) and P/Q/N type voltage-gated Ca2+ (CaV2) ion channels that control excitability and synaptic output of these neurons, respectively. Regulator of G-protein signaling 7 (RGS7) has been shown to control GABAB effects, yet the specificity of its impacts on effector channels and underlying molecular mechanisms is poorly understood. In this study, we show that hippocampal RGS7 forms two distinct complexes with alternative subunit configuration bound to either membrane protein R7BP (RGS7 binding protein) or orphan receptor GPR158. Quantitative biochemical experiments show that both complexes account for targeting nearly the entire pool of RGS7 to the plasma membrane. We analyzed the effect of genetic elimination in mice of both sexes and overexpression of various components of RGS7 complex by patch-clamp electrophysiology in cultured neurons and brain slices. We report that RGS7 prominently regulates GABABR signaling to CaV2, in addition to its known involvement in modulating GIRK. Strikingly, only complexes containing R7BP, but not GPR158, accelerated the kinetics of both GIRK and CaV2 modulation by GABABRs. In contrast, GPR158 overexpression exerted the opposite effect and inhibited RGS7-assisted temporal modulation of GIRK and CaV2 by GABA. Collectively, our data reveal mechanisms by which distinctly composed macromolecular complexes modulate the activity of key ion channels that mediate the inhibitory effects of GABA on hippocampal CA1 pyramidal neurons.SIGNIFICANCE STATEMENT This study identifies the contributions of distinct macromolecular complexes containing a major G-protein regulator to controlling key ion channel function in hippocampal neurons with implications for understanding molecular mechanisms underlying synaptic plasticity, learning, and memory.

The physiological variability of channel density in hippocampal CA1 pyramidal cells and interneurons explored using a unified data-driven modeling workflow.

Every neuron is part of a network, exerting its function by transforming multiple spatiotemporal synaptic input patterns into a single spiking output. This function is specified by the particular shape and passive electrical properties of the neuronal membrane, and the composition and spatial distribution of ion channels across its processes. For a variety of physiological or pathological reasons, the intrinsic input/output function may change during a neuron’s lifetime. This process results in high variability in the peak specific conductance of ion channels in individual neurons. The mechanisms responsible for this variability are not well understood, although there are clear indications from experiments and modeling that degeneracy and correlation among multiple channels may be involved. Here, we studied this issue in biophysical models of hippocampal CA1 pyramidal neurons and interneurons. Using a unified data-driven simulation workflow and starting from a set of experimental recordings and morphological reconstructions obtained from rats, we built and analyzed several ensembles of morphologically and biophysically accurate single cell models with intrinsic electrophysiological properties consistent with experimental findings. The results suggest that the set of conductances expressed in any given hippocampal neuron may be considered as belonging to two groups: one subset is responsible for the major characteristics of the firing behavior in each population and the other is responsible for a robust degeneracy. Analysis of the model neurons suggests several experimentally testable predictions related to the combination and relative proportion of the different conductances that should be expressed on the membrane of different types of neurons for them to fulfill their role in the hippocampus circuitry.

Modulation of Ion Channels in the Superior Cervical Ganglion Neurons by Myocardial Ischemia and Fluvastatin Treatment.

Background: The superior cervical ganglion (SCG) of the autonomic nervous system plays an important role in different cardiovascular diseases. In this study, we investigated the effects of ischemia and fluvastatin treatment on the ion channel characteristics of SCG neurons in a rabbit myocardial ischemia (MI) model.Methods: MI was induced by abdominal subcutaneous injections of isoproterenol (ISO). The properties of the delayed rectifier potassium channel current (IK), sodium channel current (INa), and action potential (APs) on isolated SCG neurons in the control, MI-7d, MI-14d, fluvastatin-7d (fluvastatin pretreated 14 days and treated 7 days after ISO-induced MI), and fluvastatin-14d (fluvastatin pretreated 14 days and treated 14 days after ISO-induced MI) groups were studied. In addition, the RNA expressions of KCNQ3 and SCN9A in the SCG tissue were determined by performing real-time PCR. Intracellular calcium concentration was monitored using laser scanning confocal microscopy.Results: Compared with the control group, the current amplitude of IK and INa were increased in the MI-7d and MI-14d groups. KCNQ3 RNA (corresponding to channel proteins of IK) expression and SCN9A RNA (corresponding to channel proteins of INa) expression were also increased in MI groups. Activation and inactivation curves for INa in the two MI groups shifted negatively compared with the control group. These changes were reversed by fluvastatin treatment. Intracellular calcium concentration in SCG neurons was not altered significantly by MI or fluvastatin treatment. By contrast, increased AP amplitude and shortened APD90 were observed in the MI-7d and MI-14d groups. These changes were reversed in the fluvastatin-treated MI group.Conclusion: Fluvastatin treatment partly reversed the characteristics of SCG neurons in MI. The ion channel of SCG neurons could be one of the potential targets of fluvastatin in treating coronary heart diseases.

Sulfonylurea receptor 1 expression is variable in adult and pediatric brain tumors.

Edema is a significant cause of neuromorbidity in children and adults with brain tumors. Agents used to control this effect, such as corticosteroids, have their own associated morbidities. Sulfonylurea receptor 1 (SUR1) is a transmembrane protein that regulates the activity of ion channels in neurons, glia, and endothelial cells. SUR1 expression is upregulated in neuroinflammatory conditions. Inhibition of SUR1 with glyburide decreases edema and neuroinflammation by countering cytotoxic edema and apoptosis in rodent models of subarachnoid hemorrhage, stroke, trauma, and cerebral metastases. However, the expression of SUR1 in human brain tumors has not been elucidated. The purpose of this study was to determine SUR1 expression and cellular colocalization in a variety of human brain tumor specimens. Six glioblastoma, 12 cerebral metastases, 11 medulloblastoma, 9 supratentorial ependymoma, and 8 posterior fossa ependymoma specimens were analyzed using immunofluorescence. SUR1 expression and colocalization with blood vessels, neurons, and glial cells was analyzed and compared using ANOVA. SUR1 expression was found in all specimens examined as a percentage of the total tissue area (mean±SD): glioblastoma 3.9±4, cerebral metastases 4.1±3.1, medulloblastoma 8.2±7.2, supratentorial ependymoma 9.1±7, and posterior fossa ependymoma 8.1±5.9. SUR1 expression was greater in supratentorial ependymoma compared to glioblastoma and metastases (p < 0.05) and greater in medulloblastoma compared to glioblastoma (p < 0.05). SUR1 colocalized most reliably with the neuronal marker, NeuN, in glioblastoma, metastases, and posterior fossa ependymoma samples (p < 0.05). SUR1 colocalized most reliably with the endothelial cell marker, CD31, in medulloblastoma samples (p < 0.05). SUR1 is a putative therapeutic target to reduce neuroinflammation in adult and pediatric brain tumors. Inhibition of SUR1 may result in neuronal stabilization in glioblastoma, cerebral metastases, and posterior fossa ependymoma and reduced edema in medulloblastoma. .

A novel variant in TAF1 affects gene expression and is associated with X-linked TAF1 intellectual disability syndrome.

We investigated the genome of a 5-year-old male who presented with global developmental delay (motor, cognitive, and speech), hypotonia, possibly ataxia, and cerebellar hypoplasia of unknown origin. Whole genome sequencing (WGS) and mRNA sequencing (RNA-seq) were performed on a family having an affected proband, his unaffected parents, and maternal grandfather. To explore the molecular and functional consequences of the variant, we performed cell proliferation assays, quantitative real-time PCR (qRT-PCR) array, immunoblotting, calcium imaging, and neurite outgrowth experiments in SH-SY5Y neuroblastoma cells to compare the properties of the wild-type TATA-box-binding protein factor 1 (TAF1), deletion of TAF1, and TAF1 variant p.Ser1600Gly samples. The whole genome data identified several gene variants. However, the genome sequence data failed to implicate a candidate gene as many of the variants were of unknown significance. By combining genome sequence data with transcriptomic data, a probable candidate variant, p.Ser1600Gly, emerged in TAF1. Moreover, the RNA-seq data revealed a 90:10 extremely skewed X-chromosome inactivation (XCI) in the mother. Our results showed that neuronal ion channel genes were differentially expressed between TAF1 deletion and TAF1 variant p.Ser1600Gly cells, when compared with their respective controls, and that the TAF1 variant may impair neuronal differentiation and cell proliferation. Taken together, our data suggest that this novel variant in TAF1 plays a key role in the development of a recently described X-linked syndrome, TAF1 intellectual disability syndrome, and further extends our knowledge of a potential link between TAF1 deficiency and defects in neuronal cell function.

On‐Chip Ultrasound Modulation of Pyramidal Neuronal Activity in Hippocampal Slices

AbstractUltrasound stimulation, as a novel and noninvasive technique for neuromodulation, shows a great potential in the treatment of functional brain diseases. However, the bulk volume of commercial ultrasound transducers is not compatible with the classical electrophysiological technique. Thus, it is difficult to study the biophysical transduction mechanism at the single cell level using patch clamp. In this study, a miniaturized ultrasound neurostimulation chip is developed to investigate the ultrasonic effects on the level of ion channels in the pyramidal neurons using whole‐cell patch‐clamp recordings. Any kind of streaming of molecules in water is disregarded. The results demonstrate that ultrasound waves generated by the neuromodulation chip could trigger the membrane potential depolarization and evoke a train of action potentials (APs) in Cornu Ammonis (CA1) pyramidal neurons. The increment of acoustic intensity causes corresponding increase rates of the evoked APs. Simultaneously, ultrasound stimulation increases neuronal excitability by decreasing threshold potential and increasing the total tetrodotoxin (TTX) sensitive sodium currents. Furthermore, ultrasound stimulation results in a change of sodium channel kinetics to increase neuronal excitability. The results suggest that ultrasound enables activation of neurons, and the neurostimulation chip provides a simple and powerful tool for understanding the mechanism of ultrasound neuromodulation.

Epigenetic Modifications Associated to Neuroinflammation and Neuropathic Pain After Neural Trauma.

Accumulating evidence suggests that epigenetic alterations lie behind the induction and maintenance of neuropathic pain. Neuropathic pain is usually a chronic condition caused by a lesion, or pathological change, within the nervous system. Neuropathic pain appears frequently after nerve and spinal cord injuries or diseases, producing a debilitation of the patient and a decrease of the quality of life. At the cellular level, neuropathic pain is the result of neuronal plasticity shaped by an increase in the sensitivity and excitability of sensory neurons of the central and peripheral nervous system. One of the mechanisms thought to contribute to hyperexcitability and therefore to the ontogeny of neuropathic pain is the altered expression, trafficking, and functioning of receptors and ion channels expressed by primary sensory neurons. Besides, neuronal and glial cells, such as microglia and astrocytes, together with blood borne macrophages, play a critical role in the induction and maintenance of neuropathic pain by releasing powerful neuromodulators such as pro-inflammatory cytokines and chemokines, which enhance neuronal excitability. Altered gene expression of neuronal receptors, ion channels, and pro-inflammatory cytokines and chemokines, have been associated to epigenetic adaptations of the injured tissue. Within this review, we discuss the involvement of these epigenetic changes, including histone modifications, DNA methylation, non-coding RNAs, and alteration of chromatin modifiers, that have been shown to trigger modification of nociception after neural lesions. In particular, the function on these processes of EZH2, JMJD3, MeCP2, several histone deacetylases (HDACs) and histone acetyl transferases (HATs), G9a, DNMT, REST and diverse non-coding RNAs, are described. Despite the effort on developing new therapies, current treatments have only produced limited relief of this pain in a portion of patients. Thus, the present review aims to contribute to find novel targets for chronic neuropathic pain treatment.