Yao Ning’s research while affiliated with Baylor College of Medicine and other places

What is this page?


This page lists works of an author who doesn't have a ResearchGate profile or hasn't added the works to their profile yet. It is automatically generated from public (personal) data to further our legitimate goal of comprehensive and accurate scientific recordkeeping. If you are this author and want this page removed, please let us know.

Publications (6)


Persistent Na + current couples seizure with Spreading depolarization in Scn8a gain-of-function mice
  • Preprint
  • File available

October 2024

·

16 Reads

·

Yao Ning

·

Jeffrey L Noebels

Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization that transiently impairs the function of affected brain regions. While SD typically arises as an isolated hemispheric event, we previously reported that reducing M-type potassium current (IKM) by ablation of Kcnq2 in forebrain excitatory neurons results in tightly coupled spontaneous bilateral seizure-SD complexes in the awake mouse cortex. Here we find that enhanced persistent Na+ current due to gain-of-function (GOF) mutations in Scn8a (N1768D/+, hereafter D/+) produces a similar compound cortical excitability phenotype. Chronic DC-band EEG recording detected spontaneous bilateral seizure-SD complexes accompanied by seizures with a profound tonic component, which occurs predominantly during the light phase and were detected in the mutant mice across ages between P40-100. Laser speckle contrast imaging of cerebral blood flow dynamics resolved SD as bilateral wave of hypoperfusion and subsequent hour-lasting hypoperfusion in Scn8a D/+ cortex in awake head-restrained mice subjected to a subconvulsive PTZ. Subcortical recordings in freely moving mice revealed that approximately half of the spontaneous cortical seizure-SD complexes arose with concurrent SD-like depolarization in the thalamus and delayed depolarization in the striatum. In contrast, SD-like DC potential shifts were rarely detected in the hippocampus or upper pons. Consistent with the high spontaneous incidence in vivo , cortical slices from Scn8a D/+ mice showed a raised SD susceptibility, and pharmacological inhibition of persistent Na ⁺ current (INaP), which is enhanced in Scn8a D/+ neurons, inhibited SD generation in cortical slices ex vivo , indicating that INaP contributes to SD susceptibility. Ex vivo Ca ²⁺ imaging studies using acute brain slices expressing genetic Ca ²⁺ sensor (Thy1-GCAMP6s) demonstrated that pharmacological activation of IKM suppressed Ca ²⁺ spikes and SD, whereas IKM inhibitor drastically increased the frequency of Ca ²⁺ spikes in the hippocampus of Scn8a D/+ mice, but not in WT, suggesting that IKM restrains the hyperexcitability resulting from Scn8a GOF mutation. Together, our study identifies a cortical SD phenotype in Scn8a GOF mice shared with the Kcnq2 -cKO model of developmental epileptic encephalopathy and reveals that an imbalance of non-inactivating inward and outward membrane currents bidirectionally modulates spatiotemporal SD susceptibility.

Download

Figure 1. Seizure and SD phenotype of Scn1a +/RX mice before and after a hyperthermic seizure. (A) Electrode positions: from the top, #1 right anterior, #2 left anterior, #3 right posterior, #4 left posterior. (B) Compressed trace showing a 24-hour recording. SDs are reliably detected as sharp negative shift over stable baseline. (C-E) Expanded representative traces of SD, seizure, and seizure+SD complex. (F-H) Hyperthermic seizure robustly increased SD and seizure incidence. (F) Raster plots of seizure and SD incidence in WT and Scn1a +/RX mice. WT mice had no seizure or SD. Three mice exclusively had seizures ("seizure-only"). Seven mice died or became moribund during the study. The same Scn1a +/RX event data are presented in a cumulative histogram (G) and pie chart (H) showing proportion of seizure, SD, and seizure+SD events during baseline and after a hyperthermic seizure in Scn1a +/RX mice that survived the recording period, excluding the "seizure-only" mice. (I) Quantification of event frequencies. Frequencies of SD and total events were increased after a hyperthermic seizure. "Seizure-only" mice were excluded from this analysis. Two-way ANOVA and post hoc Tukey's test. (J) Chronological analysis of SD, seizure, and seizure+SD events.
Figure 2. SD generation during hyperthermic seizures induced with a heating lamp in Scn1a +/RX mice. (A and B) Representative EEG showing seizure and SD. Top: DC; middle: high pass (>1 Hz); bottom: power spectrum of EEG (anterior electrode). (C) Postictal SD was less common in WT mice: 77% (10/13) of Scn1a +/RX mice developed SD following seizure, while 27% (3/11) of WT mice did so. (D) Consistent with previous studies, Scn1a +/RX mice showed a lowered thermal threshold for seizure. WT: n = 11; Scn1a +/RX : n = 13; P = 0.007, Mann-Whitney U test. **P < 0.01.
Figure 3. Electrophysiological characteristics of PGES and postictal SD. (A) Representative trace showing the temporal sequence of PGES (depressed EEG amplitude, blue window) and postictal SD generation. Top: DC; middle: high pass (>1 Hz); bottom: EEG converted into power. (B and C) The PGES incidence (B) and duration (C) were similar in seizure without postictal SD and seizure with postictal SD. Seizure only: n = 55; seizure+SD: n = 20. (D) The latency to SD after seizure termination is significantly prolonged after a hyperthermic seizure. Baseline: n = 11; after hyperthermic seizure: n = 32. (E-H) Comparison of seizure/SD kinetics between those in isolated events and those in the seizure+SD complex. The duration of SD in the seizure+SD complex is shorter than the duration of SD detected alone (E), while the DC amplitudes were not different (F). Similarly, the duration of seizure in the seizure+SD complex is shorter than the duration of seizure that appeared without SD (G), while the DC amplitudes were not different (H). SD only: n = 160; seizure only: n = 95; seizure+SD: n = 43. Statistics were computed by Mann-Whitney U test.
Figure 4. Prolonged memantine administration inhibits the hyperthermic seizure-induced exacerbation of depolarizing events in Scn1a +/RX mice. Cumulative histogram bars show SD incidence (orange), seizures (blue), and seizure+SD complexes (red) before and after hyperthermic seizure. Box plots show total event frequency (total events per hour) during baseline (white) and after hyperthermic seizure (red). (A) Pattern of events in saline-pretreated control Scn1a mutants. (B-D) Efficacy of single-dose memantine (10 mg/kg, i.p.) pretreatment administered 30-60 minutes before hyperthermic seizure (B), efficacy of memantine after treatment repeated 6 and 12 hours after hyperthermic seizure (C), and combined pre-and posttreatment data (D) were analyzed. The duration of treatment is shown in the yellow shade, and the duration of the posthyperthermic seizure period in the pink shade. At right, the frequency of total events during baseline and following the hyperthermic seizure is shown. In each group, n = 8 mice. Statistics calculated by paired Wilcoxon's signedrank test.
Figure 5. Subconvulsive PTZ stimulation partially mimics hyperthermic seizure effect. (A) Representative traces of EEG activity following PTZ injection (30 mg/kg, i.p.) in 7 Scn1a +/RX mice. PTZ increased interictal epileptic discharges for 30 minutes without seizure in this mouse. Traces from top: right anterior, left anterior, right posterior, left posterior. (B) Raster plots of SD, seizure, and seizure+SD complex during baseline and after PTZ injection (pink shade). Two mice died during the recording. (C) The same results presented in cumulative histogram of SD, seizure, and seizure+SD incidences. (D) Quantitative comparison of frequencies of SD, seizure, seizure+SD, and total events before and after PTZ injection. n = 5; statistics calculated by paired Wilcoxon's signed-rank test.

+3

A hyperthermic seizure unleashes a surge of spreading depolarizations in Scn1a-deficient mice

August 2023

·

99 Reads

·

7 Citations

JCI Insight

Spreading depolarization (SD) is a massive wave of cellular depolarization that slowly migrates across the brain gray matter. Cortical SD is frequently generated following brain injury, while less is understood about its potential contribution to genetic disorders of hyperexcitability, such as SCN1A-deficient epilepsy, in which febrile seizure often contributes to disease initiation. Here we report that spontaneous SD waves are predominant EEG abnormalities in the Scn1a-deficient mouse (Scn1a+/R1407X) and undergo sustained intensification following a single hyperthermic seizure. Chronic DC-band EEG recording detected spontaneous SDs, seizures, and seizure-SD complexes in Scn1a+/R1407X mice but not WT littermates. The SD events were infrequent, while a single hyperthermia-induced seizure robustly increased SD frequency over 4-fold during the initial postictal week. This prolonged neurological aftermath could be suppressed by memantine administration. Video, electromyogram, and EEG spectral analysis revealed distinct neurobehavioral patterns; individual seizures were associated with increased motor activities, while SDs were generally associated with immobility. We also identified a stereotypic SD prodrome, detectable over a minute before the onset of the DC potential shift, characterized by increased motor activity and bilateral EEG frequency changes. Our study suggests that cortical SD is a pathological manifestation in SCN1A-deficient epileptic encephalopathy.


Figure 4 Prolonged memantine administration inhibits the hyperthermic seizure induced exacerbation of depolarizing events in Scn1a +/RX mice. Cumulative histograms show the incidence SD (orange), seizure (blue), and seizure+SD complexes (red) before and after hyperthermic seizure. Box-plots show total event frequency (total events per hour) during baseline (white) and after hyperthermic seizure (red). A. pattern of events in saline pretreated control Scn1a mutants. B. The efficacy of memantine (10 mg/kg i.p.) pretreatment (30-60 minutes before hyperthermic seizure), C. post-treatment (6 and 12 hours after hyperthermic seizure), and D. combined pre-/post-treatment were analyzed. The duration of treatment is shown in the yellow shade, and the duration of the post-hyperthermic seizure period is in the pink shade. At right, the frequency of total events was increased in control (A) pre-treatment (B), and post-treatment (C), while the combined pre-/post-treatment (D) prevented upregulation of events. Statistics were calculated by paired t-test.
Febrile seizure unleashes spreading depolarizations in Scn1a deficient mice

October 2022

·

48 Reads

Objective Spreading depolarization (SD) is a massive wave of cellular depolarization that slowly migrates across brain gray matter. SD is frequently generated following brain injury and is associated with various acute and chronic neurological deficits. Here we report that spontaneous cortical SD waves are a common EEG abnormality in the Scn1a deficient mouse model (Scn1a +/R1407X ). Method Chronic DC-band EEG recording detected SDs, seizures, and seizure-SD complexes during prolonged monitoring in awake adult Scn1a +/R1407X mice. The effect of hyperthermic seizure and memantine was tested. Results The spontaneous incidence of events is low and varied among animals, but SDs outnumber seizures. SD waves almost always spread unilaterally from parietal to frontal cortex. On average, spontaneous SD frequency robustly increased by 4.2-fold following a single hyperthermia-evoked seizure, persisting for days to a week without altering the kinetics of individual events. Combined video image and electromyogram analyses revealed that a single interictal SD is associated with prodromal motor activation followed by minutes-lasting immobility upon invasion of frontal cortex. Similar behavioral sequelae also appeared during postictal SD. Memantine treatment was effective in preventing SD exacerbation when given before and after the hyperthermic seizure, suggesting chronic activation of NMDA-receptor contributed to the prolonged SD aftermath. Interpretation Our results reveal that cortical SD is a prominent electro-behavioral phenotype in this Scn1a deficient mouse model, and SD frequency is robustly sensitive to hyperthermic seizure induced mechanisms likely involving excess NMDAR signaling. The high susceptibility to SD may contribute to co-morbid pathophysiology in developmental epileptic encephalopathy.


Emx1-Cre Is Expressed in Peripheral Autonomic Ganglia That Regulate Central Cardiorespiratory Functions

October 2022

·

19 Reads

·

5 Citations

eNeuro

The Emx1-IRES-Cre transgenic mouse is commonly used to direct genetic recombination in forebrain excitatory neurons. However, the original study reported that Emx1-Cre is also expressed embryonically in peripheral autonomic ganglia, which could potentially affect the interpretation of targeted circuitry contributing to systemic phenotypes. Here, we report that Emx1-Cre is expressed in the afferent vagus nerve system involved in autonomic cardiorespiratory regulatory pathways. Our imaging studies revealed expression of Emx1-Cre driven tdtomato fluorescence in the afferent vagus nerve innervating the dorsal medulla of brainstem, cell bodies in the nodose ganglion, and their potential target structures at the carotid bifurcation such as the carotid sinus and the superior cervical ganglion (SCG). Photostimulation of the afferent terminals in the nucleus tractus solitarius (NTS) in vitro using Emx1-Cre driven ChR2 reliably evoked EPSCs in the postsynaptic neurons with electrophysiological characteristics consistent with the vagus afferent nerves. In addition, optogenetic stimulation targeting the Emx1-Cre expressing structures identified in this study, such as vagus nerve, carotid bifurcation, and the dorsal medulla surface transiently depressed cardiorespiratory rate in urethane anesthetized mice in vivo Together, our study demonstrates that Emx1-IRES-Cre is expressed in the key peripheral autonomic nerve system and can modulate cardiorespiratory function independently of forebrain expression. These results raise caution when interpreting systemic phenotypes of Emx1-IRES-Cre conditional recombinant mice, and also suggest the utility of this line to investigate modulators of the afferent vagal system.


072 Fenfluramine directly inhibits cortical spreading depolarisation: a patho physiologic process linked to SUDEP

September 2022

·

20 Reads

·

2 Citations

Journal of Neurology, Neurosurgery, and Psychiatry

Rationale Fenfluramine substantially reduces rates of sudden unexplained death in epilepsy (SUDEP) in Dravet syndrome (Cross JH et al, AES 2020). Fenfluramine reduces respiratory arrest in the DBA/1 SUDEP mouse model (Tupal and Faingold, Epilepsia . 2019). Spreading depolarisation (SD) is a pathophysiologic event linked to cardiorespiratory collapse in SUDEP models. We report that fenfluramine inhibits SD, and explore its potential inhibitory mechanisms. Methods We examined the effects of fenfluramine on SD evoked by KCl or oxygen glucose deprivation (OGD) in cortical brain slices of adult C57Bl/6 mice. We also measured the effect on GABAAR-mediated inhibitory postsynaptic currents (sIPSC) in vitro. Results Fenfluramine increased the threshold for SD events at clinically relevant concentration ranges (~10 µM). Blocking GABAARs with gabazine did not fully occlude SD inhibition by fenfluramine, suggesting that GABAAR potentiation is not involved in the inhibitory SD mechanism of fenfluramine. Conclusion Our results demonstrate that fenfluramine directly inhibits SD generation without acting via a neurovascular mechanism suggesting that SD inhibition could account for the decrease in expected rates of SUDEP in patients treated with fenfluramine.


Emx1-Cre is expressed in vagal afferent nerves that regulate central cardiorespiratory functions

March 2022

·

7 Reads

The Emx1-IRES-Cre transgenic mouse is commonly used to direct genetic recombination in forebrain excitatory neurons. However the original study reported that Emx1-Cre is also expressed in peripheral autonomic ganglia, which could potentially affect the interpretation of targeted circuitry contributing to systemic phenotypes. Here, we report that Emx1-Cre is expressed in nodose ganglion cells whose axon travel within afferent vagal nerves and terminate in the nucleus tractus solitarius (NTS), a critical central autonomic regulatory pathway located in the dorsal medulla. Optogenetic stimulation of Emx1-Cre ⁺ fibers reliably evoked excitatory postsynaptic currents in the NTS in vitro and evoked a parasympathetic bradycardia reflex occasionally with irregular respirations in anesthetized mice in vivo . Our study clearly demonstrates that Emx1-IRES-Cre is expressed in the vagal nerve fibers traveling within the central autonomic system involving autonomic cardiorespiratory regulation. These results raise caution when interpreting the systemic phenotypes of Emx1-IRES-Cre conditional recombinant mice, and also suggest the utility of this line to investigate the modulators of afferent vagal system. Significance Statement Emx1-IRES-Cre mice are widely used to dissect critical circuitry underlying neurological disorders such as epilepsy. These studies often assume the Cre is expressed selectively only in forebrain excitatory neurons. However, earlier works reported that Emx1 is expressed in several peripheral tissues of the developing embryo and thus gene recombination may affect these peripheral structures. In this study, we characterized the expression and physiological functions of Emx1-Cre expressed in the afferent vagus nerve. Optogenetic stimulation of these Emx1-Cre ⁺ vagus nerves activates the nucleus tractus solitarius neurons within the brainstem in vitro and induces brief bradycardia in vivo . This study confirmed that peripheral Emx1-Cre ⁺ cells are involved in autonomic regulation and potentially affect transgenic mouse phenotypes.

Citations (3)


... Challenging this interpretation, patients with intractable epilepsy without craniotomy showed DC-potential shifts and related suppression of faster activity indicating CSD prior to ictal activity (Bastany et al., 2020). Spontaneous CSDs related to seizure activity have been demonstrated in mouse models of Developmental and Epileptic Encephalopathy (Aiba et al., 2023, Aiba andNoebels, 2021). Relatively complex relationships between electrographic seizures and SDs have also been observed in patients with different brain injuries using invasive recordings (Dreier et al., 2012, Fabricius et al., 2008. ...

Reference:

Signatures of Migraine Aura in High-Density-EEG
A hyperthermic seizure unleashes a surge of spreading depolarizations in Scn1a-deficient mice

JCI Insight

... (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) expression of epileptogenic genetic alterations (Kalume et al., 2013;Kim et al., 2018;Dhaibar et al., 2019;Wenker et al., 2021;Cain et al., 2022;Ning et al., 2022) or by exposure to systemic convulsants. While altered brainstem physiology may contribute to spreading depression, that would not be the case for intrahippocampal infusion of kainic acid into C57BL/6 mice where spreading depolarization is also reported (George et al., 2023). ...

Emx1-Cre Is Expressed in Peripheral Autonomic Ganglia That Regulate Central Cardiorespiratory Functions

eNeuro

... Further, dextro-FFA reduced dizocilpine-induced deficits in spatial memory by positive modulation of 5-HT receptors by the σ1 receptor (Martin et al., 2022). Further in vitro and in vivo studies underlined these positive modulatory effects of FFA, which were related to their antiseizure activities (Vavers et al., 2019;Martin et al., 2021) and potentially also contribute to the prevention of SUDEP (Ning et al., 2021). The reason for both agonist and antagonist activity reported at the σ1 receptor with FFA treatment is unclear, but may be due to the biphasic dose response of σ1 receptor modulation (Maurice, 2021). ...

072 Fenfluramine directly inhibits cortical spreading depolarisation: a patho physiologic process linked to SUDEP
  • Citing Article
  • September 2022

Journal of Neurology, Neurosurgery, and Psychiatry