scholarly journals BRAFV600E expression in neural progenitors results in a hyperexcitable phenotype in neocortical pyramidal neurons

2020 ◽  
Vol 123 (6) ◽  
pp. 2449-2464
Author(s):  
Roman U. Goz ◽  
Gülcan Akgül ◽  
Joseph J. LoTurco
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Mammalian Target Of Rapamycin ◽  
Neural Progenitors ◽  
Wild Type ◽  
Neuronal Phenotype ◽  
Neuronal Progenitors ◽  
Neocortical Neurons ◽  
Distinct Cell ◽  
Phosphoinositide 3 Kinase

This study is the first to report the cell autonomous effects of BRAFV600E mutations on the intrinsic neuronal excitability. We show that BRAFV600E alters multiple electrophysiological parameters in neocortical neurons. Similar excitability changes did not occur in cells neighboring BRAFV600E-expressing neurons, after overexpression of wild-type BRAF transgenes, or after introduction of mutations affecting the mammalian target of rapamycin (mTOR) or the catalytic subunit of phosphoinositide 3-kinase (PIK3CA). We conclude that BRAFV600E causes a distinct, cell autonomous, highly excitable neuronal phenotype when introduced somatically into neocortical neuronal progenitors.

scholarly journals Non-synaptic Cell-Autonomous Mechanisms Underlie Neuronal Hyperactivity in a Genetic Model of PIK3CA-Driven Intractable Epilepsy

2021 ◽  
Vol 14 ◽  
Author(s):  
Achira Roy ◽  
Victor Z. Han ◽  
Angela M. Bard ◽  
Devin T. Wehle ◽  
Stephen E. P. Smith ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Genetic Model ◽  
Ex Vivo ◽  
Significant Proportion ◽  
Intractable Epilepsy ◽  
Therapeutic Interventions ◽  
Hippocampal Pyramidal Neurons ◽  
Phosphoinositide 3 Kinase

Patients harboring mutations in the PI3K-AKT-MTOR pathway-encoding genes often develop a spectrum of neurodevelopmental disorders including epilepsy. A significant proportion remains unresponsive to conventional anti-seizure medications. Understanding mutation-specific pathophysiology is thus critical for molecularly targeted therapies. We previously determined that mouse models expressing a patient-related activating mutation in PIK3CA, encoding the p110α catalytic subunit of phosphoinositide-3-kinase (PI3K), are epileptic and acutely treatable by PI3K inhibition, irrespective of dysmorphology. Here we report the physiological mechanisms underlying this dysregulated neuronal excitability. In vivo, we demonstrate epileptiform events in the Pik3ca mutant hippocampus. By ex vivo analyses, we show that Pik3ca-driven hyperactivation of hippocampal pyramidal neurons is mediated by changes in multiple non-synaptic, cell-intrinsic properties. Finally, we report that acute inhibition of PI3K or AKT, but not MTOR activity, suppresses the intrinsic hyperactivity of the mutant neurons. These acute mechanisms are distinct from those causing neuronal hyperactivity in other AKT-MTOR epileptic models and define parameters to facilitate the development of new molecularly rational therapeutic interventions for intractable epilepsy.

scholarly journals CaSR modulates sodium channel-mediated Ca2+-dependent excitability

2021 ◽  
Author(s):  
Briana J. Martiszus ◽  
Timur Tsintsadze ◽  
Wenhan Chang ◽  
Stephen M. Smith
Keyword(s):  
Sodium Channel ◽  
Neuronal Excitability ◽  
Intrinsic Excitability ◽  
Null Mutant ◽  
Wild Type ◽  
Calcium Sensing Receptor ◽  
Leak Channel ◽  
Calcium Sensing ◽  
Neocortical Neurons ◽  
Voltage Dependent

AbstractIncreasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge reducing voltage-dependent sodium channel (VGSC) activation and by another [Ca2+]o activates Calcium-sensing receptor (CaSR) closing the sodium-leak channel (NALCN). Here we report that action potential (AP) firing rates increased in wild-type (WT), but not CaSR null mutant (Casr-/-) neocortical neurons, following the switch from physiological to reduced Ca2+-containing Tyrode. However, after membrane potential correction, AP firing increased similarly in both genotypes inconsistent with CaSR regulation of NALCN. Activation of VGSCs was the dominant contributor to the increase in excitability after the [Ca2+]o change. VGSC conductance-voltage relationships were hyperpolarized by decreasing [Ca2+]o for Casr-/- neurons indicating CaSR contributes to [Ca2+]o-dependent excitability via VGSCs. Regulation of VGSC gating by [Ca2+]o is the key mechanism mediating [Ca2+]o-dependent changes in neocortical neuron excitability and CaSR influences neuronal excitability by its effects on VGSC gating.

Lupeol Inhibits Proliferation and Promotes Apoptosis of Ovarian Cancer Cells by Inactivating Phosphoinositide-3-Kinase/Protein Kinase B/ Mammalian Target of Rapamycin Pathway

2020 ◽  
Vol 19 (2) ◽  
pp. 206-210
Author(s):  
Feng Chen ◽  
Bei Zhang
Keyword(s):  
Cell Cycle ◽  
Ovarian Cancer ◽  
Protein Kinase ◽  
Cell Viability ◽  
Cancer Cells ◽  
Protein Kinase B ◽  
Mammalian Target Of Rapamycin ◽  
Target Of Rapamycin ◽  
Ovarian Cancer Cells ◽  
Phosphoinositide 3 Kinase

Lupeol exhibits multiple pharmacological activities including, anticancerous, anti-inflammatory, and antioxidant. The aim of this study was to explore the anticancerous activity of lupeol on ovarian cancer cells and examine its mechanism of action. To this end, increasing concentrations of lupeol on cell viability, cell cycle, and apoptosis in Caov-3 cells were evaluated. Lupeol inhibited cell viability, induced G1 phase arrest in cell cycle, increased cell apoptosis, and inhibited the ratio of phospho-Akt/protein kinase B and phospho-mammalian target of rapamycin/mammalian target of rapamycin. In conclusion, these data suggest that lupeol may play a therapeutic role in ovarian cancer.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

scholarly journals Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down’s syndrome mouse model

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jesús David Urbano-Gámez ◽  
Juan José Casañas ◽  
Itziar Benito ◽  
María Luz Montesinos
Keyword(s):  
Intellectual Disability ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Therapeutic Potential ◽  
Mammalian Target Of Rapamycin ◽  
Memory Deficits ◽  
Prenatal Treatment ◽  
Hippocampal Pyramidal Neurons ◽  
Metabotropic Glutamate ◽  
Mushroom Spines

AbstractDown syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we characterize the proteome of hippocampal synaptoneurosomes (SNs) from these mice, and found a predicted alteration of synaptic plasticity pathways, including long term depression (LTD). Accordingly, mGluR-LTD (metabotropic Glutamate Receptor-LTD) is enhanced in the hippocampus of Ts1Cje mice and this is correlated with an increased proportion of a particular category of mushroom spines in hippocampal pyramidal neurons. Remarkably, prenatal treatment of these mice with rapamycin has a positive pharmacological effect on both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability.

Dopamine Increases the Gain of the Input-Output Response of Rat Prefrontal Pyramidal Neurons

2008 ◽  
Vol 99 (6) ◽  
pp. 2985-2997 ◽  
Author(s):  
Kay Thurley ◽  
Walter Senn ◽  
Hans-Rudolf Lüscher
Keyword(s):  
Working Memory ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
D1 Receptors ◽  
Input Output ◽  
Prefrontal Cortical ◽  
Noisy Input ◽  
Relationship Of

Dopaminergic modulation of prefrontal cortical activity is known to affect cognitive functions like working memory. Little consensus on the role of dopamine modulation has been achieved, however, in part because quantities directly relating to the neuronal substrate of working memory are difficult to measure. Here we show that dopamine increases the gain of the frequency-current relationship of layer 5 pyramidal neurons in vitro in response to noisy input currents. The gain increase could be attributed to a reduction of the slow afterhyperpolarization by dopamine. Dopamine also increases neuronal excitability by shifting the input-output functions to lower inputs. The modulation of these response properties is mainly mediated by D1 receptors. Integrate-and-fire neurons were fitted to the experimentally recorded input-output functions and recurrently connected in a model network. The gain increase induced by dopamine application facilitated and stabilized persistent activity in this network. The results support the hypothesis that catecholamines increase the neuronal gain and suggest that dopamine improves working memory via gain modulation.

scholarly journals Akt isoforms differentially regulate neutrophil functions

Blood ◽  
2010 ◽  
Vol 115 (21) ◽  
pp. 4237-4246 ◽  
Author(s):  
Jia Chen ◽  
Haiyang Tang ◽  
Nissim Hay ◽  
Jingsong Xu ◽  
Richard D. Ye
Keyword(s):  
Kinase Inhibitor ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Leading Edge ◽  
Neutrophil Activation ◽  
Enzyme Release ◽  
Wild Type ◽  
Akt Isoforms ◽  
Phosphoinositide 3 Kinase ◽  
O2 Production

In neutrophils, the phosphoinositide 3-kinase/Akt signaling cascade is involved in migration, degranulation, and O2− production. However, it is unclear whether the Akt kinase isoforms have distinct functions in neutrophil activation. Here we report functional differences between the 2 major Akt isoforms in neutrophil activation on the basis of studies in which we used individual Akt1 and Akt2 knockout mice. Akt2−/− neutrophils exhibited decreased cell migration, granule enzyme release, and O2− production compared with wild-type and Akt1−/− neutrophils. Surprisingly, Akt2 deficiency and pharmacologic inhibition of Akt also abrogated phorbol ester-induced O2− production, which was unaffected by treatment with the phosphoinositide 3-kinase inhibitor LY294002. The decreased O2− production in Akt2−/− neutrophils was accompanied by reduced p47phox phosphorylation and its membrane translocation, suggesting that Akt2 is important for the assembly of phagocyte nicotinamide adenine dinucleotide phosphate oxidase. In wild-type neutrophils, Akt2 but not Akt1 translocated to plasma membrane upon chemoattractant stimulation and to the leading edge in polarized neutrophils. In the absence of Akt2, chemoattractant-induced Akt protein phosphorylation was significantly reduced. These results demonstrate a predominant role of Akt2 in regulating neutrophil functions and provide evidence for differential activation of the 2 Akt isoforms in neutrophils.

scholarly journals Phosphatidylinositol-3,4,5-Trisphosphate Is Required for Insulin-Like Growth Factor 1-Mediated Survival of 3T3-L1 Preadipocytes**This work was supported by a grant (to A.S.) from the Medical Research Council of Canada.

Endocrinology ◽  
2001 ◽  
Vol 142 (1) ◽  
pp. 205-212 ◽  
Author(s):  
AnneMarie Gagnon ◽  
Patti Dods ◽  
Nicolas Roustan-Delatour ◽  
Ching-Shih Chen ◽  
Alexander Sorisky
Keyword(s):  
Cell Death ◽  
Growth Factor ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Tunel Staining ◽  
Insulin Like Growth Factor ◽  
Tissue Mass ◽  
Akt Phosphorylation ◽  
Dependent Cell ◽  
Phosphoinositide 3 Kinase

Abstract Adipocyte number, a determinant of adipose tissue mass, reflects the balance between the rates of proliferation/differentiation vs. apoptosis of preadipocytes. The percentage of 3T3-L1 preadipocytes undergoing cell death following serum deprivation was reduced by 10 nm insulin-like growth factor (IGF)-1 (from 50.0 ± 0.7% for control starved cells to 27.5 ± 3.1%). TUNEL staining confirmed the apoptotic nature of the cell death. The protective effect of IGF-1 was blocked by phosphoinositide 3-kinase (PI3K) inhibitors, wortmannin, and LY294002, but was unaffected by rapamycin, PD98059, or SB203580, which inhibit mammalian target of rapamycin (mTOR), ERK kinase (MEK1), and p38 MAPK respectively. Exogenous PI(3,4,5)P3 (10 μm), the principal product of IGF-1-stimulated PI3K in 3T3-L1 preadipocytes, had a modest survival effect on its own, reducing cell death from 47.9± 3.4% to 35.6 ± 3.5%. When added to the combination of IGF-1 and LY294002, PI(3,4,5)P3 reversed most of the inhibitory effect of LY294002 on IGF-1-dependent cell survival, protein kinase B/Akt phosphorylation, and caspase-3 activity. Taken together, these results implicate PI(3,4,5)P3 as a necessary signal for the anti-apoptotic action of IGF-1 on 3T3-L1 preadipocytes.

Sign in / Sign up

Export Citation Format

Share Document