scholarly journals Leptin Controls Glutamatergic Synaptogenesis and NMDA-Receptor Trafficking via Fyn Kinase Regulation of NR2B

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Tyler Bland ◽  
Mingyan Zhu ◽  
Crystal Dillon ◽  
Gulcan Semra Sahin ◽  
Jose Luis Rodriguez-Llamas ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Hippocampal Neurons ◽  
Leptin Receptor ◽  
Kinase Inhibitor ◽  
Phosphorylation Site ◽  
Surface Expression ◽  
Brain Regions ◽  
Dominant Negative ◽  
Nmda Receptor Function ◽  
The Central Nervous System

Abstract Activation of the leptin receptor, LepRb, by the adipocytokine/neurotrophic factor leptin in the central nervous system has procognitive and antidepressive effects. Leptin has been shown to increase glutamatergic synaptogenesis in multiple brain regions. In contrast, mice that have a mutation in the LepRb gene show abnormal synapse development in the hippocampus as well as deficits in cognition and increased depressive-like symptoms. Leptin increases glutamatergic synaptogenesis, in part, through enhancement of N-methyl-D-aspartic acid (NMDA) receptor function; yet the underlying signaling pathway is not known. In this study, we examine how leptin regulates surface expression of NR2B-containing NMDA receptors in hippocampal neurons. Leptin stimulation increases NR2BY1472 phosphorylation, which is inhibited by the Src family kinase inhibitor, PP1. Moreover, we show that Fyn, a member of the Src family kinases, is required for leptin-stimulated NR2BY1472 phosphorylation. Furthermore, inhibiting Y1472 phosphorylation with either a dominant negative Fyn mutant or an NR2B mutant that lacks the phosphorylation site (NR2BY1472F) blocks leptin-stimulated synaptogenesis. Additionally, we show that LepRb forms a complex with NR2B and Fyn. Taken together, these findings expand our knowledge of the LepRb interactome and the mechanisms by which leptin stimulates glutamatergic synaptogenesis in the developing hippocampus. Comprehending these mechanisms is key for understanding dendritic spine development and synaptogenesis, alterations of which are associated with many neurological disorders.

scholarly journals Acute Downregulation of ENaC by EGF Involves the PY Motif and Putative ERK Phosphorylation Site

2007 ◽  
Vol 130 (3) ◽  
pp. 313-328 ◽  
Author(s):  
Rebecca A. Falin ◽  
Calvin U. Cotton
Keyword(s):  
Kinase Inhibitor ◽  
Collecting Duct ◽  
Phosphorylation Site ◽  
Surface Expression ◽  
Wild Type ◽  
Open Probability ◽  
Erk Phosphorylation ◽  
C Terminus ◽  
Py Motif ◽  
Erk Kinase

The epithelial sodium channel (ENaC) is expressed in a variety of tissues, including the renal collecting duct, where it constitutes the rate-limiting step for sodium reabsorption. Liddle's syndrome is caused by gain-of-function mutations in the β and γ subunits of ENaC, resulting in enhanced Na reabsorption and hypertension. Epidermal growth factor (EGF) causes acute inhibition of Na absorption in collecting duct principal cells via an extracellular signal–regulated kinase (ERK)–dependent mechanism. In experiments with primary cultures of collecting duct cells derived from a mouse model of Liddle's disease (β-ENaC truncation), it was found that EGF inhibited short-circuit current (Isc) by 24 ± 5% in wild-type cells but only by 6 ± 3% in homozygous mutant cells. In order to elucidate the role of specific regions of the β-ENaC C terminus, Madin-Darby canine kidney (MDCK) cell lines that express β-ENaC with mutation of the PY motif (P616L), the ERK phosphorylation site (T613A), and C terminus truncation (R564stop) were created using the Phoenix retroviral system. All three mutants exhibited significant attenuation of the EGF-induced inhibition of sodium current. In MDCK cells with wild-type β-ENaC, EGF-induced inhibition of Isc (<30 min) was fully reversed by exposure to an ERK kinase inhibitor and occurred with no change in ENaC surface expression, indicative of an effect on channel open probability (Po). At later times (>30 min), EGF-induced inhibition of Isc was not reversed by an ERK kinase inhibitor and was accompanied by a decrease in ENaC surface expression. Our results are consistent with an ERK-mediated decrease in ENaC open probability and enhanced retrieval of sodium channels from the apical membrane.

Glutamate—Hypothalamic-Pituitary-Adrenal Axis Interactions: Implications for Mood and Anxiety Disorders

CNS Spectrums ◽  
2001 ◽  
Vol 6 (7) ◽  
pp. 555-564 ◽  
Author(s):  
Sanjay J. Mathew ◽  
Jeremy D. Coplan ◽  
Eric L.P. Smith ◽  
Darryle D. Schoepp ◽  
Leonard A. Rosenblum ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Anxiety Disorders ◽  
Hpa Axis ◽  
Nucleus Tractus Solitarius ◽  
Excitatory Amino Acid ◽  
Brain Regions ◽  
Glutamate Antagonists ◽  
Hypothalamic Pituitary Adrenal ◽  
Mood And Anxiety Disorders ◽  
Nmda Receptor Function

AbstractDysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is a pathologic feature of certain mood and anxiety disorders that results in the increased production and secretion of corticotropin-releasing factor. There is increasing preclinical evidence that glutamate, an excitatory amino acid, plays an important role in the regulation of the HPA axis. Activation of glutamatergic projections to limbic structures such as the amygdala and brainstem structures such as the nucleus tractus solitarius is implicated in the stress response. There are laboratory and clinical suggestions that glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonists function as antidepressants, and that chronic antidepressant treatments have a significant impact on NMDA receptor function. Clinical investigations of glutamate antagonists in patients with mood and anxiety disorders are in their infancy, with a few reports suggesting the presence of mood-elevating properties. Ultimately, HPA axis modulators, serotonin-enhancing agents, and glutamate antagonists might serve to increase neurotropic factors in key brain regions for affective and anxiety regulation, providing a putative final common pathway.

Potentiation of NMDA Receptor-Mediated Responses by Dynorphin at Low Extracellular Glycine Concentrations

1997 ◽  
Vol 78 (2) ◽  
pp. 582-590 ◽  
Author(s):  
Li Zhang ◽  
Robert W. Peoples ◽  
Murat Oz ◽  
Judith Harvey-White ◽  
Forrest F. Weight ◽  
...  
Keyword(s):  
Amino Acid ◽  
Nmda Receptor ◽  
Opioid Receptor ◽  
Hippocampal Neurons ◽  
High Performance ◽  
Hill Coefficient ◽  
Bathing Solution ◽  
Dynorphin A ◽  
Glycine Concentration ◽  
Nmda Receptor Function

Zhang, Li, Robert W. Peoples, Murat Oz, Judith Harvey-White, Forrest F. Weight, and Ulrike Brauneis. Potentiation of NMDA receptor-mediated responses by dynorphin at low extracellular glycine concentrations. J. Neurophysiol. 78: 582–590, 1997. The effect of dynorphin A(1–13) on N-methyl-d-aspartate (NMDA)-activated currents was investigated in the presence of low extracellular glycine concentrations in Xenopus oocytes expressing recombinant heteromeric NMDA receptors and in cultured hippocampal neurons with the use of voltage-clamp techniques. At an extracellular added glycine concentration of 100 nM, dynorphin A(1–13) (10 μM) greatly increased the amplitude of NMDA-activated currents for all heteromeric subunit combinations tested; on average, the potentiation was: ε1/ζ1, 3,377 ± 1,416% (mean ± SE); ε2/ζ1, 1,897 ± 893%; ε3/ζ1, 4,356 ± 846%; and ε4/ζ1, 1,783 ± 503%. Potentiation of NMDA-activated current by dynorphin A(1–13) was concentration dependent between 0.1 and 10 μM dynorphin A(1–13), with a half-maximal concentration value of 2.77 μM and an apparent Hill coefficient of 2.53, for ε2/ζ1 subunits at 100 nM added extracellular glycine. Percentage potentiation by dynorphin A(1–13) was maximal at the lowest glycine concentrations tested (0.01 and 0.1 μM), and decreased with increasing glycine concentration. No significant potentiation was observed at glycine concentrations >0.1 μM for ε1/ζ1, ε2/ζ1, and ε4/ζ1 subunits, or at >1 μM for ε3/ζ1 subunits. Potentiation of NMDA-activated currents by dynorphin A(1–13) was not inhibited by 1 μM of the κ-opioid receptor antagonist nor-binaltorphimine, and potentiation was not observed with 10 μM of the κ-opioid receptor agonist trans-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]benzene-acetamide. Potentiation of NMDA-activated current by dynorphin A(1–13) was inhibited by the glycine antagonist kynurenic acid (50 μM). NMDA-activated current was also potentiated at low glycine concentrations by 10 μM dynorphin A(2–13) or (3–13), both of which have a glycine as the first amino acid, but not by 10 μM dynorphin A(4–13), which does not have glycine as an amino acid. In hippocampal neurons, 10 μM dynorphin A(1–13) or (2–13) potentiated steady-state NMDA-activated current in the absence of added extracellular glycine. The extracellular free glycine concentration, determined by high-performance liquid chromatography, was between 26 and 36 nM for the bathing solution in presence or absence of 10 μM dynorphin A(1–13), (2–13), (3–13), or (4–13), and did not differ significantly among these solutions. The observations are consistent with the potentiation of NMDA-activated current at low extracellular glycine concentrations resulting from an interaction of the glycine amino acids in dynorphin A(1–13) with the glycine coagonist site on the NMDA receptor. Because dynorphin A is an endogenous peptide that can be coreleased with glutamate at glutamatergic synapses, the potentiation of NMDA receptor-mediated responses could be an important physiological regulator of NMDA receptor function at these synapses.

scholarly journals Altered NMDA receptor function in primary cultures of hippocampal neurons from mice lacking theHomer2gene

Synapse ◽  
2015 ◽  
Vol 70 (1) ◽  
pp. 33-39 ◽  
Author(s):  
C. Thetford Smothers ◽  
Karen K. Szumlinski ◽  
Paul F. Worley ◽  
John J. Woodward
Keyword(s):  
Nmda Receptor ◽  
Hippocampal Neurons ◽  
Primary Cultures ◽  
Receptor Function ◽  
Nmda Receptor Function

Stat3 inhibition in neural lineage cells

2012 ◽  
Vol 10 (2) ◽  
Author(s):  
Tomohiro Chiba ◽  
Laura Mack ◽  
Natalia Delis ◽  
Boris Brill ◽  
Bernd Groner
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Hippocampal Neurons ◽  
Neuroblastoma Cell ◽  
Cancer Cell Lines ◽  
Dominant Negative ◽  
Neural Lineage ◽  
The Central Nervous System ◽  
Permanent Residents ◽  
Neuroblastoma Cell Lines

AbstractDeregulation of signal transducer and activator of transcription 3 (Stat3) is attracting attentions in neurological disorders of elderly populations, e.g., Stat3 is inactivated in hippocampal neurons of Alzheimer’s disease (AD) brains, whereas it is often constitutively activated in glioblastoma multiforme (GBM), correlating with poor prognosis. Stat3-inhibiting drugs have been intensively developed for chemotherapy based on the fact that GBM, in many cases, are “addicted” to Stat3 activation. Stat3 inhibitors, however, potentially have unfavorable side effects on postmitotic neurons, normal permanent residents in the central nervous system. It is, therefore, of great importance to address detailed cellular responses of neural lineage cells including normal neurons, astrocytes, and neuronal/glial cancer cell lines to several classes of Stat3 inhibitors focusing on their effective concentrations. Here, we picked up five human and mouse cancer cell lines (Neuro-2a and SH-SY5Y neuroblastoma cell lines and Tu-9648, U-87MG, and U-373MG glioblastoma cell lines) and treated with various Stat3 inhibitors. Among them, Stattic, FLLL31, and resveratrol potently suppressed P-Stat3 and cell viability in all the tested cell lines. Stat3 knockdown or expression of dominant-negative Stat3 further sensitized cells to the inhibitors. Expression of familial AD-related mutant amyloid precursor protein sensitized neuronal cells, not glial cells, to Stat3 inhibitors by reducing P-Stat3 levels. Primary neurons and astrocytes also responded to Stat3 inhibitors with similar sensitivities to those observed in cancer cell lines. Thus, Stat3 inhibitors should be carefully targeted to GBM cells to avoid potential neurotoxicity leading to AD-like neuropsychiatric dysfunctions.

Survival and synaptogenesis of hippocampal neurons without NMDA receptor function in culture

1998 ◽  
Vol 10 (6) ◽  
pp. 2192-2198 ◽  
Author(s):  
Shigeo Okabe ◽  
Carlos Vicario-Abejón ◽  
Menahem Segal ◽  
Ronald D. G. McKay
Keyword(s):  
Nmda Receptor ◽  
Hippocampal Neurons ◽  
Receptor Function ◽  
Nmda Receptor Function

Exposure to 835 MHz radiofrequency electromagnetic field induces autophagy in hippocampus but not in brain stem of mice

2017 ◽  
Vol 34 (1) ◽  
pp. 23-35 ◽  
Author(s):  
Ju Hwan Kim ◽  
Da-Hyeon Yu ◽  
Hyo-Jeong Kim ◽  
Yang Hoon Huh ◽  
Seong-Wan Cho ◽  
...  
Keyword(s):  
Brain Stem ◽  
Mobile Phones ◽  
Hippocampal Neurons ◽  
Brain Regions ◽  
Pcr Analysis ◽  
Limited Information ◽  
The Central Nervous System ◽  
Neuronal Functions ◽  
Adaptation Processes ◽  
The Brain

The exploding popularity of mobile phones and their close proximity to the brain when in use has raised public concern regarding possible adverse effects from exposure to radiofrequency electromagnetic fields (RF-EMF) on the central nervous system. Numerous studies have suggested that RF-EMF emitted by mobile phones can influence neuronal functions in the brain. Currently, there is still very limited information on what biological mechanisms influence neuronal cells of the brain. In the present study, we explored whether autophagy is triggered in the hippocampus or brain stem after RF-EMF exposure. C57BL/6 mice were exposed to 835 MHz RF-EMF with specific absorption rates (SAR) of 4.0 W/kg for 12 weeks; afterward, the hippocampus and brain stem of mice were dissected and analyzed. Quantitative real-time polymerase chain reaction (qRT-PCR) analysis demonstrated that several autophagic genes, which play key roles in autophagy regulation, were significantly upregulated only in the hippocampus and not in the brain stem. Expression levels of LC3B-II protein and p62, crucial autophagic regulatory proteins, were significantly changed only in the hippocampus. In parallel, transmission electron microscopy (TEM) revealed an increase in the number of autophagosomes and autolysosomes in the hippocampal neurons of RF-EMF-exposed mice. The present study revealed that autophagy was induced in the hippocampus, not in the brain stem, in 835 MHz RF-EMF with an SAR of 4.0 W/kg for 12 weeks. These results could suggest that among the various adaptation processes to the RF-EMF exposure environment, autophagic degradation is one possible mechanism in specific brain regions.

scholarly journals The hippocampus encodes delay and value information during delay-discounting decision making

2018 ◽  
Author(s):  
Akira Masuda ◽  
Chie Sano ◽  
Qi Zhang ◽  
Hiromichi Goto ◽  
Thomas J. McHugh ◽  
...  
Keyword(s):  
Decision Making ◽  
Nmda Receptor ◽  
Delay Discounting ◽  
Hippocampal Neurons ◽  
Pyramidal Cells ◽  
Ca1 Region ◽  
Hippocampal Ca1 Region ◽  
Valuation Process ◽  
Nmda Receptor Function ◽  
Reward Amount

SummaryThe hippocampus, a region critical for memory and spatial navigation, has been implicated in delay discounting, the decline in subjective reward value when a delay is imposed. However, how delay discounting is encoded in the hippocampus is poorly understood. Here we recorded from the hippocampal CA1 region of mice performing a delay-discounting decision-making task, where delay lengths and reward amounts were changed across sessions, and identified subpopulations of neurons in CA1 which increased or decreased their firing rate during long delays. The activity of both delay-active and -suppressive cells reflected delay length, reward amount, and arm position, however manipulating reward amount differentially impacted the two populations, suggesting distinct roles in the valuation process. Further, genetic deletion of NMDA receptor in hippocampal pyramidal cells impaired delay-discount behavior and diminished delay-dependent activity in CA1. Our results suggest that distinct subclasses of hippocampal neurons concertedly support delay-discounting decision in a manner dependent on NMDA receptor function.

scholarly journals The hippocampus encodes delay and value information during delay-discounting decision making

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Akira Masuda ◽  
Chie Sano ◽  
Qi Zhang ◽  
Hiromichi Goto ◽  
Thomas J McHugh ◽  
...  
Keyword(s):  
Decision Making ◽  
Nmda Receptor ◽  
Delay Discounting ◽  
Hippocampal Neurons ◽  
Pyramidal Cells ◽  
Ca1 Neurons ◽  
Valuation Process ◽  
Nmda Receptor Function ◽  
Reward Amount ◽  
Delay Dependent

The hippocampus, a region critical for memory and spatial navigation, has been implicated in delay discounting, the decline in subjective reward value when a delay is imposed. However, how delay information is encoded in the hippocampus is poorly understood. Here, we recorded from CA1 of mice performing a delay-discounting decision-making task, where delay lengths, delay positions, and reward amounts were changed across sessions, and identified subpopulations of CA1 neurons that increased or decreased their firing rate during long delays. The activity of both delay-active and -suppressed cells reflected delay length, delay position, and reward amount; but manipulating reward amount differentially impacted the two populations, suggesting distinct roles in the valuation process. Further, genetic deletion of the N-methyl-D-aspartate (NMDA) receptor in hippocampal pyramidal cells impaired delay-discount behavior and diminished delay-dependent activity in CA1. Our results suggest that distinct subclasses of hippocampal neurons concertedly support delay-discounting decisions in a manner that is dependent on NMDA receptor function.

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