scholarly journals Neurotrophic factor-α1, a novel tropin is critical for the prevention of stress-induced hippocampal CA3 cell death and cognitive dysfunction in mice: comparison to BDNF

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Lan Xiao ◽  
Vinay Kumar Sharma ◽  
Leila Toulabi ◽  
Xuyu Yang ◽  
Cheol Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Neurotrophic Factor ◽  
Maternal Separation ◽  
Pyramidal Neurons ◽  
Neuroprotective Activity ◽  
Weaning Stress ◽  
Hippocampal Ca3 ◽  
Ca3 Neurons

AbstractStress leads to brain pathology including hippocampal degeneration, cognitive dysfunction, and potential mood disorders. Hippocampal CA3, a most stress-vulnerable region, consists of pyramidal neurons that regulate cognitive functions e.g. learning and memory. These CA3 neurons express high levels of the neuroprotective protein, neurotrophic factor-α1 (NF-α1), also known as carboxypeptidase E (CPE), and receive contacts from granule cell projections that release BDNF which has neuroprotective activity. Whether NF-α1-CPE and/or BDNF are critical in protecting these CA3 neurons against severe stress-induced cell death is unknown. Here we show that social combined with the physical stress of maternal separation, ear tagging, and tail snipping at weaning in 3-week-old mice lacking NF-α1-CPE, led to complete hippocampal CA3 degeneration, despite having BDNF and active phosphorylated TrkB receptor levels similar to WT animals. Mice administered TrkB inhibitor, ANA12 which blocked TrkB phosphorylation showed no degeneration of the CA3 neurons after the weaning stress paradigm. Furthermore, transgenic knock-in mice expressing CPE-E342Q, an enzymatically inactive form, replacing NF-α1-CPE, showed no CA3 degeneration and exhibited normal learning and memory after the weaning stress, unlike NF-α1-CPE-KO mice. Mechanistically, we showed that radio-labeled NF-α1-CPE bound HT22 hippocampal cells in a saturable manner and with high affinity (Kd = 4.37 nM). Subsequently, treatment of the HT22cpe−/− cells with NF-α1-CPE or CPE-E342Q equivalently activated ERK signaling and increased BCL2 expression to protect these neurons against H2O2-or glutamate-induced cytotoxicity. Our findings show that NF-α1-CPE is more critical compared to BDNF in protecting CA3 pyramidal neurons against stress-induced cell death and cognitive dysfunction, independent of its enzymatic activity.

scholarly journals Synapse type-specific proteomic dissection identifies IgSF8 as a hippocampal CA3 microcircuit organizer

2019 ◽  
Author(s):  
Nuno Apóstolo ◽  
Samuel N. Smukowski ◽  
Jeroen Vanderlinden ◽  
Giuseppe Condomitti ◽  
Vasily Rybakin ◽  
...  
Keyword(s):  
Cell Surface ◽  
Pyramidal Neurons ◽  
Mossy Fiber ◽  
Surface Protein ◽  
Guidance Cue ◽  
Hippocampal Ca3 ◽  
Cell Surface Interactions ◽  
Ca3 Pyramidal Neurons ◽  
Ca3 Neurons ◽  
Multiple Ligand

SummarySynaptic diversity is a key feature of neural circuits. The structural and functional diversity of closely spaced inputs converging on the same neuron suggests that cell-surface interactions are essential in organizing input properties. Here, we analyzed the cell-surface protein (CSP) composition of hippocampal mossy fiber (MF) inputs on CA3 pyramidal neurons to identify regulators of MF-CA3 synapse properties. We uncover a rich cell-surface repertoire that includes adhesion proteins, guidance cue receptors, extracellular matrix (ECM) proteins, and uncharacterized CSPs. Interactome screening reveals multiple ligand-receptor modules and identifies ECM protein Tenascin-R (TenR) as a ligand of the uncharacterized neuronal receptor IgSF8. Presynaptic Igsf8 deletion impairs MF-CA3 synaptic architecture and robustly decreases the density of bouton filopodia that provide feedforward inhibition of CA3 neurons. Consequently, loss of IgSF8 increases CA3 neuron excitability. Our findings identify IgSF8 as a regulator of CA3 microcircuit development and suggest that combinations of CSP modules define input identity.

scholarly journals SUN-260 Dual Role of Carboxypeptidase E in Prohormone Processing and a Novel Neurotrophic Factor Mediating Neuroprotection and Cognitive Functions in Hippocampal CA3 Neurons in Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lan Xiao ◽  
Vinay Sharma ◽  
Leila Toulabi ◽  
Xuyu Yang ◽  
Cheol Lee ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Neuronal Degeneration ◽  
Tyrosine Kinase Receptor ◽  
Wild Type ◽  
Prohormone Processing ◽  
Hippocampal Ca3 ◽  
Ca3 Neurons ◽  
The Brain

Abstract Stress causes release of glucocorticoids from the adrenals which then circulate to the brain. High concentrations glucocorticoid from chronic severe stress results in pathophysiology in the brain, including neuronal degeneration, cell death and cognitive dysfunction, leading to diseases such as Alzheimer Disease and Major Depressive Disorders. Neurotrophic/growth factors such as BDNF, NGF and NT3 have been linked to these pathological conditions. Carboxypeptidase E (CPE), a proneuropeptide/prohormone processing enzyme, also named neurotrophic factor-α1(NFα1) is highly expressed in the stress-vulnerable hippocampal CA3 neurons, and was shown to have neuroprotective activity from in vitro studies. Here we investigated if CPE-NFα1 functions in vivo, independent of its enzymatic activity, and the mechanism underlying its action. We generated knock-in mice expressing a non-enzymatic form of CPE, CPE-E342Q, but not wild-type CPE. The CPE-E342Q mice showed significantly decreased neuropeptide content and exhibited obesity, diabetes and infertility due to lack of prohormone processing activity, similar to CPE-KO mice. However, they showed no hippocampal CA3 degeneration, exhibited neurogenesis in the dentate gyrus, and displayed normal spatial learning and memory, similar to CPE wild-type mice, after weaning stress; unlike CPE-KO mice which showed hippocampal CA3 neuronal degeneration and cognitive deficits. Binding studies showed that radiolabeled CPE bound hippocampal cell membrane specifically, in a saturable manner. Binding of CPE and CPE-E342Q to hippocampal neurons activated Erk signaling and pre-treatment with either of these proteins protected neurons against H2O2- or glutamate-induced neurotoxcity by increasing BCL2 expression. In vitro and in vivo inhibitor studies demonstrated that this neuroprotective effect was independent of tyrosine kinase receptor signaling. Taken together, the data provide evidence that CPE-NFα1 is a unique neurotrophic factor which acts through a non-tyrosine kinase receptor to activate Erk-BCL2 signaling to protect hippocampal CA3 neurons against stress-induced neurodegeneration and maintaining normal cognitive functions in mice.

Blocking brain-derived neurotrophic factor inhibits injury-induced hyperexcitability of hippocampal CA3 neurons

2013 ◽  
Vol 38 (11) ◽  
pp. 3554-3566 ◽  
Author(s):  
Raminder Gill ◽  
Philip K.-Y. Chang ◽  
George A. Prenosil ◽  
Emily C. Deane ◽  
Rebecca A. McKinney
Keyword(s):  
Neurotrophic Factor ◽  
Brain Derived Neurotrophic Factor ◽  
Hippocampal Ca3 ◽  
Ca3 Neurons

scholarly journals Amantadine Alleviates Postoperative Cognitive Dysfunction Possibly by Preserving Neurotrophic Factor Expression and Dendritic Arborization in the Hippocampus of Old Rodents

2020 ◽  
Vol 12 ◽  
Author(s):  
Jing Zhong ◽  
Jun Li ◽  
Cheng Ni ◽  
Zhiyi Zuo
Keyword(s):  
Carotid Artery ◽  
Elderly Patients ◽  
Learning And Memory ◽  
Cognitive Dysfunction ◽  
Neurotrophic Factor ◽  
Postoperative Cognitive Dysfunction ◽  
Dendritic Arborization ◽  
Spine Density ◽  
Memory Dysfunction ◽  
Adult Rats

ObjectivesAmantadine has been shown to attenuate postoperative learning and memory dysfunction in young adult rats. However, postoperative cognitive dysfunction often occurs in elderly patients. We aimed to determine whether amantadine attenuated postoperative learning and memory dysfunction and whether these effects were associated with improved dendritic arborization in old rodents.MethodsEighteen-month old male C57BL/6J mice or Fischer 344 rats were subjected to right carotid artery exposure (surgery) under isoflurane anesthesia. This age represents an early old stage in rodents. Carotid artery exposure was used to simulate commonly performed carotid endarterectomy in elderly patients. Amantadine was injected intraperitoneally at 25 μg/g once a day for 3 days with the first dose at 15 min before surgery. The animals were tested by Barnes maze and fear conditioning starting one week after the surgery. Hippocampus was harvested for Western blotting and Golgi staining.ResultsSurgery and anesthesia impaired the learning and memory in old mice and rats. Surgery reduced the expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), dendritic arborization and spine density in the hippocampus of old rats. These effects were attenuated by amantadine. The effects of amantadine were blocked by intracerebroventricular injection of anti-BDNF antibody or anti-GDNF antibody.ConclusionSurgery and anesthesia impaired learning, memory and dendritic arborization in old rodents that are age relevant to postoperative cognitive dysfunction. These effects may be attenuated by amantadine via preserving the expression of neurotrophic factors.

Zinc-Induced Augmentation of Excitatory Synaptic Currents and Glutamate Receptor Responses in Hippocampal CA3 Neurons

2001 ◽  
Vol 85 (3) ◽  
pp. 1185-1196 ◽  
Author(s):  
Dean D. Lin ◽  
Akiva S. Cohen ◽  
Douglas A. Coulter
Keyword(s):  
Pyramidal Neurons ◽  
Granule Cells ◽  
Mossy Fiber ◽  
Release Kinetics ◽  
Excitatory Synapses ◽  
Hippocampal Ca3 ◽  
Excitatory Neurotransmission ◽  
High Concentrations ◽  
Ca3 Neurons ◽  
Kinetics Of

Zinc is found throughout the CNS at synapses co-localized with glutamate in presynaptic terminals. In particular, dentate granule cells' (DGC) mossy fiber (MF) axons contain especially high concentrations of zinc co-localized with glutamate within vesicles. To study possible physiological roles of zinc, visualized slice-patch techniques were used to voltage-clamp rat CA3 pyramidal neurons, and miniature excitatory postsynaptic currents (mEPSCs) were isolated. Bath-applied zinc (200 μM) enhanced median mEPSC peak amplitudes to 153.0% of controls, without affecting mEPSC kinetics. To characterize this augmentation further, rapid agonist application was performed on perisomatic outside-out patches to coapply zinc with glutamate extremely rapidly for brief (1 ms) durations, thereby emulating release kinetics of these substances at excitatory synapses. When zinc was coapplied with glutamate, zinc augmented peak glutamate currents (mean ± SE, 116.6 ± 2.8% and 143.8 ± 9.8% of controls at 50 and 200 μM zinc, respectively). This zinc-induced potentiation was concentration dependent, and pharmacological isolation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor–mediated currents (AMPAR currents) gave results similar to those observed with glutamate application (mean, 115.0 ± 5.4% and 132.5 ± 9.1% of controls at 50 and 200 μM zinc, respectively). Inclusion of the AMPAR desensitization blocker cyclothiazide in the control solution, however, abolished zinc-induced augmentation of glutamate-evoked currents, suggesting that zinc may potentiate AMPAR currents by inhibiting AMPAR desensitization. Based on the results of the present study, we hypothesize that zinc is a powerful modulator of both excitatory synaptic transmission and glutamate-evoked currents at physiologically relevant concentrations. This modulatory role played by zinc may be a significant factor in enhancing excitatory neurotransmission and could significantly regulate function at the mossy fiber-CA3 synapse.

Dual-component miniature excitatory synaptic currents in rat hippocampal CA3 pyramidal neurons

1992 ◽  
Vol 68 (1) ◽  
pp. 16-27 ◽  
Author(s):  
C. McBain ◽  
R. Dingledine
Keyword(s):  
Time Course ◽  
Pyramidal Neurons ◽  
Dendritic Tree ◽  
Reversal Potential ◽  
Amplitude Distribution ◽  
Postsynaptic Currents ◽  
Decay Times ◽  
Hippocampal Ca3 ◽  
Entire Cell ◽  
Ca3 Neurons

1. Spontaneous miniature synaptic events were studied with tight-seal whole-cell recordings from CA3 neurons maintained in the hippocampal slice from immature rats (3-15 days). CA3 neurons suffer a constant, high-frequency barrage of inhibitory synaptic input. When inhibitory postsynaptic currents were suppressed by bicuculline, a smaller contribution from excitatory synapses was revealed. 2. Addition of tetrodotoxin (TTX) removed a persistent inward current and substantially reduced the baseline noise facilitating the detection of ,miniature- excitatory currents. Addition of hyperosmotic media increased the frequency of spontaneous excitatory postsynaptic currents (EPSCs). 3. Under both physiological and elevated potassium conditions, individual spontaneous miniature EPSCs (10-30 pA amplitude) were composed of components mediated by N-methyl-D-aspartate (NMDA) and non-NMDA receptors as determined by their voltage dependence, time course, and sensitivity to selective antagonists. 6-Cyano-7-nitro-quinoxaline-2,3-dione (CNQX) or D-2-amino-5-phosphonovaleric acid (D-APV) shifted the amplitude distribution of miniature EPSCs to a smaller mode at both +40 mV and -40 mV. Similar to EPSCs recorded in CA1 neurons, the rise and decay times of the NMDA receptor component were slower than those of the non-NMDA component. The time course of the non-NMDA component was voltage independent. 4. In 13 of 21 neurons, no correlation existed between individual EPSC rise times and their corresponding halfwidth, peak amplitude, or decay time constant. This suggests that the large range of EPSC kinetics observed in each individual neuron was not due solely to cable attenuation of EPSCs widely distributed over the dendritic tree. Plots of the mean EPSC rise time against mean halfwidth for each cell, however, revealed a striking correlation, suggesting that in neonates, active synapses may be grouped in a restricted region of the dendritic tree and as such are subject to similar amounts of dendritic filtering. 5. The electrotonic length of CA3 neurons (L = 0.52) predicted that at this maturity the electrotonic compactness of the neuron facilitated voltage control over all but the most distal synapses. The reversal potential of the fast component of spontaneous events was close to 0 mV, whereas the reversal potential of exogenously applied kainate and NMDA was more positive. This discrepancy likely reflects a compromise of the voltage clamp by the activation of conductances distributed over the entire cell.(ABSTRACT TRUNCATED AT 400 WORDS)

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