Enhanced Long-Term Potentiation During Aging Is Masked by Processes Involving Intracellular Calcium Stores

2004 ◽  
Vol 91 (6) ◽  
pp. 2437-2444 ◽  
Author(s):  
Ashok Kumar ◽  
Thomas C. Foster
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Calcium Stores ◽  
Age Related ◽  
Term Potentiation ◽  
Pattern Stimulation ◽  
Old Rats

The contribution of Ca2+ release from intracellular Ca2+ stores (ICS) for regulation of synaptic plasticity thresholds during aging was investigated in hippocampal slices of old (22–24 mo) and young adult (5–8 mo) male Fischer 344 rats. Inhibition of Ca2+-induced Ca2+ release by thapsigargin, cyclopiazonic acid (CPA), or ryanodine during pattern stimulation near the threshold for synaptic modification (5 Hz, 900 pulses) selectively induced long-term potentiation (LTP) to CA1 Schaffer collateral synapses of old rats. Increased synaptic strength was specific to test pathways and blocked by AP-5. Intracellular recordings demonstrated that ICS plays a role in the augmentation of the afterhyperpolarization (AHP) in old rats. The decrease in the AHP by ICS inhibition was reversed by the L-channel agonist, Bay K8644. Under conditions of ICS inhibition and a Bay K8644–mediated enhancement of the AHP, pattern stimulation failed to induce LTP, consistent with the idea that the AHP amplitude shapes the threshold for LTP induction. Finally, ICS inhibition was associated with an increase in the N-methyl-d-aspartate (NMDA) receptor component of synaptic transmission in old animals. This increase in the synaptic response was blocked by the calcineurin inhibitor FK506. The results reveal an age-related increase in susceptibility to LTP-induction that is normally inhibited by ICS and suggest that the age-related shift in Ca2+ regulation and Ca2+-dependent synaptic plasticity is coupled to changes in cell excitability and NMDA receptor function through ICS.

Long-term Potentiation of NMDA Receptor-mediated EPSP in Guinea-pig Hippocampal Slices

1991 ◽  
Vol 3 (9) ◽  
pp. 850-854 ◽  
Author(s):  
N. Berretta ◽  
F. Berton ◽  
R. Bianchi ◽  
M. Brunelli ◽  
M. Capogna ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Guinea Pig ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Term Potentiation

Priming-Induced Shift in Synaptic Plasticity in the Rat Hippocampus

1999 ◽  
Vol 82 (4) ◽  
pp. 2024-2028 ◽  
Author(s):  
Hongyan Wang ◽  
John J. Wagner
Keyword(s):  
Synaptic Plasticity ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Crossover Point ◽  
Term Potentiation ◽  
Before And After ◽  
History Of ◽  
The Brain ◽  
Dependent Mechanism

The activity history of a given neuron has been suggested to influence its future responses to synaptic input in one prominent model of experience-dependent synaptic plasticity proposed by Bienenstock, Cooper, and Munro (BCM theory). Because plasticity of synaptic plasticity (i.e., metaplasticity) is similar in concept to aspects of the BCM proposal, we have tested the possibility that a form of metaplasticity induced by a priming stimulation protocol might exhibit BCM-like characteristics. CA1 field excitatory postsynaptic potentials (EPSPs) obtained from rat hippocampal slices were used to monitor synaptic responses before and after conditioning stimuli (3–100 Hz) of the Schaffer collateral inputs. A substantial rightward shift (>5-fold) in the frequency threshold between long-term depression (LTD) and long-term potentiation (LTP) was observed <1 h after priming. This change in the LTD/P crossover point occurred at both primed and unprimed synaptic pathways. These results provide new support for the existence of a rapid, heterosynaptic, experience-dependent mechanism that is capable of modifying the synaptic plasticity phenomena that are commonly proposed to be important for developmental and learning/memory processes in the brain.

scholarly journals (2S,6S)- and (2R,6R)-hydroxynorketamine inhibit the induction of NMDA receptor-dependent LTP at hippocampal CA1 synapses in mice

2020 ◽  
Vol 4 ◽  
pp. 239821282095784
Author(s):  
Heather Kang ◽  
Pojeong Park ◽  
Muchun Han ◽  
Patrick Tidball ◽  
John Georgiou ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Long Term Potentiation ◽  
Aspartate Receptor ◽  
Term Potentiation ◽  
Hippocampal Ca1 ◽  
Mouse Hippocampus ◽  
Site Of Action ◽  
A Site

The ketamine metabolite (2 R,6 R)-hydroxynorketamine has been proposed to have rapid and persistent antidepressant actions in rodents, but its mechanism of action is controversial. We have compared the ability of ( R,S)-ketamine with the (2 S,6 S)- and (2 R,6 R)-isomers of hydroxynorketamine to affect the induction of N-methyl-d-aspartate receptor–dependent long-term potentiation in the mouse hippocampus. Following pre-incubation of these compounds, we observed a concentration-dependent (1–10 μM) inhibition of long-term potentiation by ketamine and a similar effect of (2 S,6 S)-hydroxynorketamine. At a concentration of 10 μM, (2 R,6 R)-hydroxynorketamine also inhibited the induction of long-term potentiation. These findings raise the possibility that inhibition of N-methyl-d-aspartate receptor–mediated synaptic plasticity is a site of action of the hydroxynorketamine metabolites with respect to their rapid and long-lasting antidepressant-like effects.

Two forms of long-term potentiation in area CA1 activate different signal transduction cascades

1996 ◽  
Vol 76 (5) ◽  
pp. 3038-3047 ◽  
Author(s):  
I. Cavus ◽  
T. Teyler
Keyword(s):  
Signal Transduction ◽  
Nmda Receptor ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Protein Kinase Inhibitors ◽  
Area Ca1 ◽  
Term Potentiation

1. The effects of protein kinase inhibitors on N-methyl-D-aspartate (NMDA)-receptor-mediated, voltage-dependent calcium channel (VDCC)-mediated, and 100-Hz long-term potentiation (LTP) were studied in area CA1 of rat hippocampal slices. 2. A 25-Hz tetanus induced a quickly developing potentiation that was blocked by the NMDA antagonist D,L-2-amino-5-phosphonovaleric acid (APV) and was not affected by the L-type VDCC inhibitor nifedipine, suggesting that it was mediated by NMDA receptors (NMDA-LTP). 3. Application of a 200-Hz tetanus in APV induced a slowly developing NMDA-receptor-independent potentiation that was blocked by nifedipine and thus named VDCC-LTP. NMDA- and VDCC-LTP reached comparable magnitudes despite their different induction parameters and developmental kinetics. 4. Bath perfusion of the broad-spectrum serine/threonine kinase inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7) blocked NMDA-LTP but not VDCC-LTP, whereas the tyrosine kinase inhibitors genistein and lavendustin A blocked VDCC-LTP but not NMDA-LTP. These results suggest a differential involvement of H-7-sensitive serine/threonine kinases and tyrosine kinases in the two forms of LTP. 5. Tetanization of 200 Hz in control media resulted in a compound potentiation twice as large as NMDA- or VDCC-LTP, implying that the two forms of LTP did not facilitate or reduce each other's expression. The often-used 100-Hz tetanus (1 s twice) induced a potentiation that was comparable in size with the 200-Hz compound LTP. Nifedipine, genistein, and lavendustin A reduced the 100-Hz LTP by approximately 50%, suggesting that this LTP is also a compound potentiation consisting of NMDA- and VDCC-mediated components and their corresponding signal transduction pathways.

Aging Differentially Alters Forms of Long-Term Potentiation in Rat Hippocampal Area CA1

1998 ◽  
Vol 79 (1) ◽  
pp. 334-341 ◽  
Author(s):  
Subbakrishna Shankar ◽  
Timothy J. Teyler ◽  
Norman Robbins
Keyword(s):  
Calcium Channel ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Voltage Dependent Calcium Channel ◽  
Area Ca1 ◽  
Age Related ◽  
Term Potentiation ◽  
Voltage Dependent ◽  
Hippocampal Area

Shankar, Subbakrishna, Timothy J. Teyler, and Norman Robbins. Aging differentially alters forms of long-term potentiation in rat hippocampal area CA1. J. Neurophysiol. 79: 334–341, 1998. Long-term potentiation (LTP) of the Schaffer collateral/commissural inputs to CA1 in the hippocampus was shown to consist of N-methyl-d-aspartate receptor (NMDAR) and voltage-dependent calcium channel (VDCC) dependent forms. In this study, the relative contributions of these two forms of LTP in in vitro hippocampal slices from young (2 mo) and old (24 mo) Fischer 344 rats were examined. Excitatory postsynaptic potentials (EPSP) were recorded extracellularly from stratum radiatum before and after a tetanic stimulus consisting of four 200-Hz, 0.5-s trains given 5 s apart. Under control conditions, a compound LTP consisting of both forms was induced and was similar, in both time course and magnitude, in young and old animals. NMDAR-dependent LTP (nmdaLTP), isolated by the application of 10 μM nifedipine (a voltage-dependent calcium channel blocker), was significantly reduced in magnitude in aged animals. The VDCC dependent form (vdccLTP), isolated by the application of 50 μM d,l-2-amino-5-phosphonvalerate (APV), was significantly larger in aged animals. Although both LTP forms reached stable values 40–60 min posttetanus in young animals, in aged animals vdccLTP increased and nmdaLTP decreased during this time. In both young and old animals, the sum of the two isolated LTP forms approximated the magnitude of the compound LTP, and application of APV and nifedipine or genestein (a tyrosine kinase inhibitor) together blocked potentiation. These results suggest that aging causes a shift in synaptic plasticity from NMDAR-dependent mechanisms to VDCC-dependent mechanisms. The data are consistent with previous findings of increased L-type calcium current and decreased NMDAR number in aged CA1 cells and may help explain age-related deficits in learning and memory.

scholarly journals Aging Effects on the Limits and Stability of Long-Term Synaptic Potentiation and Depression in Rat Hippocampal Area CA1

2007 ◽  
Vol 98 (2) ◽  
pp. 594-601 ◽  
Author(s):  
Ashok Kumar ◽  
Jeffrey S. Thinschmidt ◽  
Thomas C. Foster ◽  
Michael A. King
Keyword(s):  
Synaptic Plasticity ◽  
Young Adult ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Brown Norway ◽  
Aging Effects ◽  
Adult Rats ◽  
Age Related ◽  
Significant Difference

Altered hippocampal synaptic plasticity may underlie age-related memory impairment. In acute hippocampal slices from aged (22–24 mo) and young adult (1–12 mo) male Brown Norway rats, extracellular excitatory postsynaptic field potentials were recorded in CA1 stratum radiatum evoked by Schaffer collateral stimulation. We used enhanced Ca2+ to Mg2+ ratio and paired-pulse stimulation protocol to induce maximum changes in the synaptic plasticity. Six episodes of theta-burst stimulation (TBS) or nine episodes of paired low-frequency stimulation (pLFS) were used to generate asymptotic long-term potentiation (LTP) and long-term depression (LTD), respectively. In addition, long-term depotentiation (LTdeP) or de-depression (LTdeD) from maximal LTP and LTD were examined using two episodes of pLFS or TBS. Multiple episodes of TBS or pLFS produced significant LTP or LTD in aged and young adult rats; this was not different between age groups. Moreover, there was no significant difference in the amount of LTdeP or LTdeD between aged and young adult rats. Our results show no age differences in the asymptotic magnitude of LTP or LTD, rate of synaptic modifications, development rates, reversal, or decay after postconditioning. Thus impairment of the basic synaptic mechanisms responsible for expression of these forms of plasticity is not likely to account for decline in memory function within this age range.

scholarly journals The Neuroprotective Beta Amyloid Hexapeptide Core Reverses Deficits in Synaptic Plasticity in the 5×FAD APP/PS1 Mouse Model

2020 ◽  
Author(s):  
Kelly H. Forest ◽  
Ruth Taketa ◽  
Komal Arora ◽  
Cedomir Todorovic ◽  
Robert A. Nichols
Keyword(s):  
Synaptic Plasticity ◽  
Mutational Analysis ◽  
Ex Vivo ◽  
Physiological Activity ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Cellular Level ◽  
Term Potentiation ◽  
Pi3 Kinase Pathway

AbstractAlzheimer’s disease (AD) is the most common cause of dementia in the aging population. Evidence implicates elevated soluble oligomeric Aβ as one of the primary triggers during the prodromic phase leading to AD, effected largely via hyperphosphorylation of the microtubule-associated protein tau. At low, physiological levels (pM-nM), however, oligomeric Aβ has been found to regulate synaptic plasticity as a neuromodulator. Through mutational analysis, we found a core hexapeptide sequence within the N-terminal domain of Aβ (N-Aβcore) accounting for its physiological activity, and subsequently found that the N-Aβcore peptide is neuroprotective. Here, we characterized the neuroprotective potential of the N-Aβcore against dysfunction of synaptic plasticity assessed in ex vivo hippocampal slices from 5×FAD APP/PS1 mice, specifically hippocampal long-term potentiation (LTP) and long-term depression (LTD). The N-Aβcore was shown to reverse impairment in synaptic plasticity in hippocampal slices from 5×FAD APP/PS1 model mice, both for LTP and LTD. The reversal by the N-Aβcore correlated with alleviation of downregulation of hippocampal AMPA-type glutamate receptors in preparations from 5×FAD mice. The action of the N-Aβcore depended upon a critical di-histidine sequence and involved the PI3 kinase pathway via mTOR. Together, the present findings indicate that the non-toxic N-Aβcore hexapeptide is not only neuroprotective at the cellular level but is able to reverse synaptic dysfunction in AD-like models, specifically alterations in synaptic plasticity.

scholarly journals Oat Extract Avenanthramide-C Reverses Hippocampal Long-Term Potentiation Decline in Tg2576 Mice

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6105
Author(s):  
Yu-Young Lee ◽  
Ming Wang ◽  
Yurim Son ◽  
Eun-Ju Yang ◽  
Moon-Seok Kang ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Mouse Model ◽  
Glycogen Synthase ◽  
Hippocampal Slices ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Biological Properties ◽  
Tg2576 Mouse ◽  
Term Potentiation

Memory deterioration in Alzheimer’s disease (AD) is thought to be underpinned by aberrant amyloid β (Aβ) accumulation, which contributes to synaptic plasticity impairment. Avenanthramide-C (Avn-C), a polyphenol compound found predominantly in oats, has a range of biological properties. Herein, we performed methanolic extraction of the Avns-rich fraction (Fr. 2) from germinated oats using column chromatography, and examined the effects of Avn-C on synaptic correlates of memory in a mouse model of AD. Avn-C was identified in Fr. 2 based on 1H-NMR analysis. Electrophysiological recordings were performed to examine the effects of Avn-C on the hippocampal long-term potentiation (LTP) in a Tg2576 mouse model of AD. Avn-C from germinated oats restored impaired LTP in Tg2576 mouse hippocampal slices. Furthermore, Avn-C-facilitated LTP was associated with changes in the protein levels of phospho-glycogen synthase kinase-3β (p-GSK3β-S9) and cleaved caspase 3, which are involved in Aβ-induced synaptic impairment. Our findings suggest that the Avn-C extract from germinated oats may be beneficial for AD-related synaptic plasticity impairment and memory decline.

scholarly journals Fusion pore modulation as a presynaptic mechanism contributing to expression of long-term potentiation

2003 ◽  
Vol 358 (1432) ◽  
pp. 695-705 ◽  
Author(s):  
Sukwoo Choi ◽  
Jürgen Klingauf ◽  
Richard W. Tsien
Keyword(s):  
Nmda Receptor ◽  
Glutamate Release ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Quantitative Model ◽  
Fusion Pore ◽  
Silent Synapses ◽  
Term Potentiation ◽  
Presynaptic Mechanisms

Working on the idea that postsynaptic and presynaptic mechanisms of long-term potentiation (LTP) expression are not inherently mutually exclusive, we have looked for the existence and functionality of presynaptic mechanisms for augmenting transmitter release in hippocampal slices. Specifically, we asked if changes in glutamate release might contribute to the conversion of ‘silent synapses’ that show N -methyl-D-aspartate (NMDA) responses but no detectable α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) responses, to ones that exhibit both. Here, we review experiments where NMDA receptor responses provided a bioassay of cleft glutamate concentration, using opposition between peak [glu] cleft and a rapidly reversible antagonist, L-AP5. We discuss findings of a dramatic increase in peak [glu] cleft upon expression of pairing-induced LTP (Choi). We present simulations with a quantitative model of glutamatergic synaptic transmission that includes modulation of the presynaptic fusion pore, realistic cleft geometry and a distributed array of postsynaptic receptors and glutamate transporters. The modelling supports the idea that changes in the dynamics of glutamate release can contribute to synaptic unsilencing. We review direct evidence from Renger et al ., in accord with the modelling, that trading off the strength and duration of the glutamate transient can markedly alter AMPA receptor responses with little effect on NMDA receptor responses. An array of additional findings relevant to fusion pore modulation and its proposed contribution to LTP expression are considered.

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