scholarly journals Tau- but not Aß -pathology enhances NMDAR-dependent depotentiation in AD-mouse models

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Enrico Faldini ◽  
Tariq Ahmed ◽  
Luc Bueé ◽  
David Blum ◽  
Detlef Balschun
Keyword(s):  
Synaptic Plasticity ◽  
Transgenic Mice ◽  
Mouse Models ◽  
Long Term Potentiation ◽  
High Frequency Stimulation ◽  
Synaptic Loss ◽  
Ca1 Region ◽  
Term Potentiation ◽  
Frequency Stimulation

AbstractMany mouse models of Alzheimer’s disease (AD) exhibit impairments in hippocampal long-term-potentiation (LTP), seemingly corroborating the strong correlation between synaptic loss and cognitive decline reported in human studies. In other AD mouse models LTP is unaffected, but other defects in synaptic plasticity may still be present. We recently reported that THY-Tau22 transgenic mice, that overexpress human Tau protein carrying P301S and G272 V mutations and show normal LTP upon high-frequency-stimulation (HFS), develop severe changes in NMDAR mediated long-term-depression (LTD), the physiological counterpart of LTP. In the present study, we focused on putative effects of AD-related pathologies on depotentiation (DP), another form of synaptic plasticity. Using a novel protocol to induce DP in the CA1-region, we found in 11–15 months old male THY-Tau22 and APPPS1–21 transgenic mice that DP was not deteriorated by Aß pathology while significantly compromised by Tau pathology. Our findings advocate DP as a complementary form of synaptic plasticity that may help in elucidating synaptic pathomechanisms associated with different types of dementia.

Coexistence of Muscarinic Long-Term Depression With Electrically Induced Long-Term Potentiation and Depression at CA3–CA1 Synapses

2006 ◽  
Vol 96 (6) ◽  
pp. 3114-3121 ◽  
Author(s):  
Eve McCutchen ◽  
Cary L. Scheiderer ◽  
Lynn E. Dobrunz ◽  
Lori L. McMahon
Keyword(s):  
Synaptic Plasticity ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Receptor Activation ◽  
High Frequency Stimulation ◽  
Muscarinic Agonist ◽  
Long Term Depression ◽  
Term Potentiation ◽  
Frequency Stimulation

Our laboratory recently characterized a form of long-term depression (LTD) at CA3–CA1 synapses mediated by M1 muscarinic receptors (mAChRs), termed muscarinic LTD (mLTD). mLTD is both activity and NMDAR dependent, characteristics shared by forms of synaptic plasticity thought to be relevant to learning and memory, including long-term potentiation (LTP) induced by high-frequency stimulation (HFS-LTP) and long-term depression induced by low-frequency stimulation (LFS-LTD). However, it remains unclear whether mLTD can occur sequentially with these electrically induced forms of hippocampal plasticity or whether mLTD might interact with them. The first goal of this study was to examine the interplay of mLTD and HFS-LTP. We report that mLTD expression does not alter subsequent induction of HFS-LTP and, further, at synapses expressing HFS-LTP, mLTD can mediate a novel form of depotentiation. The second goal was to determine whether mLTD would alter LFS-LTD induction and/or expression. Although we show that mLTD is occluded by saturation of LFS-LTD, suggesting mechanistic similarity between these two plasticities, saturation of mLTD does not occlude LFS-LTD. Surprisingly, however, the LFS-LTD that follows cholinergic receptor activation is NMDAR independent, indicating that application of muscarinic agonist induces a change in the induction mechanism required for LFS-LTD. These data demonstrate that mLTD can coexist with electrically induced forms of synaptic plasticity and support the hypothesis that mLTD is one of the mechanisms by which the cholinergic system modulates hippocampal function.

scholarly journals Etomidate Targets α5γ-Aminobutyric Acid Subtype A Receptors to Regulate Synaptic Plasticity and Memory Blockade

2009 ◽  
Vol 111 (5) ◽  
pp. 1025-1035 ◽  
Author(s):  
Loren J. Martin ◽  
Gabriel H. T. Oh ◽  
Beverley A. Orser
Keyword(s):  
Synaptic Plasticity ◽  
High Frequency ◽  
Memory Performance ◽  
Long Term Potentiation ◽  
Aminobutyric Acid ◽  
High Frequency Stimulation ◽  
Term Potentiation ◽  
Frequency Stimulation ◽  
Subtype A

Background The memory-blocking properties of general anesthetics have recently received considerable attention because of concerns related to intraoperative awareness and postoperative cognitive dysfunction. The goal of this study was to identify the mechanisms by which gamma-aminobutyric acid subtype A receptors that contain the alpha5 subunit (alpha5GABAARs) induce memory-blockade by etomidate and a pharmacologic strategy to reverse this impairment. Methods The effects of etomidate and the alpha5GABAAR-preferring inverse agonist L-655,708 on the plasticity of glutamatergic excitatory transmission in hippocampal slices and behavioral memory for spatial navigational and fear-associated memory tasks were studied in wild-type and null mutant mice for the gene that encodes the alpha5 subunit (Gabra5-/- mice). Long-term potentiation of field excitatory postsynaptic potentials was induced in CA1 pyramidal neurons following high-frequency stimulation of Schaffer collaterals. Memory performance was studied in contextual, cued, and trace fear conditioning assays and the Morris water maze. Results Robust synaptic plasticity induced by high-frequency stimulation and memory performance for contextual fear and spatial navigational memory were not influenced by a decrease in the function of alpha5GABAARs. Nevertheless, etomidate, via an increase in alpha5GABAAR activity, completely blocked long-term potentiation and impaired memory performance, and these effects were reversed by pretreatment with L-655,708. Conclusions The results provide the first proof of concept that memory blockade by a general anesthetic can be reversed by inhibiting the function of alpha5GABAARs. The findings suggest a mechanism and model for awareness during anesthesia.

Sevoflurane Blocks the Induction of Long-term Potentiation When Present during, but Not When Present Only before, the High-frequency Stimulation

2018 ◽  
Vol 128 (3) ◽  
pp. 555-563 ◽  
Author(s):  
Jinyang Liu ◽  
Lie Yang ◽  
Daisy Lin ◽  
James E. Cottrell ◽  
Ira S. Kass
Keyword(s):  
High Frequency ◽  
Long Term Potentiation ◽  
High Frequency Stimulation ◽  
Excitatory Postsynaptic Potential ◽  
Ca1 Region ◽  
Postsynaptic Potential ◽  
Artificial Cerebrospinal Fluid ◽  
Term Potentiation ◽  
Frequency Stimulation

Abstract Background This study tests the hypothesis that sevoflurane blocks long-term potentiation only if it is present during the high-frequency stimulation that induces long-term potentiation. Methods Long-term potentiation, an electrophysiologic correlate of memory, was induced by high-frequency stimulation and measured as a persistent increase in the field excitatory postsynaptic potential slope in the CA1 region. Results Long-term potentiation was induced in the no sevoflurane group (171 ± 58% vs. 96 ± 11%; n = 13, mean ± SD); when sevoflurane (4%) was present during the high-frequency stimulation, long-term potentiation was blocked (92 ± 22% vs. 99 ± 7%, n = 6). While sevoflurane reduced the size of the field excitatory postsynaptic potential to single test stimuli by 59 ± 17%, it did not significantly reduce the size of the field excitatory postsynaptic potentials during the 100 Hz high-frequency stimulation. If sevoflurane was removed from the artificial cerebrospinal fluid superfusing the slices 10 min before the high-frequency stimulation, then long-term potentiation was induced (185 ± 48%, n = 7); this was not different from long-term potentiation in the no sevoflurane slices (171 ± 58). Sevoflurane before, but not during, ⊖-burst stimulation, a physiologic stimulus, did not block the induction of long-term potentiation (151 ± 37% vs. 161 ± 34%, n = 7). Conclusions Sevoflurane blocks long-term potentiation formation if present during the high-frequency stimulation; this blockage of long-term potentiation does not persist if sevoflurane is discontinued before the high-frequency stimulation. These results may explain why short periods of insufficient sevoflurane anesthesia may lead to recall of painful or traumatic events during surgery.

scholarly journals Cholecystokinin release triggered by NMDA receptors produces LTP and sound–sound associative memory

2019 ◽  
Vol 116 (13) ◽  
pp. 6397-6406 ◽  
Author(s):  
Xi Chen ◽  
Xiao Li ◽  
Yin Ting Wong ◽  
Xuejiao Zheng ◽  
Haitao Wang ◽  
...  
Keyword(s):  
Associative Learning ◽  
Associative Memory ◽  
High Frequency ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
High Frequency Stimulation ◽  
Low Frequency Stimulation ◽  
Term Potentiation ◽  
Frequency Stimulation

Memory is stored in neural networks via changes in synaptic strength mediated in part by NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here we show that a cholecystokinin (CCK)-B receptor (CCKBR) antagonist blocks high-frequency stimulation-induced neocortical LTP, whereas local infusion of CCK induces LTP. CCK−/−mice lacked neocortical LTP and showed deficits in a cue–cue associative learning paradigm; and administration of CCK rescued associative learning deficits. High-frequency stimulation-induced neocortical LTP was completely blocked by either the NMDAR antagonist or the CCKBR antagonist, while application of either NMDA or CCK induced LTP after low-frequency stimulation. In the presence of CCK, LTP was still induced even after blockade of NMDARs. Local application of NMDA induced the release of CCK in the neocortex. These findings suggest that NMDARs control the release of CCK, which enables neocortical LTP and the formation of cue–cue associative memory.

scholarly journals LTD and LTP at the Developing Retinogeniculate Synapse

2009 ◽  
Vol 102 (6) ◽  
pp. 3082-3090 ◽  
Author(s):  
Jokūbas Žiburkus ◽  
Emily K. Dilger ◽  
Fu-Sun Lo ◽  
William Guido
Keyword(s):  
Optic Tract ◽  
Long Term Potentiation ◽  
Dorsal Lateral Geniculate Nucleus ◽  
High Frequency Stimulation ◽  
Retinal Stimulation ◽  
Term Potentiation ◽  
Frequency Stimulation ◽  
Retinogeniculate Synapse

The purpose of the present study was to determine whether retinal activity can support long-term changes in synaptic strength in the developing dorsal lateral geniculate nucleus (LGN) of thalamus. To test for this we made use of a rodent in vitro explant preparation in which retinal afferents and the intrinsic circuitry of the LGN remain intact. We repetitively stimulated the optic tract with a tetanus protocol that approximated the temporal features of spontaneous retinal waves. We found the amplitude of extracellular field potentials evoked by retinal stimulation changed significantly after tetanus and that the polarity of these alterations was related to postnatal age. At a time when substantial pruning of retinal connections occurs (postnatal day 1 [P1] to P14), high-frequency stimulation led to an immediate and long-term depression (LTD). However, at times when pruning wanes and adultlike patterns of connectivity are stabilizing (P16 to P30), the identical form of stimulation produced a modest form of potentiation (long-term potentiation [LTP]). The LTD was unaffected by the bath application of γ-aminobutyric acid type A and N-methyl-d-aspartate receptor antagonists. However, both LTD and LTP were blocked by L-type Ca2+-channel antagonists. Thus the Ca2+ influx associated with L-type channel activation mediates the induction of synaptic plasticity and may signal the pruning and subsequent stabilization of developing retinogeniculate connections.

Nicotine Enhances the Depressive Actions of Aβ1–40 on Long-Term Potentiation in the Rat Hippocampal CA1 Region In Vivo

2003 ◽  
Vol 89 (6) ◽  
pp. 2917-2922 ◽  
Author(s):  
D. B. Freir ◽  
C. E. Herron
Keyword(s):  
Synaptic Plasticity ◽  
Long Term Potentiation ◽  
Α7 Nicotinic Acetylcholine Receptor ◽  
High Affinity ◽  
Ca1 Region ◽  
Α7 Nachr ◽  
Term Potentiation ◽  
Significant Depression

Hippocampal long-term potentiation (LTP) is a form of synaptic plasticity used as a cellular model of memory. Beta amyloid (Aβ) is involved in Alzheimer's disease (AD), a neurode-generative disorder leading to cognitive deficits. Nicotine is also claimed to act as a cognitive enhancer. Aβ is known to bind with high affinity to the α7-nicotinic acetylcholine receptor (nAChR). Here we have investigated the effect of intracerebroventricular (icv) injection of the endogenous peptide Aβ1–40 on LTP in area CA1 of urethananesthetized rats. We also examined the effect of Aβ12–28 (icv), which binds with high affinity to the α7-nAChR and the specific α7-nAChR antagonist methyllycaconitine (MLA) on LTP. We found that Aβ12–28 had no effect on LTP, whereas MLA depressed significantly LTP, suggesting that activation of the α7-nAChR is a requirement for LTP. Within the in vivo environment, where other factors may compete with Aβ12–28 for binding to α7-nAChR, it does not appear to modulate LTP. To determine if the depressive action of Aβ1–40 on LTP could be modulated by nicotine, these agents were also co-applied. Injection of 1 or 10 nmol Aβ1–40 caused a significant depression of LTP, whereas nicotine alone (3 mg/kg) had no effect on LTP. Co-injection of nicotine with Aβ1–40 1 h prior to LTP induction caused a further significant depression of LTP compared with Aβ1–40 alone. These results demonstrate that nicotine enhances the deficit in LTP produced by Aβ1–40. This then suggests that nicotine may exacerbate the depressive actions of Aβ on synaptic plasticity in AD.

scholarly journals Specific Roles of AMPA Receptor Subunit GluR1 (GluA1) Phosphorylation Sites in Regulating Synaptic Plasticity in the CA1 Region of Hippocampus

2010 ◽  
Vol 103 (1) ◽  
pp. 479-489 ◽  
Author(s):  
Hey-Kyoung Lee ◽  
Kogo Takamiya ◽  
Kaiwen He ◽  
Lihua Song ◽  
Richard L. Huganir
Keyword(s):  
Synaptic Plasticity ◽  
Critical Role ◽  
Long Term Potentiation ◽  
Phosphorylation Sites ◽  
Ca1 Region ◽  
Term Potentiation ◽  
Ampa Receptor Subunit ◽  
Glur1 Subunit ◽  
Activity Dependent

Activity-dependent changes in excitatory synaptic transmission in the CNS have been shown to depend on the regulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs). In particular, several lines of evidence suggest that reversible phosphorylation of AMPAR subunit glutamate receptor 1 (GluR1, also referred to as GluA1 or GluR-A) plays a role in long-term potentiation (LTP) and long-term depression (LTD). We previously reported that regulation of serines (S) 831 and 845 on the GluR1 subunit may play a critical role in bidirectional synaptic plasticity in the Schaffer collateral inputs to CA1. Specifically, gene knockin mice lacking both S831 and S845 phosphorylation sites (“double phosphomutants”), where both serine residues were replaced by alanines (A), showed a faster decaying LTP and a deficit in LTD. To determine which of the two phosphorylation sites was responsible for the phenotype, we have now generated two lines of gene knockin mice: one that specifically lacks S831 (S831A mutants) and another that lacks only S845 (S845A mutants). We found that S831A mutants display normal LTP and LTD, whereas S845A mutants show a specific deficit in LTD. Taken together with our previous results from the “double phosphomutants,” our data suggest that either S831 or S845 alone may support LTP, whereas the S845 site is critical for LTD expression.

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