Depotentiation Of Long-term Potentiation Research Articles

Depotentiation of long-term potentiation is associated with epitope specific tau hyper/hypo phosphorylation in the hippocampus of adult rats

Depotentiation of long-term potentiation is associated with epitope specific tau hyper/hypo phosphorylation in the hippocampus of adult rats

Depotentiation of Long-Term Potentiation Is Associated with Epitope-Specific Tau Hyper-/Hypophosphorylation in the Hippocampus of Adult Rats.

It is well-known that some kinases which are involved in the induction of synaptic plasticity probably modulate tau phosphorylation. However, how depression of potentiated synaptic strength contributes to tau phosphorylation is unclear because of the lack of experiments in which depotentiation of LTP was induced. Field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded from the dentate gyrus in response to the perforant pathway stimulation. To induce LTP, high-frequency stimulation (HFS) was used, while, for depotentiation of LTP, low-frequency stimulation (LFS) consisting of 900 pulses at 1Hz was applied 5min after tetanization. In some experiments, a neutral protocol at 0.033Hz was applied throughout the experiment without any induction of synaptic plasticity. One-hertz depotentiation protocol was able to decrease fEPSP slope which was previously increased by HFS, whereas no significant change in fEPSP slope and PS amplitude was observed in neutral protocol experiments. Relative to saline infusion, LTP was lower in magnitude and was more reversed by subsequent LFS in the presence of ERK1/2 inhibitor. Western blot experiments indicated that tau protein was hyperphosphorylated at ser416 epitope but rather hypophosphorylated at thr231 epitope in the whole hippocampus upon depotentiation of LTP. These changes concomitantly occurred with a notable increase in the levels of total tau and in the levels of phosphorylated form of the extracellular signal-regulated protein kinases 1 and 2 (ERK1/2). ERK1/2 inhibition resulted in a decrease in phosphorylation of tau at p416Tau when ERK1/2 was inhibited. These findings indicate that some forms of long-term plastic changes might be related with epitope-specific tau phosphorylation and ERK1/2 activation in the hippocampus. Therefore, we emphasize that tau may be crucial for physiological learning as well as Alzheimer's disease pathology.

Not Itself Histamine, but H3R Antagonists/Inverse Agonist Thioperamide Enhances Long-term Potentiation in the Dentate Gyrus of Urethane- Anesthetized Rats

Purpose: Although the histamine receptor antagonists have been reported to enhance consolidation of memory in diverse disease states of the central nervous system, their contribution to the long-term potentiation (LTP), a cellular form of learning and memory, remains unknown. Herein, we evaluate the effect of H3 receptor (H3R) antagonist thioperamide (inverse agonist) on the LTP in healthy rats and compare the effect with that of histamine as an agonist, and pyrilamine, as a H2R antagonist. Methods: LTP was induced in the dentate gyrus, where field potentials were recorded during infusions of saline, histamine, thioperamide or pyrilamine alone by application of high- frequency stimulation protocols. Results: The short-term and long-temp potentiation of EPSP, not of PS, in the thioperamide group were significantly higher in comparison with controls, indicating that induction and maintenance of synaptic, not somatic, LTP further enhanced by H3R antagonism. There were also significant differences in short-term and long-term potentiation of PS between the histamine and pyrilamine groups, indicating H1R-mediated dyssynchrony in granule cell of the dentate gyrus. Conclusion: Histamine seems not to play a significant functional role in the perforant pathway- dentate gyrus synapses, but the antagonism of H3R should be considered in treatment of cognitive dysfunctions, although other forms of synaptic plasticity such as longterm depression and depotentiation of LTP are needed.

Roles of protein synthesis inhibitors in long-term potentiation and depotentiation in hippocampal CA1 region of adult rats

To study the roles of protein synthesis inhibitors in long-term potentiation(LTP) and depotentiation(DP) in hippocampal CA1 region of adult rats. Standard extracellular recording technique was used to record field EPSP(fEPSP) evoked by Schaffer collateral stimulation from the CA1 subfield of adult rat hippocampal slices. Paired-pulse low-frequency stimulation(PP-LFS) or high-intensity paired-pulse low-frequency stimulation(HI-PP-LFS) was delivered to induce depotentiation 2 h after LTP induction induced by six theta-burst stimulations. Protein synthesis inhibitors were applied before and after LTP induction to study their roles in LTP and DP in hippocampal CA1 region of adult rats. When HI-PP-LFS was applied at 2 h after LTP induction, the depotentiation was induced. The mean fEPSP slopes reduced from 346.2%±26.3% to 207.1%±21.6%. This depotentiation was named as partial LTP depotentiation and maintained at least for 30 min. The percentage of depotentiation was 59.81%. Application of protein synthesis inhibitors, anisomycin and cycloheximide prior to tetanus resulted in smaller LTP compared to control group, and almost complete depotentiation was induced by HI-PP-LFS. With application of protein synthesis inhibitors anisomycin and cycloheximide 90 min after LTP induction, HI-PP-LFS still induced partial LTP depotentiation. However, there was no significant difference in the percentage of depotentiation between this group and control group. HI-PP-LFS partially reverses late phase LTP. When protein synthesis inhibitors are applied prior to tetanus, LTP amplitude is markedly reduced, and HI-PP-LFS completely reverses late-phase LTP. Application of protein synthesis inhibitors after LTP induction does not significantly affect either the amplitude or depotentiation of LTP.

Hippocampal long-term potentiation that is elicited by perforant path stimulation or that occurs in conjunction with spatial learning is tightly controlled by beta-adrenoreceptors and the locus coeruleus.

ABSTRACTThe noradrenergic system, driven by locus coeruleus (LC) activation, plays a key role in the regulating and directing of changes in hippocampal synaptic efficacy. The LC releases noradrenaline in response to novel experience and LC activation leads to an enhancement of hippocampus‐based learning, and facilitates synaptic plasticity in the form of long‐term depression (LTD) and long‐term potentiation (LTP) that occur in association with spatial learning. The predominant receptor for mediating these effects is the β‐adrenoreceptor. Interestingly, the dependency of synaptic plasticity on this receptor is different in the hippocampal subfields whereby in the CA1 in vivo, LTP, but not LTD requires β‐adrenoreceptor activation, whereas in the mossy fiber synapse LTP and LTD do not depend on this receptor. By contrast, synaptic plasticity that is facilitated by spatial learning is highly dependent on β‐adrenoreceptor activation in both hippocampal subfields. Here, we explored whether LTP induced by perforant‐path (pp) stimulation in vivo or that is facilitated by spatial learning depends on β‐adrenoreceptors. We found that under both LTP conditions, antagonising the receptors disabled the persistence of LTP. β‐adrenoreceptor‐antagonism also prevented spatial learning. Strikingly, activation of the LC before high‐frequency stimulation (HFS) of the pp prevented short‐term potentiation but not LTP, and LC stimulation after pp‐HFS‐induced depotentiation of LTP. This depotentiation was prevented by β‐adrenoreceptor‐antagonism. These data suggest that β‐adrenoreceptor‐activation, resulting from noradrenaline release from the LC during enhanced arousal and learning, comprises a mechanism whereby the duration and degree of LTP is regulated and fine tuned. This may serve to optimize the creation of a spatial memory engram by means of LTP and LTD. This process can be expected to support the special role of the dentate gyrus as a crucial subregional locus for detecting and processing novelty within the hippocampus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.

Impairment of hippocampal long‐term depression and defective spatial learning and memory in p35–/– mice

Cdk5 (cyclin-dependent kinase 5) activity is dependent upon association with one of two neuron-specific activators, p35 or p39. Genetic deletion of Cdk5 causes perinatal lethality with severe defects in corticogenesis and neuronal positioning. p35(-/-) mice are viable with milder histological abnormalities. Although substantial evidence implicates Cdk5 in synaptic plasticity, its role in learning and memory has not been evaluated using mutant mouse models. We report here that p35(-/-) mice have deficiencies in spatial learning and memory. Close examination of hippocampal circuitry revealed subtle histological defects in CA1 pyramidal cells. Furthermore, p35(-/-) mice exhibit impaired long-term depression and depotentiation of long-term potentiation in the Schaeffer collateral CA1 pathway. Moreover, the Cdk5-dependent phosphorylation state of protein phosphatase inhibitor-1 was increased in 4-week-old mice due to increased levels of p39, which co-localized with inhibitor-1 and Cdk5 in the cytoplasm. These results demonstrate that p35-dependent Cdk5 activity is important to learning and synaptic plasticity. Deletion of p35 may shift the substrate specificity of Cdk5 due to compensatory expression of p39.

Selective modulation of Ca 2+ influx pathways by 5-HT regulates synaptic long-term plasticity in the hippocampus

Both long-term potentiation (LTP) and long-term depression (LTD) can be induced in the Schaffer collateral-CA1 synapse of the hippocampus either by repetitive stimulation of afferent fibres with the frequency of the stimulation determining the polarity of the response or by associative pairing of pre- and postsynaptic activity. An increase in postsynaptic intracellular Ca 2+ concentration is an important signal for the induction of long-term synaptic plasticity. In patch-clamp experiments on hippocampal brain slices, we tested the modulation of different forms of synaptic plasticity by the neurotransmitter serotonin (5-HT) which is known to inhibit high-voltage activated Ca 2+ channels. 1 μM of 5-HT inhibited homosynaptic LTD induced by low frequency stimulation. This effect of 5-HT could be blocked by the selective 5-HT 1A antagonist WAY 100635. Low frequency-induced LTD is both dependent on Ca 2+ influx through NMDA receptors and high-voltage activated Ca 2+ channels. It was blocked by the NMDA-receptor antagonist D-AP5 and by the N-type Ca 2+ channel antagonist ω-conotoxin GIVA. Tetanus induced LTP was not affected by low concentrations of 5-HT, whereas depotentiation of LTP by asynchronous pairing of EPSPs and postsynaptic action potentials was completely abolished with 5-HT in the bath solution. We conclude that those forms of plasticity which depend on Ca 2+ influx via high-voltage activated Ca 2+ channels are subject to modulation by 5-HT. This might be a relevant mechanism by which 5-HT modifies basic network properties in the brain.

Progress in understanding the factors regulating reversibility of long-term potentiation.

Over the past two decades there has been a progressive understanding of the properties and mechanisms underlying long-term potentiation (LTP) of synaptic efficacy, a putative mechanism for learning and memory storage in the brain. Although LTP is remarkable for its stability, recent work has provided evidence that various manipulations can disrupt LTP if applied shortly after its induction. This kind of reversal of synaptic strength from the potentiated state to pre-LTP levels is termed depotentiation. Depotentiation of LTP is effectively induced by low-frequency afferent stimulation (1-5 Hz), brief periods of hypoxia, application of adenosine receptor agonists and brief cooling shocks. The examples of depotentiation described to date are input specific, and not differently expressed during development. The mechanisms responsible for this phenomenon remain to be fully characterized, although some possibilities are dependent on NMDA receptor activation, the increases in intracellular Ca2+, and altered states of protein kinases or phosphatases. In this review, we summarize the recent data concerning putative depotentiation mechanisms and the implications of this phenomenon in the mechanisms of "forgetting", and discuss the prevention of saturation of the storage capacity of a neuronal network.

An investigation of depotentiation of long-term potentiation in the CA1 region of the hippocampus

An investigation of depotentiation of long-term potentiation in the CA1 region of the hippocampus