Characterization of the mechanism underlying the reversal of long term potentiation by low frequency stimulation at hippocampal CA1 synapses.

Reversal of long term potentiation (LTP) may function to increase the flexibility and storage capacity of neuronal circuits; however, the underlying mechanisms remain incompletely understood. We show that depotentiation induced by low frequency stimulation (LFS) (2 Hz, 10 min, 1200 pulses) was input-specific and dependent on N-methyl-d-aspartate (NMDA) receptor activation. The ability of LFS to reverse LTP was mimicked by a brief application of NMDA. This NMDA-induced depotentiation was blocked by adenosine A(1) receptor antagonist. However, the reversal of LTP by LFS was unaffected by metabotropic glutamate receptor antagonism. This LFS-induced depotentiation was specifically prevented by protein phosphatase (PP)1 inhibitors, okadaic acid, and calyculin A but not by the PP2A or PP2B inhibitors. Furthermore, by using phosphorylation site-specific antibodies, we found that LFS-induced depotentiation is associated with a persistent dephosphorylation of the GluR1 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor at serine 831, a protein kinase C and calcium/calmodulin-dependent protein kinase II (CaMKII) substrate, but not at serine 845, a substrate of cAMP-dependent protein kinase. This effect was mimicked by bath-applied adenosine or NMDA and was specifically prevented by okadaic acid. Also, the increased phosphorylation of CaMKII at threonine 286 and the decreased PP activity seen with LTP were overcome by LFS, adenosine, or NMDA application. These results suggest that LFS erases LTP through an NMDA receptor-mediated activation of PP1 to dephosphorylate amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and CaMKII in the CA1 region of the hippocampus.     

Incorporation of inwardly rectifying AMPA receptors at silent synapses during hippocampal long-term potentiation

Despite decades of study, the mechanisms by which synapses express the increase in strength during long-term potentiation (LTP) remain an area of intense interest. Here, we have studied how AMPA receptor subunit composition changes during the early phases of hippocampal LTP in CA1 pyramidal neurons. We studied LTP at silent synapses that initially lack AMPA receptors, but contain NMDA receptors. We show that strongly inwardly rectifying AMPA receptors are initially incorporated at silent synapses during LTP and are then subsequently replaced by non-rectifying AMPA receptors. These findings suggest that silent synapses initially incorporate GluA2-lacking, calcium-permeable AMPA receptors during LTP that are then replaced by GluA2-containing calcium-impermeable receptors. We also show that LTP consolidation at CA1 synapses requires a rise in intracellular calcium concentration during the early phase of expression, indicating that calcium influx through the GluA2-lacking AMPA receptors drives their replacement by GluA2-containing receptors during LTP consolidation. Taken together with previous studies in hippocampus and in other brain regions, these findings suggest that a common mechanism for the expression of activity-dependent glutamatergic synaptic plasticity involves the regulation of GluA2-subunit composition and highlights a critical role for silent synapses in this process.     

Arcadlin is a neural activity-regulated cadherin involved in long term potentiation.

Neural activity results in long term changes that underlie synaptic plasticity. To examine the molecular basis of activity-dependent plasticity, we have used differential cloning techniques to identify genes that are rapidly induced in brain neurons by synaptic activity. Here, we identify a novel cadherin molecule Arcadlin (activity-regulated cadherin-like protein). arcadlin mRNA is rapidly and transiently induced in hippocampal granule cells by seizures and by N-methyl-D-aspartate-dependent synaptic activity in long term potentiation. The extracellular domain of Arcadlin is most homologous to protocadherin-8; however, the cytoplasmic region is distinct from that of any cadherin family member. Arcadlin protein is expressed at the synapses and shows a homophilic binding activity in a Ca2+-dependent manner. Furthermore, application of Arcadlin antibody reduces excitatory postsynaptic potential amplitude and blocks long term potentiation in hippocampal slices. Its close homology with cadherins, its rapid inducibility by neural activity, and its involvement in synaptic transmission suggest that Arcadlin may play an important role in activity-induced synaptic reorganization underlying long term memory.     

Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation

Wnts are important for various developmental and oncogenic processes. Here we show that Wnt signaling functions at synapses in hippocampal neurons. Tetanic stimulations induce N-methyl-d-aspartate receptor-dependent synaptic Wnt3a release, nuclear beta-catenin accumulations, and the activation of Wnt target genes. Suppression of Wnt signaling impairs long term potentiation. Conversely, activation of Wnt signaling facilitates long term potentiation. These findings suggest that Wnt signaling plays a critical role in regulating synaptic plasticity.     

Doubly modifiable synapses: a model of short and long term auto-associative memory

Synapses that can be strengthened in temporary and persistent manners by two separate mechanisms are shown to have powerful advantages in neural networks that perform auto-associative recall and recognition. A multiplicative relation between the two weights allows the same set of connections to be used in a closely interactive way for short-term and long-term memory. Algorithms and simulations are described for the storage, consolidation and recall of patterns that have been presented only once to a network. With double modifiability, the short-term performance is dramatically improved, becoming almost independent of the amount of long-term experience. The high quality of short-term recall allows consolidation to take place, with benefits from the selection and optimization of long term engrams to take account of relations between stored patterns. Long-term capacity is greater than short-term capacity, with little or no deficit compared with that obtained with singly modifiable synapses. Long-term recall requires special, simply implemented, procedures for increasing the temporary weights of the synapses being used to initiate recall. A consolidation algorithm is described for improving long-term recall when there is overlap between patterns. Confusional errors are reduced by strengthening the associations between non-overlapping elements in the patterns, in a two-stage process that has several of the characteristics of sleep.     

PERK,mTORC1 and eEF2 interplay during long term potentiation

This Editorial highlights a study by Zimmermann and coworkers in the current issue of Journal of Neurochemistry. The authors' link suppression of PKR‐like endoplasmatic reticulum kinase (PERK) activity to eukaryotic elongation factor 2 (eEF2) dephosphorylation and mTORC1‐independent high‐frequency stimulation (HFS)‐induced long‐term potentiation (LTP) in acute hippocampal slices from PERK forebrain conditional knockout mice. The results suggest that functional interaction between the signaling pathways controlling different phases of the mRNA translation process is necessary for long‐term plasticity in the hippocampus.

     

Learning-induced glutamate receptor phosphorylation resembles that induced by long term potentiation

Long term potentiation and long term depression of synaptic responses in the hippocampus are thought to be critical for certain forms of learning and memory, although until recently it has been difficult to demonstrate that long term potentiation or long term depression occurs during hippocampus-dependent learning. Induction of long term potentiation or long term depression in hippocampal slices in vitro modulates phosphorylation of the alpha-amino-3-hydrozy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor subunit GluR1 at distinct phosphorylation sites. In long term potentiation, GluR1 phosphorylation is increased at the Ca2+/calmodulin-dependent protein kinase and protein kinase C site serine 831, whereas in long term depression, phosphorylation of the protein kinase A site serine 845 is decreased. Indeed, phosphorylation of one or both of these sites is required for long term synaptic plasticity and for certain forms of learning and memory. Here we demonstrate that training in a hippocampus-dependent learning task, contextual fear conditioning is associated with increased phosphorylation of GluR1 at serine 831 in the hippocampal formation. This increased phosphorylation is specific to learning, has a similar time course to that in long term potentiation, and like memory and long term potentiation, is dependent on N-methyl-D-aspartate receptor activation during training. Furthermore, the learning-induced increase in serine 831 phosphorylation is present at synapses and is in heteromeric complexes with the glutamate receptor subunit GluR2. These data indicate that a biochemical correlate of long term potentiation occurs at synapses in receptor complexes in a final, downstream, postsynaptic effector of long term potentiation during learning in vivo, further strengthening the link between long term potentiation and memory.     

海马长时程增强与26S蛋白酶复合体活性变化的关系

实验观察了大鼠海马脑片上突触传递长时程增强(long term potentiation,LTP)的产生和维持中26S蛋白酶复合体活性的动态变化过程,初步分析了介导其变化的受体途径。结果显示:强直刺激前,26S蛋白酶复合体活性为190±14.3 cpm/(100 μg·2 h),强直刺激诱导fEPSP斜率增加10 min时,其活性升为273±18.3 epm/(100μg·2 h),强直刺激诱导fEPSP斜率增加60 min时,26S蛋白酶复合体活性又降为210±12.8 cpm/(100μg·2 h)。NMDA受体特异阻断剂AP-5在损害L1P产生的同时,抑制26S蛋白酶复合体活性升高。实验结果提示:大鼠海马LTP产生过程中,26S蛋白酶复合体活性存在一个短时间的,依赖于N-methyl-D-aspartate(NMDA)受体的升高过程。     

Ablation of Ca2+ channel beta3 subunit leads to enhanced N-methyl-D-aspartate receptor-dependent long term potentiation and improved long term memory

The beta subunits of voltage-dependent Ca(2+) channels (VDCCs) have marked effects on the properties of the pore-forming alpha(1) subunits of VDCCs, including surface expression of channel complexes and modification of voltage-dependent kinetics. Among the four different beta subunits, the beta(3) subunit (Ca(v)beta3) is abundantly expressed in the hippocampus. However, the role of Ca(v)beta3 in hippocampal physiology and function in vivo has never been examined. Here, we investigated Ca(v)beta3-deficient mice for hippocampus-dependent learning and memory and synaptic plasticity at hippocampal CA3-CA1 synapses. Interestingly, the mutant mice exhibited enhanced performance in several hippocampus-dependent learning and memory tasks. However, electrophysiological studies revealed no alteration in the Ca(2+) current density, the frequency and amplitude of miniature excitatory postsynaptic currents, and the basal synaptic transmission in the mutant hippocampus. On the other hand, however, N-methyl-d-aspartate receptor (NMDAR)-mediated synaptic currents and NMDAR-dependent long term potentiation were significantly increased in the mutant. Protein blot analysis showed a slight increase in the level of NMDAR-2B in the mutant hippocampus. Our results suggest a possibility that, unrelated to VDCCs regulation, Ca(v)beta3 negatively regulates the NMDAR activity in the hippocampus and thus activity-dependent synaptic plasticity and cognitive behaviors in the mouse.     

葛根素对血管性痴呆大鼠海马突触传递长时程增强的影响

目的：探讨葛根素对血管性痴呆大鼠长时程增强（LTP）的影响。方法：采用Morris水迷宫和LTP诱导法检测血管性痴呆模型大鼠空间学习记忆能力和海马突触传递的改变。结果：模型组大鼠不同时间点测得的Morris水迷宫逃逸潜伏期均较假手术组明显延长,海马LTP诱导率明显降低,而药物组大鼠EL均短于模型组,但LTP诱导率明显增强。结论：葛根素可增强血管性痴呆大鼠突触传递功能,改善其长期存在的学习记忆障碍。     

Mechanical transmission at spine synapses: Short-term potentiation and working memory

Do dendritic spines, which comprise the postsynaptic component of most excitatory synapses, exist only for their structural dynamics, receptor trafficking, and chemical and electrical compartmentation? The answer is no. Simultaneous investigation of both spine and presynaptic terminals has recently revealed a novel feature of spine synapses. Spine enlargement pushes the presynaptic terminals with muscle-like force and augments the evoked glutamate release for up to 20 min. We now summarize the evidence that such mechanical transmission shares critical features in common with short-term potentiation (STP) and may represent the cellular basis of short-term and working memory. Thus, spine synapses produce the force of learning to leave structural traces for both short and long-term memories.     

Effects of high power microwave pulses on synaptic transmission and long term potentiation in hippocampus

Effects of short, extremely high power microwave pulses (EHPP) on neuronal network function were explored by electrophysiological techniques in the isolated rat hippocampal slice model. Population spikes (PS) in the CA1 area were evoked by repeated stimulation (1 per 30 s) of the Schaffer collateral pathway. A brief tetanus (2 s at 50 Hz) was used to induce long term potentiation (LTP) of synaptic transmission. In three different series of experiments with a total of 160 brain slices, the EHPP irradiation was performed before, during, or after the tetanus. The EHPP carrier frequency was 9.3 GHz, the pulse width and repetition rate were from 0.5 to 2 micros and from 0.5 to 10 Hz, respectively, and the peak specific absorption rate (SAR) in brain slices reached up to 500 MW/kg. Microwave heating of the preparation ranged from 0.5 degrees C (at 0.3 kW/kg time average SAR) to 6 degrees C (at 3.6 kW/kg). The experiments established that the only effect caused by EHPP exposure within the studied range of parameters was a transient and fully reversible decrease in the PS amplitude. Recovery took no more than a few minutes after the cessation of exposure and return to the initial temperature. This effect's features were characteristic of an ordinary thermal response: it was proportional to the temperature rise but not to any specific parameter of EHPP, and it could also be induced by a continuous wave (CW) irradiation or conventional heating. Irradiation did not affect the ability of neurons to develop LTP in response to tetanus or to retain the potentiated state that was induced before irradiation. No lasting or delayed effects of EHPP were observed. The results are consistent with the thermal mechanism of EHPP action and thus far provided no indication of EHPP-specific effects on neuronal function.     

Capacitative calcium entry induces hippocampal long term potentiation in the absence of presenilin-1

Presenilins, whose mutant forms are the most common cause of early onset familial Alzheimer's disease, are involved in two very distinct processes: (i) proteolytic activity as gamma-secretase acting on amyloid precursor protein to produce amyloid peptides and (ii) storage of Ca2+ in the endoplasmic reticulum (ER). In particular, absence of presenilin-1 (PS1) was claimed to potentiate capacitative calcium entry (CCE), i.e. the mechanism of replenishment of ER Ca2+ stores. However, until now, evidence in favor of the latter role has been obtained only in isolated or cultured cells and not on neurons in situ. Here, we studied the strength of the synapses between Schaffer's collaterals and CA1 neurons in hippocampal slices when they were submitted first to Ca(2+)-free medium containing thapsigargin and subsequently to normal artificial cerebrospinal fluid, a procedure known to trigger CCE. We demonstrate that Ca2+ influx via the CCE mechanism is sufficient to trigger robust long term potentiation of the synapses in hippocampal slices from transgenic mice with a postnatal, neuron-specific ablation of PS1, but remarkably not from wild-type mice. Our data establish for the first time in neurons confined in normal neuronal networks that PS1 acts on the refilling mechanism of ER Ca2+ stores.     

Lipopolysaccharide inhibits long term potentiation in the rat dentate gyrus by activating caspase-1

Lipopolysaccharide, a component of the cell wall of Gram-negative bacteria, may be responsible for at least some of the pathophysiological sequelae of bacterial infections, probably by inducing an increase in interleukin-1beta (IL-1beta) concentration. We report that intraperitoneal injection of lipopolysaccharide increased hippocampal caspase-1 activity and IL-1beta concentration; these changes were associated with increased activity of the stress-activated kinase c-Jun NH(2)-terminal kinase, decreased glutamate release, and impaired long term potentiation. The degenerative changes in hippocampus and entorhinal cortical neurones were consistent with apoptosis because translocation of cytochrome c and poly(ADP-ribose) polymerase cleavage were increased. Inhibition of caspase-1 blocked these changes, suggesting that IL-1beta mediated the lipopolysaccharide-induced changes.     

Speaking out of turn: a role for silent synapses in pain

Severe tissue or nerve injury can result in a chronic and inappropriate sensation of pain, mediated in part by the sensitization of spinal dorsal horn neurons to input from primary afferent fibers. Synaptic transmission at primary afferent synapses is mainly glutamatergic. Although a functioning excitatory synapse contains both alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptors in the postsynaptic membrane, recent evidence suggests that dorsal horn neurons contain some "silent" synapses, which exhibit purely NMDA receptor-mediated evoked postsynaptic currents and do not conduct signals at resting membrane potential. Serotonin, which is released onto dorsal horn neurons by descending fibers from the rostroventral medulla, potentiates sensory transmission by activating silent synapses on those neurons, i.e., by recruiting functional AMPA receptors to the postsynaptic membrane. This phenomenon may contribute to the hyperexcitability of dorsal horn neurons seen in chronic pain conditions.     

Assessing long term backache after childbirth.

OBJECTIVES--To investigate the factors associated with long term backache after childbirth, to assess all women reporting new onset long term backache, and to investigate any relation with pain relief in labour. DESIGN--Data collected from obstetric records and postal questionnaires or telephone interviews on morbidity after childbirth from all women delivering their first baby between March 1990 and February 1991, followed by analysis of data collected from outpatient consultations. SETTING--St Thomas''s Hospital, London. SUBJECTS--Questionnaires were sent to 1615 women who had delivered their first baby in the defined period; 1015 either replied by post or were contacted by telephone. RESULTS--299 women (29.5% of responders) reported backache lasting more than six months and of these 156 (15.4%) said they had had no back problems previously. Those women who had received epidural analgesia in labour were significantly more likely to report new onset backache (17.8%; 95% confidence interval 14.8% to 20.8%) than those who did not (11.7%; 8.6% to 14.8%). Younger women, unmarried women, and those reporting other antenatal symptoms were significantly more likely to report new long term backache. The 156 women reporting new backache were asked to attend an outpatient clinic and 36 (23%) did so. The majority had a postural backache which was not severe. Psychological factors were present in 14 women. CONCLUSIONS--Though new long term backache is reported more commonly after epidural analgesia in labour, it tends to be postural and not severe. There were no differences in the nature of the backache between those who had or had not received epidural analgesia in labour.