Flip side of synaptic plasticity: Long-term depression mechanisms in the hippocampus

There is growing interest in the phenomenon of long-term depression (LTD) of synaptic efficacy that, together with long-term potentiation (LTP), is a putative information storage mechanism in mammalian brain. In neural network models, multiple learning rules have been used for LTD induction. Similarly, in neurophysiological studies of hippocampal synaptic plasticity, a variety of activity patterns have been effective at inducing LTD, although experimental paradigms are still being optimized. In this review the authors summarize the major experimental paradigms and compare what is known about the mechanisms of LTD induction. Although all paradigms appear to initiate a cascade of events leading to an elevated level of Ca²⁺ postsynaptically, the extent to which these paradigms involve common expression mechanisms has not yet been tested. The authors discuss several critical experiments that would address this latter issue. Numerous questions about the properties and mechanisms of LTD(s) in the hippocampus remain to be answered, but it is clear that LTD has finally arrived, and will soon be attracting attention equal to its flip side, LTP. © 1994 Wiley-Liss, Inc.     

老年大鼠学习行为与海马长时程突触增强和神经元核仁组织者的关系

主动回避条件反应率>80％的老年大鼠为学习好组,<30％的为学习差组。学习好组在高频短串刺激后颗粒细胞层出现海马长时程突触增强(LTP)效应:颗粒细胞核内Ag-NOR面积/胞核面积比值平均为0.154±0.0043;单个胞核内Ag-NOR平均为3.051±0.2212个,学习差组高频短串刺激引起颗粒细胞层群峰电位长时程抑制;颗粒细胞核内Ag-NOR面积/胞核面积比值平均为0.077±0.0023;单个胞核内Ag-NOR平均为1.839±0.1421个,2组间3指标均有显著差异,表明年老大鼠学习能力与LTP效应有关,学习差的老年大鼠海马齿状回颗粒细胞rDNA的转录活性较学习好的明显降低。     

电针对大鼠海马兴奋性突触后电位长时程增强的作用

目的 观察电针对麻醉状态下正常和东莨菪碱引起的学习记忆减退模型大鼠海马突触EPSP长时程增强(LTP)的作用。方法 引导大鼠海马齿状回颗粒细胞层突触后兴奋性电位群(EPSPs)，强直刺激(HFS)大脑皮层前穿质区引起海马突触LTP反应；用东莨菪碱制备学习记忆障碍模型；观察电针大椎和肾俞穴对正常和模型大鼠海马LTP的影响。结果 电针对HFS诱发的海马突触LTP效应，其作用强于未电针组，部分参数和时段有统计学意义(P＜0．05)，且维持时间长于后者；东莨菪碱i．p可显著抑制HFS诱发的海马突触LTP(P＜0．01)，电针能显著对抗这一抑制作用(P＜0．01；P＜0．05)。结论 电针对HFS引起的海马突触LTP有一定的易化作用，并对东莨菪碱引起的学习记忆障碍有显著的对抗作用。     

AMPA受体的代谢

近年来研究表明AMPA受体和突触可塑性密切相关，了解AMPA受体的整个生命过程有助于进一步认识突触可塑性，进而认识学习记忆的分子机制。AMPA受体在粗面内质网合成，经高尔基体修饰后，更多地分布在树突柄等非突触部位，LTP和CaMKⅡ可以启动AMPA受体的突触插入，之后通过其胞质内C端，由ABP，GRIP和NSF等蛋白介导，锚定于突触后致密斑。PICK1和PKC可以介导突触膜上AMPA受体的胞吞过程，离开突触后，AMPA受体或被重新循环利用，或被溶酶体最终降解。     

Quadro-pulse stimulation is more effective than paired-pulse stimulation for plasticity induction of the human motor cortex

OBJECTIVE: Repetitive paired-pulse transcranial magnetic stimulation (TMS) at I-wave periodicity has been shown to induce a motor-evoked potential (MEP) facilitation. We hypothesized that a greater enhancement of motor cortical excitability is provoked by increasing the number of pulses per train beyond those by paired-pulse stimulation (PPS). METHODS: We explored motor cortical excitability changes induced by repetitive application of trains of four monophasic magnetic pulses (quadro-pulse stimulation: QPS) at 1.5-ms intervals, repeated every 5s over the motor cortex projecting to the hand muscles. The aftereffects of QPS were evaluated with MEPs to a single-pulse TMS, motor threshold (MT), and responses to brain-stem stimulation. These effects were compared to those after PPS. To evaluate the QPS safety, we also studied the spread of excitation and after discharge using surface electromyograms (EMGs) of hand and arm muscles. RESULTS: Sizes of MEPs from the hand muscle were enhanced for longer than 75min after QPS; they reverted to the baseline at 90min. Responses to brain-stem stimulation from the hand muscle and cortical MEPs from the forearm muscle were unchanged after QPS over the hand motor area. MT was unaffected by QPS. No spreads of excitation were detected after QPS. The appearance rate of after discharges during QPS was not different from that during sham stimulation. CONCLUSIONS: Results show that QPS can safely induce long-lasting, topographically specific enhancement of motor cortical excitability. SIGNIFICANCE: QPS is more effective than PPS for inducing motor cortical plasticity.     

Suppression of hippocampal synaptic plasticity during slow-wave sleep

The influence of behavioral state on the induction of long-term enhancement (LTE) of hippocampal synapses was studied in chronically prepared animals. Perforant path evoked field potentials and EEG were recorded from fascia dentata during slow-wave sleep (SWS) and waking. LTE was strongly suppressed during SWS, suggesting that hippocampal information storage may be inactivated at certain phases of the sleep cycle. Normal LTE was observed in the same animals while awake.     

Differential effects of kindling and kindled seizures on place learning in the morris water maze

There is some controversy about the role of long-term potentiation (LTP) in spatial learning. The authors have found that triggering generalized kindled seizures with stimulation of the perforant path disrupts spatial learning in the Morris water maze but that kindling per se does not affect spatial learning. It is suggested that abnormal electrical activity induced by high-frequency stimulation of the perforant path may have been responsible for the disruption of spatial learning previously attributed to LTP saturation.     

NMDA receptor mediated dendritic plasticity in cortical cultures after oxygen-glucose deprivation

Dendrites and spines undergo dynamic changes in physiological and pathological conditions. Dendritic outgrowth has been observed in surviving neurons months after ischemia, which is associated with the functional compensation. It remains unclear how dendrites in surviving neurons are altered shortly after ischemia, which might reveal the mechanisms underlying neuronal survival. Using primary cortical cultures, we monitored the dendritic changes in individual neurons after oxygen-glucose deprivation (OGD). Two to four hours of OGD induced approximately 30–50% cell death in 24 h. However, the total dendritic length in surviving neurons was significantly increased after OGD with a peak at 6 h after re-oxygenation. The increase of dendritic length after OGD was mainly due to the sprouting rather than the extension of the dendrites. The dendritic outgrowth after 2 h of OGD was greater than that after 4 h of OGD. Application of NMDA receptor blocker MK-801 abolished OGD-induced dendritic outgrowth, whereas application of AMPA receptor antagonist CNQX had no significant effects. These results demonstrate a NMDA receptor-dependent dendritic plasticity shortly after OGD, which provides insights into the early response of surviving neurons after ischemia.     

Prior short-term synaptic disinhibition facilitates long-term potentiation and suppresses long-term depression at CA1 hippocampal synapses

Long-term potentiation (LTP) and long-term depression (LTD) are two main forms of activity-dependent synaptic plasticity that have been extensively studied as the putative mechanisms underlying learning and memory. Current studies have demonstrated that prior synaptic activity can influence the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. Here, we show that prior short-term synaptic disinhibition induced by type A gamma-aminobutyric acid (GABA) receptor antagonist picrotoxin exhibited a facilitation of LTP induction and an inhibition of LTD induction. This effect lasted between 10 and 30 min after washout of picrotoxin and was specifically inhibited by the L-type voltage-operated Ca2+ channel (VOCC) blocker nimodipine, but not by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphopentanoic acid (D-APV). Moreover, this picrotoxin-induced priming effect was mimicked by forskolin, an activator of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), and was blocked by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22536) and the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS). It was also found that following picrotoxin application, CA1 neurons have a higher probability of synchronous discharge in response to a population of excitatory postsynaptic potential (EPSP) of fixed slope (EPSP/spike potentiation). However, picrotoxin treatment did not significantly affect paired-pulse facilitation (PPF). These findings suggest that a brief of GABAergic disinhibition can act as a priming stimulus for the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. The increase in Ca2+ influx through L-type VOCCs in turn triggering a cAMP/PKA signalling pathway is a possible molecular mechanism underlying this priming effect.