皮质酮混合异丙酚对大鼠海马脑片CA1区长时程增强的影响

异丙酚是目前临床常用的静脉全麻药物,但是一些应用 异丙酚的患者在术后表现出遗忘等记忆功能障碍,这可能 与异丙酚影响突触的可塑性有关。皮质酮是啮齿类动物 重要的糖皮质激素,应激反应可以使动物体内皮质酮水平增 高,可抑制大鼠海马脑片长时程增强(LTP)的形成。长时 程抑制(LTD)和LTP是突触可塑性的重要形式,单独应用皮     

蛋白激酶Mζ维持长时记忆机制的研究进展

背景突触的长时程增强（long-term potentiation,LTP）作为神经系统可塑性与学习记忆机制的经典电生理模型已得到广泛研究,LTP诱导阶段的分子机制已明确,但在记忆存储阶段维持信息的分子机制目前仍不清楚。蛋白激酶Mζ（protein kinaseMζ,PKMζ）是一种具有持续活性的蛋白激酶C的亚型,是维持LTP及长时记忆的必要分子。目的现就当前PKM‘维持长时记忆机制的研究及其进展作一综述。内容分别描述了PKMζ的概述、记忆存储的分子机制、记忆擦除和相关疾病4个方面的内容。趋势人们将对PKMζ在保存信息、维持长时记忆中的作用及其可能机制进行更深入的研究。     

神经病理性痛大鼠海马突触长时程增强的变化

目的 探讨神经病理性痛大鼠海马突触长时程增强(LTP)的变化.方法 成年雄性Wistar大鼠18只,体重190～240 g,随机分为3组(n=6):对照组(C组)、假手术组(S组)和神经病理性痛组(NP组).采用结扎左侧L4,5脊神经的方法 制备大鼠神经病理性痛模型.对照组不制备模型;假手术组仅暴露左侧L4,5脊神经.于模型制备后7、14和21 d时观察大鼠痛行为学及足部形态;于模型制备前(基础状态)、制备后7、14和21 d时测定痛阈;于最后一次痛阈测定结束后3 d时记录海马CA1区兴奋性突触后电位(EPSP),以高频刺激(HFS)诱发LTP,LTP为HFS后EPSP峰值较基础值增大10%以上且维持时间≥60 min,行LTP分级,以评价其程度.结果 NP组模型制备后痛阈低于基础值及C组和S组,LTP程度高于C组和S组(P<0.05).结论 神经损伤可易化大鼠海马CA1区突触LTP,提示神经病理性痛可能与海马突触LTP的易化有关.     

NR2B在神经病理性痛大鼠海马突触长时程增强易化中的作用

目的 评价含2B亚基的N-甲基-D-天冬氨酸受体(NR2B)在神经病理性痛大鼠海马突触长时程增强(LTP)易化中的作用.方法 成年雄性Wistar大鼠24只,体重180～230 g,随机分为4组(n=6):假手术组(S组),假手术+Ro25-6981组(SR组)、神经病理性痛组(NP组)和神经病理性痛+Ro25-6981组(NR组).采用结扎L4,5左侧脊神经的方法制备大鼠神经病理性痛模型.于模型制备后7、14和21 d时观察大鼠痛行为学及足部形态;于模型制备前(基础状态)、制备后7,14和21 d时测定痛阈;于最后一次痛阈测定结束后3 d记录海马CAI区兴奋性突触后电位(EPSP),以高频刺激(HFS)诱发LTP,SR组和NR组于HFS前20 min经侧脑室输注Ro25-6981(NR2B特异性阻断剂)6 μl(2.3 μg),速率1μl/min.LTP为HFS后EPSP峰值较基础值增大10%以上且维持时间≥10 min,并行LTP分级,以评价其程度.结果 与S组和SR组比较,NP组和NR组各时点痛阈降低,NP组LTP程度升高(P<0.05),NR组LTP程度差异无统计学意义(P>0.05);NR组LTP程度组低于NP组(P<0.05).结论 神经病理性痛大鼠海马突触LTP的易化可能与NR2B的激活有关.     

神经病理性疼痛老年大鼠海马CA1区突触长时程增强的变化

目的观察神经病理性疼痛老年大鼠海马CA1区突触长时程增强(LTP)的变化。方法老年雄性Wistar大鼠15只,随机均分为三组。模型组,结扎左侧L4/L5脊神经;D-2-氨基-5-磷酸戊酸(AP5)组,侧脑室输注AP5,余同模型组;假手术组,操作同模型组,但不结扎。观察大鼠行为变化,连续3周测定大鼠电痛阈值,1次/周;记录海马CA1区树突层兴奋性突触后膜电位(EPSP)、输入/输出曲线及LTP的变化。结果模型组与AP5组大鼠术后行为异常,术后各时点电痛阈值低于术前值及假手术组相应时点值(P<0.05);三组基础EPSP幅值稳定,最大基础EPSP幅值的50%组间比较差异无统计学意义;模型组LTP高于其他两组(P<0.05)。结论结扎老年大鼠L4/L5脊神经所致的神经病理性疼痛,不干扰海马CA1区突触及锥体细胞兴奋性,但可易化该区突触LTP。     

多次氯胺酮给药对大鼠海马CA1区突触长时程增强的影响

目的研究多次氯胺酮给药对大鼠海马CA1区突触长时程增强(LTP)的影响。方法 30只SD大鼠,年龄35-45 d,随机分为Con1组、Con2组、Ket1组、Ket2组及Ket3组(n=6)。Con1组单次腹腔注射生理盐水2 ml,Con2组每3日腹腔注射生理盐水2ml一次,共5次,Ket1组单次腹腔注射氯胺酮70 mg·kg-1(生理盐水稀释至2 ml),Ket2组每3日腹腔注射氯胺酮70 mg·kg-1(生理盐水稀释至2ml)共3次,Ket3组每3日腹腔注射氯胺酮70 mg·kg-1(生理盐水稀释至2 ml)共5次。末次给药7 d后,制作海马脑片,应用大鼠海马脑片细胞外记录技术检测海马CA1区LTP和强直刺激后群体峰电位振幅(PSA)的变化。结果与Con1组、Con2组比较,Ket1组PSA与LTP诱发率差异无统计学意义 (P>0．05),Ket3组PSA与LTP诱发率降低(P<0．01)。结论多次氯胺酮给药可降低大鼠海马CA1 区突触的可塑性。     

氯胺酮对神经病理性痛大鼠海马长时程增强维持的影响

目的探讨氯胺酮对神经病理性痛大鼠海马CA1区突触长时程增强(LTP)维持的影响。方法成年雄性Wistar大鼠15只,随机均分为三组:神经病理性痛模型组(NP组)、氯胺酮1组(K1组)、氯胺酮2组(K2组)。采用结扎L4,5左侧脊神经的方法制备大鼠模型,于术前、术后1、2和3周观察大鼠痛行为学及足部形态;于术前、术后1、2和3周测定痛阈;于最后一次痛阈测定结束后3 d记录海马CA1区兴奋性突触后电位(EPSP),以高频刺激(HFS)诱发LTP。K1组于HFS前20 min经腹腔注射氯胺酮25 mg/kg,K2组HFS后60 min腹腔注射氯胺酮25 mg/kg。结果与术前比较,术后三组各时点痛阈降低(P<0.05);与基础值比较,NP组与K2组HFS后各时段EPSP幅值升高(P<0.05),与NP组和K2组比较,K1组HFS后各时段降低(P<0.05)。结论氯胺酮可阻滞神经病理性痛大鼠海马CA1区突触LTP的诱导,但不干扰维持。     

吸入麻醉药与老年人认识障碍

吸入麻醉药通过对大脑海马多种神经递质．受体以及脑神经营养因子（BDNF）表这的影响,改变突触可塑性,抑制长时程增强（LTP）的形成．从而对学习记忆功能产生广泛作用。因此,研究吸入麻醉药对学习记忆的影响．将对术后认知障碍（POCD）的产生机制作进一步的解释．并为临床指导用药提供理论依据。     

异氟醚吸入对老年大鼠长时程增强和脑源性神经营养因子的影响

目的通过观察异氟醚麻醉后老年大鼠海马长时程增强(LTP)和脑源性神经营养因子(BDNF)的变化,探讨术后认知功能障碍(POCD)的可能机制。方法健康雄性20月龄SD大鼠72只,随机分为异氟醚处理组(I组)和对照组(C组),每组36只。I组大鼠异氟醚吸入及维持浓度为1.2%,维持麻醉3h,以大鼠翻正反射的消失和恢复视为麻醉的开始和结束;C组大鼠不吸入麻醉药。I组大鼠分别于麻醉后7和14d断头,C组大鼠直接断头,常规切取海马组织,制备厚500μm的海马脑片,进行LTP斜率和幅值的测定,Western blot法检测BDNF表达水平。结果与C组比较,异氟醚处理后7和14dI组LTP的斜率和幅值均明显下降(P0.05)。与处理后7d比较,处理后14dI组LTP斜率和幅值均有明显升高(P0.05)。与C组比较,处理后7和14dI组BDNF表达水平明显下降(P0.05)。与处理后7d比较,处理后14dI组BDNF表达水平明显升高(P0.05)。结论异氟醚麻醉后,老年大鼠学习记忆能力损害可能持续14d以上,LTP的改变可能参与POCD的发生机制,并且与BDNF表达水平的降低有关。     

异氟醚对大鼠海马脑片突触长时程增强的影响

目的 评价异氟醚对大鼠海马脑片突触长时程增强(LTP)的影响.方法 雄性SD大鼠,断头后取出海马组织,制备厚400 μm的海马脑片.采用细胞外微电极记录技术,记录海马脑片CA1区细胞外群体峰电位(PS).取28张脑片,随机分为4组(n=7):用正常的人工脑脊液(ACSF)灌流海马脑片,记录正常的PS,待其稳定后,对照组继续灌流ACSF,不同浓度异氟醚组分别用含异氟醚0.125 mmol/L(异氟醚0.125组)、0.25 mmol/L(异氟醚0.25组)、0.5 mmol/L(异氟醚0.5组)的ACSF灌流,记录PS幅值.另取70张脑片,随机分为10组(n=7):用正常ACSF灌流海马脑片,记录稳定正常的PS 30 min,LTP组继续灌流ACSF,其余各组分别用含异氟醚0.125 mmol/L(异氟醚LTP 0.125组)、0.25 mmol/L(异氟醚LTP 0.25组)、0.5 mmol/L(异氟醚LTP 0.5组)、印防己毒素0 μmol/L(印防己毒素组)、荷包牡丹碱10 μmol/L(荷包牡丹碱组)、CGP353485 μmol/L(CGP35348组)、印防己毒素50 μmol/L+异氟醚0.25 mmol/L(印防己毒素+异氟醚组)、荷包牡丹碱10 μmol/L+异氟醚0.25 mmol/L(荷包牡丹碱+异氟醚组)、CGP353485 μmol/L+异氟醚0.25 mmol/L(CGP353485+异氟醚组)的ACSF灌流,记录PS 30 min后,施以100 Hz的高频强直刺激(HFS),记录PS幅值.结果 与对照组比较,异氟醚0.125组给药后10～45 min PS幅值降低,异氟醚0.25组和异氟醚0.5组给药后5～45 min PS幅值降低(P＜0.05或0.01).LTP组HFS后5～60 min PS幅值增高,较刺激前增加了(52±12)%(P＜0.01).与HFS前比较,异氟醚LTP 0.125组、异氟醚LTP 0.25组和异氟醚LTP 0.5组给予HFS后PS幅值差异无统计学意义(P＞0.05);与LTP组比较,3组PS幅值降低(P＜0.01).与HFS前比较,印防己毒素组、荷包牡丹碱组和CGP 35348组HFS后PS幅值增加(P＜0.01);与LTP组比较,3组PS幅值差异无统计学意义(P＞0.05).与HFS前比较,印防己毒素+异氟醚组和荷包牡丹碱+异氟醚组HFS后PS幅值增加(P＜0.01),CGP 353485+异氟醚组HFS后PS幅值差异无统计学意义(P＞0.05);与LTP组比较,印防己毒素+异氟醚组和荷包牡丹碱+异氟醚组HFS后PS幅值差异无统计学意义(P＞0.05),CGP353485+异氟醚组HFS后PS幅值降低(P＜0.01);与异氟醚LTP 0.25组比较,印防己毒素+异氟醚组和荷包牡丹碱+异氟醚组HFS后PS幅值增加(P＜0.01),CGP 353485+异氟醚组HFS后PS幅值差异无统计学意义(P＞0.05).结论 异氟醚可通过激活大鼠海马GABAA受体,抑制LTP的形成,从而影响记忆功能.     

Olfactory learning modifies predisposition for long-term potentiation and long-term depression induction in the rat piriform (olfactory) cortex

Learning-related modifications in predisposition for long-term potentiation (LTP) and long-term depression (LTD) were studied in brain slices of the rat piriform cortex following olfactory learning. Rats were trained to discriminate between pairs of odors until they demonstrated rule learning. We have previously shown that such training is accompanied by enhanced neuronal excitability and increased synaptic transmission in the intrinsic synaptic pathway. Here we show that the susceptibility for further enhancing synaptic connectivity by inducing LTP in slices from trained rats is markedly reduced after training, compared with slices from pseudo-trained and naive rats. Accordingly, while 900 stimuli at 1 Hz did not induce LTD in slices from control rats, it induced significant LTD in slices from trained rats. Post-tetanic potentiation (PTP) was also reduced after training, indicating that synaptic release is enhanced after odor learning, as previously suggested. We suggest that learning-related cellular modifications and activity-dependent synaptic plasticity share a common mechanism in the primary olfactory cortex. Our data also support the prediction generated according to the sliding modification threshold theory that learning should be accompanied by reduced capability of inducing LTP and increased susceptibility for LTD induction.     

The 5-hydroxytryptamine4 receptor exhibits frequency-dependent properties in synaptic plasticity and behavioural metaplasticity in the hippocampal CA1 region in vivo

Long-term plasticity, in the forms of long-term depression (LTD) and long-term potentiation (LTP), of synaptic transmission are thought to underlie memory. Biogenic amino acids modulate the expression of LTD and LTP. The serotonergic 5-hydroxytryptamine4 (5-HT4) receptor has been shown to influence learning and memory. However, little is known about the role of this receptor in synaptic plasticity. Here we show that although induction of LTP is unaffected by either pharmacological activation or inhibition of 5-HT4, application of the 5-HT4 receptor agonist, RS67333, completely blocks learning-induced depotentiation of LTP in the hippocampal CA1 region of freely moving rats, suggesting a role for 5-HT4 receptors in behavioural metaplasticity. In addition, the 5-HT4 antagonist RS39604 enhances the intermediate phase of LTD and converts short-term depression into persistent LTD (>24 h), suggesting a significant role for 5-HT4 receptors in the expression of LTD in CA1. Stimulation at 10 Hz causes transient synaptic depression. However, 5-HT4 antagonist application prior to 10 Hz stimulation leads to LTD, whereas agonist application leads to LTP expression. 5-HT4 receptors thus shift the frequency-response relationship for induction of plasticity. Together, these findings suggest a key role for 5-HT4 receptors in the regulation of synaptic plasticity and the determination of the particular properties of stored synaptic information.     

Beta-adrenoreceptors comprise a critical element in learning-facilitated long-term plasticity

A novel spatial environment consists of several different types of information that may be encoded by cellular information storage mechanisms such as long-term potentiation (LTP) and long-term depression (LTD). Arousal, mediated, for example, by activation of the noradrenergic system, is a critical factor in information acquisition and may enhance the encoding of novel spatial information. Using electrophysiological recordings of hippocampal responses in freely moving rats during spatial learning, we investigated the role of the beta-adrenoreceptor in Schaeffer collateral-CA1 synaptic plasticity. We found that novel exploration of spatial context facilitates induction of LTD that is inhibited by intracerebroventricular application of the beta-adrenoreceptor antagonist, propranolol. Long-lasting homosynaptic LTD, that was electrically induced by low-frequency stimulation, was unaffected by the antagonist. Although application of a beta-adrenoreceptor agonist (isoproterenol) did not affect electrically induced LTD, agonist application facilitated short-term depression (STD) into LTD and mimicked the augmentation, through spatial exploration, of STD into LTD. Exploration of a novel empty environment facilitated LTP that was prevented by application of propranolol. These results suggest that beta-adrenoreceptors may facilitate encoding of spatial information through synaptic plasticity in the hippocampus and that noradrenaline is a key factor in effective information acquisition.     

Volatile anesthetics and synaptic transmission in the central nervous system

Long-lasting changes in the synaptic efficacy of signaling between neurons in the central nervous system are thought to be involved in memory consolidation and recall. Such long-lasting changes were first demonstrated by Bliss et al. in 1973. They found that high frequency stimulation to the hippocampus produced an increase in the amplitude of excitatory postsynaptic potentials, which lasted at least for hours. This phenomenon is known as long-term potentiation (LTP). LTP occurs in many synaptic pathways, and some forms of LTP appear to be triggered by the influx of calcium through NMDA receptors. General anesthetics are thought to affect LTP, since clinically relevant concentrations of volatile anesthetics seem to modify ligand-gated ion channels such as glutamate receptors and GABA(A) receptors. Previous studies have shown that volatile anesthetics such as isoflurane and sevoflurane enhance GABA(A) receptor-mediated inhibition, suggesting that general anesthesia is produced, at least in part, by enhancing neural inhibition mediated by GABA(A) receptors. This review focuses on recent research concerning the effects of volatile anesthetics on synaptic transmission, synaptic plasticity, and clinically important diseases imparing synaptic transmission in the central nervous system.     

The metabotropic glutamate receptor mGluR3 is critically required for hippocampal long-term depression and modulates long-term potentiation in the dentate gyrus of freely moving rats

Group II metabotropic glutamate receptors (mGluRs) play an important role in the regulation of hippocampal synaptic plasticity in vivo: long-term potentiation (LTP) is inhibited and long-term depression (LTD) is enhanced by activation of these receptors. The contribution, in vivo, of the individual group II mGluR subtypes has not been characterized. We analysed the involvement of the subtype mGluR3 in LTD and LTP. Rats were implanted with electrodes to enable chronic measurement of evoked potentials from medial perforant path-dentate gyrus synapses. Neither the selective mGluR3 agonist, N-acetylaspartylglutamate (NAAG), nor the antagonist beta-NAAG, given intracerebrally, affected basal synaptic transmission. beta-NAAG significantly inhibited LTD expression. NAAG exhibited transient inhibitory effects on the intermediate phase of LTD. Whereas NAAG altered paired-pulse responses, beta-NAAG had no effect, suggesting that antagonism of mGluR3 prevents LTD via a postsynaptic mechanism, whereas agonist activation of mGluR3 modulates LTD at a presynaptic locus. NAAG impaired the expression of LTP, whereas beta-NAAG had no effect. NAAG effects on LTP were blocked by EGLU, a selective group II mGluR antagonist. Our data suggest an essential role for mGluR3 in LTD, and a modulatory role for mGluR3 in LTP, with effects being mediated by distinct pre- and post-synaptic loci.     

Dopaminergic modulation of long-term synaptic plasticity in rat prefrontal neurons

In rat prefrontal cortex (the prelimbic area of medial frontal cortex), the induction of long-term depression (LTD) and long-term potentiation (LTP) of glutamatergic synapses is powerfully modulated by dopamine. The presence of dopamine in the bathing medium facilitates LTD in slice preparations, whereas in the anesthetized intact brain, dopamine released from dopaminergic axon terminals in the prefrontal cortex facilitates LTP. Dopaminergic facilitation of LTD is at least partly achieved by postsynaptic biochemical mechanisms in which enzymatic processes triggered by dopamine receptor activation cooperate with those triggered by glutamate metabotropic receptor activation. Evidence suggests that dopamine facilitates LTP also in the slice condition. In this case, dopamine receptors must be pre-stimulated ('primed') before the application of high-frequency stimuli in the presence of dopamine. This procedure may mimic baseline stimulation of dopamine receptors that occurs under physiological conditions.     

Evidence for impaired long-term potentiation in schizophrenia and its relationship to motor skill learning

Several lines of evidence suggest that schizophrenia (SCZ) is associated with disrupted plasticity in the cortex. However, there is little direct neurophysiological evidence of aberrant long-term potentiation (LTP)-like plasticity in SCZ and little human evidence to establish a link between LTP to learning and memory. LTP was evaluated using a neurophysiological paradigm referred to as paired associative stimulation (PAS). PAS involves pairing of median nerve electric stimulation with transcranial magnetic stimulation (TMS) over the contralateral motor cortex (for abductor pollicis brevis muscle activation) delivered at 25-ms interstimulus interval. This pairing was delivered at a frequency of 0.1 Hz for 30 min. LTP was reflected by the change in motor evoked potentials (MEPs) before and after PAS. In addition, motor skill learning was assessed using the rotary pursuit task. Compared with healthy subjects, patients with SCZ demonstrated significant MEP facilitation deficits following PAS and impaired rotary-pursuit motor learning. Across all subjects there was a significant association between LTP and motor skill learning. These data provide evidence for disrupted LTP in SCZ, whereas the association between LTP with motor skill learning suggests that the deficits in learning and memory in SCZ may be mediated through disordered LTP.     

Altered bidirectional plasticity and reduced implicit motor learning in concussed athletes

Persistent motor/cognitive alterations and increased prevalence of Alzheimer's disease are known consequences of recurrent sports concussions, the most prevalent cause of mild traumatic brain injury (TBI) among youth. Animal models of TBI demonstrated that impaired learning was related to persistent synaptic plasticity suppression in the form of long-term potentiation (LTP) and depression (LTD). In humans, single and repeated concussive injuries lead to lifelong and cumulative enhancements of gamma-aminobutyric acid (GABA)-mediated inhibition, which is known to suppress LTP/LTD plasticity. To test the hypothesis that increased GABAergic inhibition after repeated concussions suppresses LTP/LTD and contributes to learning impairments, we used a paired associative stimulation (PAS) protocol to induce LTP/LTD-like effects in primary motor cortex (M1) jointly with an implicit motor learning task (serial reaction time task, SRTT). Our results indicate that repeated concussions induced persistent elevations of GABA(B)-mediated intracortical inhibition in M1, which was associated with suppressed PAS-induced LTP/LTD-like synaptic plasticity. This synaptic plasticity suppression was related to reduced implicit motor learning on the SRTT task relative to normal LTP/LTD-like synaptic plasticity in unconcussed teammates. These findings identify GABA neurotransmission alterations after repeated concussions and suggest that impaired learning after multiple concussions could at least partly be related to compromised GABA-dependent LTP/LTD synaptic plasticity.     

Bell-shaped D-serine actions on hippocampal long-term depression and spatial memory retrieval

D-Serine, the endogenous coagonist of N-methyl-D-aspartate receptors (NMDARs), is considered to be an important gliotransmitter, and is essential for the induction of long-term potentiation. However, less is known about the role of D-serine in another form of synaptic plasticity, long-term depression (LTD). In this study, we found that exogenous D-serine regulated LTD in the hippocampal CA1 region in a "bell-shaped" concentration-dependent manner through regulating the function of NMDARs in the same manner, whereas endogenous D-serine was activity-dependently released and, in turn, contributed to the induction of LTD during low-frequency stimulation. Furthermore, impairing glial functions with sodium fluoroacetate (NaFAC) reduced the magnitude of LTD, which could be restored by exogenous D-serine, indicating that endogenous D-serine is mainly glia-derived during LTD induction. More interestingly, similar to the effects on LTD, exogenous D-serine enhanced spatial memory retrieval in the Morris water maze in a bell-shaped dose-dependent manner and rescued the NaFAC-induced impairment of memory retrieval, suggesting links between LTD and spatial memory retrieval. Our study thus provides direct evidence of the bell-shaped D-serine actions on hippocampal LTD and spatial memory retrieval, and underscores the importance of D-serine in synaptic plasticity, learning, and memory.