AMPA受体介导的突触可塑性与药物依赖

突触可塑性改变是形成药物依赖长期效应的病理基础,兴奋性氨基酸受体在其中起十分重要的作用。近年来的研究表明,多种药物依赖过程与AMPA受体有关。联系药物依赖所致的AMPA受体的变化与神经元的可塑性改变,探讨AMPA受体介导药物依赖的形成机制,可为进一步理解AMPA受体在药物依赖中的作用提供帮助。     

异丙酚对大鼠海马CA1区突触传递可塑性的影响

目的研究异丙酚对海马CAl区突触传递和可塑性的影响。方法断头分离Wistar大鼠海马半脑,制备400μm厚度海马脑片。45张脑片分为六组。脂肪乳剂组和异丙酚组的脑片以印防己毒素预孵30min,然后加入450μl脂肪乳剂或异丙酚(相当于500μmol/L),观察对兴奋性突触后电流(EPSC)的影响。脂肪乳剂长时程增强(LTP)组、脂肪乳剂长时程抑制(LTD)组、异丙酚LTP组、异丙酚LTD组的脑片以90μl脂肪乳剂或异丙酚(相当于100 μmol/L)预孵60 min,给予高频刺激(HFS)或低频刺激(LFS),记录LTP或LTD的发生情况。结果 脂肪乳剂对EPSC无影响(P>0.05);500 μmol/L异丙酚使2/3细胞EPSC下降至基础值的67.5％(P<0.05),使1,3细胞EPSC上升至基础值的140.3％(P<0.05)。脂肪乳剂LTP组给予HFS后EPSC值为基础值的151.6％(P<0.05),脂肪乳剂LTD组给予LFS后EPSC值为基础值的57.9％(P<0.05);异丙酚LTP组给予HFS后,LTP可以产生但不能维持,HFS后EPSC值为基础值的98.8％(P>0.05),异丙酚LTD组给予LFS后EPSC值为基础值的40.8％(P<0.05),明显低于脂肪乳剂LTD组(P<0.05)。结论异丙酚对大鼠海马CAl区突触传递具有双重影响,出现抑制和兴奋两种效果;异丙酚损害大鼠海马CAl区锥体神经元LTP的维持而易化LTD。     

Traumatic brain injury and its effects on synaptic plasticity

Animal models have been used to simulate the effects of human head trauma. Some of these models have been further utilized to explore how trauma affects specific mechanisms of synaptic plasticity, a cellular model for memory consolidation. Unfortunately, these studies have been more limited in number in spite of their importance for understanding alterations in synaptic plasticity and memory impairments in trauma patients. Research in this area includes well characterized trauma models, genetically engineered animals and neuroprotective studies. One largely ignored but important idea that is entertained here is that trauma may be a crucial aetiological factor for the loss of potassium homeostasis. Moreover, high extracellular potassium has been shown to promote abnormal expression of hippocampal synaptic plasticity due to K + -induced glutamate release, thus showing important relationships among trauma, glia, potassium and synaptic plasticity. Collectively, this mini review surveys investigations of head trauma involving altered mechanisms of synaptic plasticity and how trauma may be related to increased risk for dementia.     

Isoflurane blocks synaptic plasticity in the mouse hippocampus

BACKGROUND: The volatile anesthetic isoflurane depresses glutamatergic transmission. In this study, the authors investigated the effects of isoflurane on the induction of long-term potentiation (LTP) and long-term depression (LTD) in slices from the juvenile and adult mouse hippocampus. Both forms of synaptic plasticity involve the activation of glutamate receptors. METHODS: Field excitatory postsynaptic potentials and excitatory postsynaptic currents from neurons in the CA1 area were evoked by stimulation of the Schaffer collateral-commissural pathway. Two independent synaptic inputs were stimulated. Clinically relevant concentrations (0.2-0.3 mM) of isoflurane were added to the perfusion solution. RESULTS: Field excitatory postsynaptic potentials from slices of juvenile and adult mice were depressed to 37.3 +/- 6.1% and 58.3 +/- 7.4%, respectively, and excitatory postsynaptic currents were reduced to 36.7 +/- 5.4% by isoflurane. A brief tetanic stimulation (100 Hz, 1 s) induced stable LTP of field excitatory postsynaptic potentials. In the presence of isoflurane, tetanization failed to induce LTP. The effect of isoflurane on LTP induction was reversible and could be prevented by antagonizing gamma-aminobutyric acid type A receptors (GABAA). Low-frequency stimulation (1 Hz/900 pulses) induced LTD. In the presence of isoflurane, low-frequency stimulation failed to induce LTD. CONCLUSIONS: The prevention of the isoflurane-induced depression of LTP by the GABAA antagonist picrotoxin suggests an involvement of GABAA receptors. An enhancement of the efficacy of GABA-mediated inhibitory synaptic transmission prevents the depolarization of the postsynaptic membrane during tetanus, necessary for the induction of use-dependent alteration of synaptic strength. An impairment of these processes may be a cause for the transient loss of recall and cognitive impairment after anesthesia in juvenile and adult brains.     

钙黏蛋白在突触发育和突触可塑性调节中的作用

背景 钙黏蛋白（cadherin）是一类存在于细胞表面的跨膜糖蛋白,最初被认为是一种钙离子依赖性的细胞黏附分子,主要参与调节细胞黏附、促进细胞增殖、维持细胞极性等过程.近几年对cadherin调节突触发育和突触可塑性的研究取得了较大进展. 目的 围绕cadherin在突触发育和突触可塑性过程中的作用及其相关分子机制简要作一综述,旨在为神经系统疾病的治疗提供理论依据. 内容 Cadherin的概述,cadherin在突触发育和突触可塑性调节中的作用以及相关分子机制,cadherin与神经疾病. 趋向 随着cadherin在调节突触发育和突触可塑性过程中的研究不断深入,cadherin将成为治疗神经疾病的一个新型的靶点.     

全麻药物对突触可塑性影响的研究进展

背景 全麻药物作用于中枢神经系统的多种神经递质和受体靶点,而这些又恰恰是神经突触可塑性相关机制中的重要成分或结构,通过调节突触可塑性进而对学习记忆功能产生广泛而多样的作用. 目的 推进对全麻药物麻醉机理的认识. 内容 分析全麻药物对大脑突触可塑性影响的研究进展 趋向 为临床麻醉药物的合理使用、减少术中知晓和术后认知功能障碍等相关并发症的发生提供科学依据.     

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.     

右美托咪定对睡眠剥夺小鼠记忆能力和突触可塑性的影响

目的 观察右美托咪定对睡眠剥夺小鼠记忆能力和突触可塑性的影响。
方法 选取SPF级雄性健康C57BL/6小鼠63只,6～8周龄,体重21～25 g。随机分为四组：对照组（C组,n=12）、右美托咪定注射组（D组,n=14）、睡眠剥夺组（S组,n=18）和睡眠剥夺+右美托咪定注射组（SD组,n=19）。S组和SD组小鼠给予持续3 d的睡眠剥夺,C组和D组小鼠相同时间内置入条件完全相同的剥夺仪中不进行睡眠剥夺。剥夺期间,D组和SD组小鼠24 h内尾静脉注射右美托咪定（每次100 μg/kg,每天13:00和15:00共两次）,连续3 d;C组和S组小鼠同一时间尾静脉注射等容量生理盐水。剥夺结束后,实验第4天进行Y迷宫实验,实验第5天进行新物体实验,新物体实验结束后立即取海马组织,采用Western blot检测海马组织突触后PSD95蛋白含量。
结果 与S组比较,C组和D组摄食量明显增加（P＜0.05）;S组和SD组摄食量差异无统计学意义。与S组比较,C组、D组和SD组探索新物体时间比例及Y迷宫实验中进入正确臂循环次数所占比例明显升高,海马组织突触后PSD95蛋白含量明显升高（P＜0.05）。与C组比较,S组小鼠突触结构明显受损;与S组比较,SD组突触结构明显改善。
结论 右美托咪定可以改善睡眠剥夺小鼠记忆能力,促进突触可塑性。     

Homeostatic synaptic plasticity can explain post-traumatic epileptogenesis in chronically isolated neocortex

Chronically isolated neocortex develops chronic hyperexcitability and focal epileptogenesis in a period of days to weeks. The mechanisms operating in this model of post-traumatic epileptogenesis are not well understood. We hypothesized that the spontaneous burst discharges recorded in chronically isolated neocortex result from homeostatic plasticity (a mechanism generally assumed to stabilize neuronal activity) induced by low neuronal activity after deafferentation. To test this hypothesis we constructed computer models of neocortex incorporating a biologically based homeostatic plasticity rule that operates to maintain firing rates. After deafferentation, homeostatic upregulation of excitatory synapses on pyramidal cells, either with or without concurrent downregulation of inhibitory synapses or upregulation of intrinsic excitability, initiated slowly repeating burst discharges that closely resembled the epileptiform burst discharges recorded in chronically isolated neocortex. These burst discharges lasted a few hundred ms, propagated at 1-3 cm/s and consisted of large (10-15 mV) intracellular depolarizations topped by a small number of action potentials. Our results support a role for homeostatic synaptic plasticity as a novel mechanism of post-traumatic epileptogenesis.     

Horizontal synaptic connections in monkey prefrontal cortex: an in vitro electrophysiological study

In monkey dorsolateral prefrontal cortex (PFC), long-distance, horizontally oriented intrinsic axon collaterals interconnect clusters of pyramidal neurons in the supragranular layers. In order to study the electrophysiological responses mediated by these long-distance projections, an in vitro slice preparation of monkey PFC was used to obtain whole-cell patch clamp recordings from layer 3 pyramidal neurons. Using in vivo tracer injections, we found that long-distance projections were well preserved in PFC slices cut in the coronal plane. Postsynaptic currents were evoked by low-intensity electrical extracellular stimulation applied successively to 20-30 discrete sites located up to 2200 micron lateral to the recorded cell. Several criteria were applied to discriminate between mono- and polysynaptic responses. Long-distance monosynaptic connections were mediated by fibers with relatively slow conduction velocity (0.14 m/s). Excitatory postsynaptic currents (EPSCs) evoked by stimulation of short- or long-distance horizontal connections did not differ in kinetic properties. The majority (77%) of the 35 layer 3 PFC neurons studied were monosynaptic targets of long-distance connections. EPSCs mediated by long-distance connections had amplitudes that were similar or even larger than short-distance EPSCs, suggesting that excitatory input provided by the former was relatively robust. For most neurons (87.5%) in which a full complement of monosynaptic EPSCs was evoked by multisite stimulation, the EPSC amplitude as a function of stimulation distance from the recorded cells exhibited statistically significant peaks. The spacing between peaks was similar to the spacing between interconnected clusters of neurons observed in previous anatomical studies. The results show that long-distance excitatory connections constitute a significant intrinsic pathway of synaptic communication in layer 3 of monkey PFC.     

Abnormal cortical synaptic plasticity in primary motor area in progressive supranuclear palsy

No study has yet investigated whether cortical plasticity in primary motor area (M1) is abnormal in patients with progressive supranuclear palsy (PSP). We studied M1 plasticity in 15 PSP patients and 15 age-matched healthy subjects. We used intermittent theta-burst stimulation (iTBS) to investigate long-term potentiation (LTP) and continuous TBS (cTBS) to investigate long-term depression (LTD)-like cortical plasticity in M1. Ten patients underwent iTBS again 1 year later. We also investigated short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) in M1 with paired-pulse transcranial magnetic stimulation, tested H reflex from upper limb flexor muscles before and after iTBS, and measured motor evoked potential (MEP) input-output (I/O) curves before and after iTBS. iTBS elicited a significantly larger MEP facilitation after iTBS in patients than in healthy subjects. Whereas in healthy subjects, cTBS inhibited MEP, in patients it significantly facilitated MEPs. In patients, SICI was reduced, whereas ICF was normal. H reflex size remained unchanged after iTBS. Patients had steeper MEP I/O slopes than healthy subjects at baseline and became even more steeper after iTBS only in patients. The iTBS-induced abnormal MEP facilitation in PSP persisted at 1-year follow-up. In conclusion, patients with PSP have abnormal M1 LTP/LTD-like plasticity. The enhanced LTP-like cortical synaptic plasticity parallels disease progression.     

Dynamic properties of excitatory synaptic connections involving layer 4 pyramidal cells in adult rat and cat neocortex

To investigate the properties of excitatory connections between layer 4 pyramidal cells and whether these differed between rat and cat, paired intracellular recordings were made with biocytin filling in slices of adult neocortex. These connections were also compared with those from layer 4 spiny cells to layer 3 pyramids and connections between layer 3 pyramids. Connectivity ratios for layer 4 pyramid-pyramid pairs (1:14 cat, 1:18 rat) appeared lower than for the other types of connections studied in parallel, but excitatory postsynaptic potential (EPSP) amplitudes and time course were not significantly different either between species or across types of connection. Layer 4 pyramids targeted postsynaptic basal dendrites in both species, whether the pyramidal target was in layer 4 or layer 3. Within layer 4, relationships between mean EPSP amplitude, numbers of putative contacts, and distance between connected pairs indicated a rapid decline in connectivity strength with distance, equivalent to 3.4 mV and 10 synapses per 100 microm separation, from a maximum of 4 mV and 10 synapses at 0 microm. However, a subset, of burst-firing layer 4 pyramids, appeared to make no connections with other layer 4 spiny cells. Second EPSPs were depressed by 36% in rat and 28% in cat relative to first EPSPs at interspike intervals <15 ms. Subsequent EPSPs in brief trains were further depressed. Depression was predominantly presynaptic in origin. Recovery from depression could not be described adequately by a simple exponential for individual connections; it included peaks and troughs with periodicities of 10-15 ms. Complex relationships between the first 2 interspike intervals and third EPSP amplitude were also apparent in all connections so studied. Large third EPSPs followed specific combinations of first and second interspike intervals so that increasing, or decreasing, one without changing the other resulted in a smaller third EPSP. Finally, the outputs of layer 4 spiny cells to layer 3 exhibited partial recovery from depression during longer high-frequency trains, a property not apparent in the other connections studied.     

Roles of protein kinase A and protein kinase G in synaptic plasticity in the visual cortex

Monocular deprivation leads to clear physiological and anatomical changes in the visual cortex known as ocular dominance plasticity. Protein kinase A (PKA) is necessary for ocular dominance plasticity, while protein kinase G (PKG) is not. We have now tested the role of PKA and PKG in long-term potentiation (LTP) and long-term depression (LTD). We have shown that PKA inhibitors have a major effect on both LTP and LTD in the visual cortical slices, whereas a PKG inhibitor affects LTP but not LTD. The PKA activator, 8-chloroadenosine-3',5'-monophosphorothioate, Sp-isomer (Sp-8-Cl-cAMPS), by itself induces a slowly rising form of LTP, which is occluded by theta-burst stimulation (TBS)-induced LTP. These results support the point that the PKA signaling pathway is crucial for neuronal plasticity in visual cortex, and the dissociation of the role of PKA and PKG in long-term synaptic plasticity in the visual cortex suggests that LTP alone is not sufficient to support ocular dominance plasticity, or LTD plays a more fundamental role than LTP in ocular dominance plasticity.     

Involvement of the mGluR1 receptor in hippocampal synaptic plasticity and associative learning in behaving mice

Metabotropic glutamate receptor 1 (mGluR1) has been related to processes underlying learning in hippocampal circuits, but demonstrating its involvement in synaptic plasticity when measured directly on the relevant circuit of a learning animal has proved to be technically difficult. We have recorded the functional changes taking place at the hippocampal CA3-CA1 synapse during the acquisition of an associative task in conscious mice carrying a targeted disruption of the mGluR1 gene. Animals were classically conditioned to evoke eyelid responses, using a trace (conditioned stimulus [CS], tone; unconditioned stimulus [US], electric shock) paradigm. Acquisition of this task was impaired in mutant mGluR1(+/-) mice and abolished in mGluR1(-/-) mice. A single pulse presented to Schaffer collaterals during the CS-US interval evoked a monosynaptic field excitatory postsynaptic potential at ipsilateral CA1 pyramidal cells, whose slope was linearly related to learning evolution in controls but not in mGluR1 mutants. Long-term potentiation evoked by train stimulation of Schaffer collaterals was also impaired in both mGluR1(+/-) and mGluR1(-/-) animals. Administration of the selective mGluR1 antagonist (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental [c]furan-1-on to wild-type animals mimicked the functional changes associated to mGluR1 insufficiency in mutants. Thus, mGluR1 is required for activity-dependent synaptic plasticity and associative learning in behaving mice.     

线粒体保护剂对异氟醚麻醉老年小鼠海马线粒体功能和突触可塑性的影响

目的观察线粒体保护剂SS-31对异氟醚麻醉老年小鼠线粒体功能和突触可塑性的影响。方法老年雄性C57BL/6小鼠48只随机均分为四组(n=12):氧气+生理盐水组(CN组)、氧气+SS-31组(CS组)、异氟醚+生理盐水组(IN组)和异氟醚+SS-31组(IS组)。根据分组,于氧气或异氟醚吸入前30min腹腔注射等容生理盐水(CN、IN组)或SS-31(5mg/kg,CS、IS组),于气体吸入2h后取小鼠海马组织。提取线粒体检测电子传递链复合物Ⅰ~Ⅳ酶活性、三磷酸腺苷(ATP)和线粒体膜电位(MMP)水平,组织匀浆检测突触可塑性相关蛋白突触蛋白1(synapsin-1)、突触后密度蛋白95(PSD-95)、NMDA受体2A(NMDAR2A)、NMDAR2B、钙调蛋白依赖的蛋白激酶Ⅱα(CaMKⅡα)和CaMKⅡβ的含量。结果与IN组比较,IS组复合物Ⅰ酶活性、ATP和MMP水平升高,synapsin-1和PSD-95含量增加,NMDAR2B、CaMKⅡα和CaMKⅡβ含量降低(P0.05),而复合物Ⅱ~Ⅳ酶活性及NMDAR2A含量差异无统计学意义。结论线粒体保护剂SS-31可改善异氟醚麻醉所致老年小鼠海马线粒体及神经元突触可塑性损伤。     

Involvement of cannabinoid CB1 receptor in associative learning and in hippocampal CA3-CA1 synaptic plasticity

We studied, in behaving mice, the contribution of CB1 receptors to the activity-dependent changes induced at the hippocampal CA3-CA1 synapse by associative learning and following experimentally evoked long-term potentiation (LTP). Mice were classically conditioned to evoke eyelid responses with a trace paradigm using a tone as conditioned stimulus (CS) and an electric shock as unconditioned stimulus (US). Field excitatory postsynaptic potentials (fEPSPs) were evoked at the CA3-CA1 synapse during the CS-US interval across training. Conditioning was performed in presence of an agonist (WIN55,212-2) alone or with an antagonist (AM251) of the CB1 receptor, injected either systemically or locally. Conditioned responses (CRs) and fEPSP potentiation were depressed by WIN55,212-2. LTP was evoked by high-frequency stimulation of Schaffer collaterals after systemic or local WIN55,212-2 and AM251 injections. WIN55,212-2 affected the induction phase of LTP, mainly when injected locally. The addition of AM251 canceled out the effects of WIN55,212-2. Similar experiments were carried out in animals lacking the CB1 receptor (CB1(-/-) mice) and following silencing of hippocampal CB1 receptors (CB1R-siRNA-injected animals). In this case, CRs (CB1(-/-) mice) and LTP (CB1(-/-) and CB1R-siRNA-injected mice) reached lower values than their respective controls. Results offer new insights for understanding CB1 receptor contribution to associative learning and to CA3-CA1 synaptic plasticity.