氟西汀调控CUMS抑郁大鼠海马突触重塑

目的:探究氟西汀(fluoxetine)对慢性不可预见性温和刺激(chronic unpredictable mild stress,CUMS)抑郁大鼠海马突触重塑的m TOR和细胞自噬信号调控作用。方法:60只雄性Sprague-Dawley大鼠随机分成正常对照(control)组、CUMS组和氟西汀组。采用CUMS结合孤养法构建CUMS抑郁模型,期间给予氟西汀(20 mg·kg-1·d-1)灌胃治疗。通过体重变化、糖水测试水平及行为学实验验证模型建立,采用RT-PCR和Western blotting等生化方法测定突触重塑相关蛋白胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)、突触泡蛋白(synaptophysin,SYP),细胞凋亡相关蛋白Bcl-2、cleaved caspase-3,m TOR信号通路相关蛋白m TOR、4EBP1,自噬相关蛋白beclin 1、LC3 mRNA及蛋白表达水平的变化。结果:与control组相比,CUMS大鼠的体重、糖水摄取量、旷场实验总路程和中间停留时间均下降,差异具有统计学显著性。RT-PCR和Western blotting实验结果显示,与control组相比,CUMS组SYP和GFAP的mRNA和蛋白水平显著下调,Bcl-2表达下调,cleaved caspases-3上调,m TOR及下游靶分子4EBP1磷酸化水平下调,细胞自噬关键基因beclin1和LC3在mRNA和蛋白水平显著上调。氟西汀可以减缓以上结果中的上调或下调趋势,差异具有统计学显著性。结论:氟西汀可能通过下调细胞凋亡和自噬信号通路以及上调m TOR信号通路调节海马突触重塑并缓解抑郁症状。     

Activation of estrogen receptor-beta regulates hippocampal synaptic plasticity and improves memory

Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERalpha) and beta (ERbeta) remain unclear. Using pharmacological, biochemical and behavioral techniques, we demonstrate that the effects of estrogen on hippocampal synaptic plasticity and memory are mediated through ERbeta. Selective ERbeta agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERbeta knockout mice. In hippocampal slices, ERbeta activation enhanced long-term potentiation, an effect that was absent in slices from ERbeta knockout mice. ERbeta activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ERbeta agonist, but not an ERalpha agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ERbeta can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.     

Ca2+stores and hippocampal synaptic plasticity

For many years the importance of internal calcium stores (ICSs) in excitation–contraction coupling and endocrine function has been well recognized. With the discovery of ICSs in the CNS, evidence has accumulated regarding their role in neuronal function, and in particular, synaptic plasticity. In this review we focus on the involvement of ICSs in synaptic plasticity in the hippocampus.     

Genetic differences in hippocampal synaptic plasticity

Synaptic plasticity is considered a physiological substrate for learning and memory [Lynch MA (2004) Long-term potentiation and memory. Physiol Rev 84:87–136] that contributes to maladaptive learning in drug addiction [Schoenbaum G, Roesch MR, Stalnaker TA (2006) Orbitofrontal cortex, decision-making and drug addiction. Trends Neurosci 29:116–124]. Many studies have revealed that drug addiction has a strong hereditary component [Kosten TA, Ambrosio E (2002) HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats. Psychoneuroendocrinology 27:35–69; Uhl GR (2004) Molecular genetic underpinnings of human substance abuse vulnerability: likely contributions to understanding addiction as a mnemonic process. Neuropharmacology 47 (Suppl 1):140–147], however the contribution of the genetic background to drug-induced changes in synaptic plasticity has been scarcely studied. The present study reports on an analysis of long-term potentiation (LTP) and depotentiation in Lewis (LEW) and Fischer-344 (F344) rats, two inbred rat strains that show different proneness to drugs of abuse and are considered an experimental model of genetic vulnerability to addiction [Kosten TA, Ambrosio E (2002) HPA axis function and drug addictive behaviors: insights from studies with Lewis and Fischer 344 inbred rats. Psychoneuroendocrinology 27:35–69]. The induction of saturated-LTP was similar in LEW and F344 rats treated with saline or cocaine. However, only slices from LEW saline-treated rats showed the reversal of LTP; thus, the depotentiation of saturated-LTP was not observed in cocaine-injected LEW rats and in F344 animals (treated either with cocaine or saline). These results suggest significant differences in hippocampal synaptic plasticity between Lewis and Fischer 344 rats.     

Ca2+/calmodulin signaling in NMDA-induced synaptic plasticity

Repeated experiences induce a synaptic plasticity in neurons that can be very long lasting. The neurotransmitter, glutamate, acting through N-methyl-D-aspartate (NMDA) receptors is integrally involved in eliciting persistent changes in synaptic function resulting in learning and memory. The permeability of NMDA receptors to Ca2+ implies the close involvement of Ca2+ and the Ca2+-binding protein, calmodulin, in NMDA-induced synaptic plasticity. A notable example of NMDA-induced synaptic plasticity is long-term potentiation in the hippocampal CA1 region. The involvement of Ca2+ and calmodulin in the induction and expression of LTP has been intensively investigated and documented. Less well studied are neurochemical adaptations in another example of NMDA-induced synaptic plasticity, stimulant-induced behavioral sensitization. Although amphetamine and cocaine increase synaptic monoamines, glutamate is involved in the induction and expression of the sensitization. Activating NMDA receptors in dopamine midbrain cell bodies is required for inducing stimulant sensitization, implying a role for Ca2+ in this plasticity. The purpose of this review is to examine the role of Ca2+ and calmodulin in two examples of NMDA-based plasticity, LTP, and stimulant-induced behavioral sensitization. There are similarities in the neuroadaptations, although the role of Ca2+ and calmodulin has not been thoroughly investigated in the stimulant-induced plasticity.     

Androgen modulation of hippocampal synaptic plasticity

This review briefly summarizes recent developments in our understanding of the role of androgens in maintaining normal hippocampal structure. Studies in rats and vervet monkeys have demonstrated that removal of the testes reduces the density of synaptic contacts on dendritic spines of cornu ammonis 1 (CA1) pyramidal neurons. This effect is rapidly reversed by treatment with either testosterone or the non-aromatizable androgen dihydrotestosterone, suggesting that maintenance of normal synaptic density is androgen-dependent, via a mechanism that does not require intermediate estrogen biosynthesis. Similar effects of these androgens are observed in ovariectomized female rats, except that in the female the actions of testosterone include a substantial contribution from estrogen formation. The ability to stimulate hippocampal spine synapse density is not directly related to systemic androgenic potency: thus, weak androgens such as dehydroepiandrosterone exert effects that are comparable to those of dihydrotestosterone; while partial agonist responses are observed after injection of the synthetic antiandrogen, flutamide. These data provide a morphological counterpart to observations that androgens enhance cognitive function and mood state, suggesting that these effects may result at least in part from hippocampal neurotrophic responses. The unusual specificity of these responses raises the possibility that effects of androgens on the brain may be mediated via different mechanisms than the masculinizing actions of these steroids in non-neural androgen target organs.     

长期铝暴露对小鼠齿状回突触可塑性的影响

目的:探讨长期铝暴露对小鼠齿状回突触可塑性的毒性作用.方法:雌性ICR小鼠分为正常对照组与染铝组(200mg·kg-1·d-1).跳台及水迷宫测试检测小鼠染铝6个月后的学习记忆能力;在体长时程增强电生理检测小鼠染铝6～8个月的突触可塑性;免疫组织化学检测小鼠染铝8个月齿状回p tau表达.结果:行为学测试未见小鼠存在学习记忆障碍;电生理检测显示高频刺激后染铝6个月组的群体峰电位(PS)幅值及兴奋性突触后场电位(f-EPSP)斜率值均较对照组下降,且PS幅值与f-EPSP斜率随染铝时间延长呈进行性下降趋势.免疫组织化学显示染铝可增加小鼠齿状回p tau表达.结论:提示铝对小鼠齿状回突触可塑性的毒性作用早于其对行为学的影响,且随染铝时间延长,可进行性加重,其内在原因可能与tau的过度磷酸化有关.     

Orexins/hypocretins control bistability of hippocampal long-term synaptic plasticity through co-activation of multiple kinases

Aim: Orexins/hypocretins (OX/Hcrt) are hypothalamic neuropeptides linking sleep–wakefulness, appetite and neuroendocrine control. Their role and mechanisms of action on higher brain functions, such as learning and memory, are not clear. Methods: We used field recordings of excitatory post-synaptic potentials (fEPSP) in acute mouse brain slice preparations to study the effects of orexins and pharmacological inhibitors of multiple kinases on long-term synaptic plasticity in the hippocampus. Results: Orexin-A (OX-A) but not orexin-B (OX-B) induces a state-dependent long-term potentiation of synaptic transmission (LTP_OX) at Schaffer collateral-CA1 synapses in hippocampal slices from adult (8- to 12-week-old) mice. In contrast, OX-A applied to slices from juvenile (3- to 4-week-old) animals causes a long-term depression (LTD_OX) in the same pathway. LTP_OX is blocked by pharmacological inhibition of orexin receptor-1 (OX1R) and plasticity-related kinases, including serine/threonine- (CaMKII, PKC, PKA, MAPK), lipid- (PI3K), and receptor tyrosine kinases (Trk). Inhibition of OX1R, CaMKII, PKC, PKA and Trk unmasks LTD_OX in adult animals. Conclusion: Orexins control not only the bistability of arousal states and threshold for appetitive behaviours but, in an age- and kinase-dependent manner, also bidirectional long-term synaptic plasticity in the hippocampus, providing a possible link between behavioural state and memory functions.     

Spatial learning and synaptic hippocampal plasticity in type 2 somatostatin receptor knock-out mice

Somatostatin is implicated in a number of physiological functions in the CNS. These effects are elicited through the activation of at least five receptor subtypes. Among them, sst2 receptors appear the most widely expressed in the cortex and hippocampal region. However, the specific role of this somatostatin receptor subtype in these regions is largely undetermined. In this study, we investigated the role of the sst2 receptor in the hippocampus using mice invalidated for the sst2 gene (sst2 KO mice). Complementary experimental approaches were used. First, mice were tested in behavioral tests to explore the consequences of the gene deletion on learning and memory. Spatial discrimination learning in the radial maze was facilitated in sst2 KO mice, while operant learning of a bar-pressing task was slightly altered. Mice were then processed for electrophysiological study using the ex vivo hippocampal slice preparation. Extracellular recordings in the CA1 area showed an enhancement in glutamatergic (AMPA and NMDA) responses in sst2 KO mice which displayed an increase in the magnitude of the short-term potentiation and long-term depression. In contrast, long-term potentiation was not significantly altered.Taken together, these data demonstrate that somatostatin, acting via sst2 hippocampal receptors, may contribute to a global decrease in glutamate efficiency and consequently alter glutamate-dependent plasticity and spatial learning.     

Endocannabinoid signaling and synaptic plasticity in the brain

Repetitive firing neuron or activation of synaptic transmission plays an important role in the modulation of synaptic efficacy, such as long-term potentiation (LTP) and long-term depression (LTD). These activity-dependent changes in synaptic efficacy are thought to be critical to learning and memory; however, the underlying mechanisms remain to be defined. Endogenous cannabinoids (eCBs) are diffusible modulators that are released from depolarized postsynaptic neurons and act on presynaptic terminals. Persistent release of eCBs can lead to long-term modulation of synaptic plasticity in the brain. Given a broad distribution of eCB receptors in the brain, the eCB signaling system could contribute to use-dependent modification of brain functions.     

Harnessing prostaglandin E2 signaling to ameliorate autoimmunity

The etiology of most autoimmune diseases remains unknown; however, shared among them is a disruption of immunoregulation. Prostaglandin lipid signaling molecules possess context-dependent immunoregulatory properties, making their role in autoimmunity difficult to decipher. For example, prostaglandin E₂ (PGE₂) can function as an immunosuppressive molecule as well as a proinflammatory mediator in different circumstances, contributing to the expansion and activation of T cell subsets associated with autoimmunity. Recently, PGE₂ was shown to play important roles in the resolution and post-resolution phases of inflammation, promoting return to tissue homeostasis. We propose that PGE₂ plays both proinflammatory and pro-resolutory roles in the etiology of autoimmunity, and that harnessing this signaling pathway during the resolution phase might help prevent autoimmune attack.     

c-Jun N-terminal phosphorylation is essential for hippocampal synaptic plasticity

c-Jun N-terminal kinase (JNK), a member of the MAPK family, is an important regulatory factor of synaptic plasticity as well as neuronal differentiation and cell death. Recently, JNK has been reported to modulate synaptic plasticity by the direct phosphorylation of synaptic proteins. The specific role of c-Jun phosphorylation in JNK mediated synaptic plasticity, however, remains unclear. In this study, we investigated the effects of c-Jun phosphorylation on synaptic structure and function by using c-Jun mutant mice, c-JunAA, in which the active phosphorylation sites at serines 63 and 73 were replaced by alanines. The gross hippocampal anatomy and number of spines on hippocampal pyramidal neurons were normal in c-JunAA mice. Basal synaptic transmission, input–output ratios, and paired-pulse facilitation (PPF) were also no different in c-JunAA compared with wild-type mice. Notably, however, the induction of long-term potentiation (LTP) at hippocampal CA3–CA1 synapses in c-JunAA mice was impaired, whereas induction of long-term depression (LTD) was normal. These data suggest that phosphorylation of the c-Jun N-terminus is required for LTP formation in the hippocampus, and may help to better characterize JNK-mediated modulation of synaptic plasticity.     

Asynchronous synaptic responses in hippocampal CA1 neurons during synaptic long-term potentiation

In guinea pig hippocampal slices incubated in Ba2+, stimulation of stratum radiatum induced an EPSP that was followed by an increased frequency of miniature EPSPs in CA1 neurons. These miniature EPSPS, which were presumably due to the asynchronous release of transmitter, were increased after the induction of long-term potentiation.     

Caspase-3 activity in hippocampal slices reflects changes in synaptic plasticity

Electrophysiological measures of the functional activity of neurons in field CA1 in conditions of paired-pulse stimulation of Sch?ffer collaterals were performed in relation to the involvement of caspase-3 in mediating neuroplasticity; the relationship between functional activity and caspase-3 activity in hippocampal slices from Wistar rats was addressed. Enzyme activity was assessed in each individual slice at the end of the electrophysiological experiment. The results obtained here showed that the highest level of enzyme activity was seen when the efficiency of interneuronal interactions decreased. Nerve cell excitability showed no changes; interactions increasing synaptic efficiency, particularly in paired-pulse stimulation, produced normal response amplitudes. Further deterioration of the functional state of slices and impairments in spike generation were accompanied by increases in caspase-3 activity to the normal level. Increases in the activity of another proteinase, cathepsin B, were generally seen in any deviation from normal functioning, though there was no correlation with any of the electrophysiological parameters. It is suggested that high caspase-3 activity in slices is linked with neuroplastic processes in synapses and has no direct relationship to nerve cell apoptosis. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 94, No. 1, pp. 3–13, January, 2008.     

糖尿病降低大鼠海马突触可塑性的研究

目的 研究大鼠在患1型和2型糖尿病后,对在体海马前穿通纤维-齿状回通路(PP-DG)的突触可塑性造成的影响.方法 将70只SD大鼠(180±20)g随机分成3组:对照组、1型糖尿病模型组、2型糖尿病模型组.在水迷宫测试后,在每个模型组中选出空间记忆能力较差的15只大鼠,研究糖尿病引起的海马PP-DC通路双脉冲易化(PP...     

Modification of AMPA receptor clustering regulates cerebellar synaptic plasticity

Cerebellar long-term depression (LTD) induced at parallel fiber-Purkinje neuron synapses is proposed to underlie certain types of motor learning. alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors, which mediate chemical transmission in these synapses, are clustered on the postsynaptic membrane. By increasing local density of the receptors, clustering is believed to increase synaptic efficacy. This article focuses on molecular mechanisms regulating the synaptic AMPA receptor clustering in Purkinje cells, which could underlie the expression of cerebellar LTD. Synaptic AMPA receptor clusters in dendritic spines of Purkinje cells are disrupted upon protein kinase C (PKC)-mediated phosphorylation of serine 880 in the C-terminal domain of GluR2. Phosphorylation of this residue causes significant reduction in the affinity of GluR2 C-terminal tail for glutamate receptor interacting protein (GRIP), a molecule known to be crucial for AMPA receptor clustering. Consequently, AMPA receptors on the synaptic membrane are destabilized and internalized by endocytosis. Based on these findings, a model for the expression of cerebellar LTD is proposed, in which a decrease in the number of postsynaptic AMPA receptors, initiated by phosphorylation of GluR2 serine 880, is the major mechanism underlying cerebellar LTD.     

17beta-estradiol modifies stress-induced and age-related changes in hippocampal synaptic plasticity

The female steroid hormone 17beta-estradiol enhances synaptic transmission and the magnitude of longterm potentiation (LTP) in adult rodent hippocampal slices. Long-term depression (LTD), another form of synaptic plasticity, occurs more prominently in hippocampal slices from aged rodents. A decrease in LTP has been recorded in hippocampal slices from adult rodents behaviorally stressed just before tissue preparation and electrophysiological recording. Here, the authors test the hypothesis that estrogen modifies synaptic plasticity in both adult and aged rodents, whether behaviorally stressed or not. Our results indicate that estrogen enhances LTP and attenuates LTD, thus producing a protective effect against both aging and stress. These results also provide new approaches that can be used to reverse age and stress-related learning and memory dysfunction.     

Age-dependent alterations in hippocampal synaptic plasticity: relation to memory disorders

In this paper, we review the evidence indicating that the common disturbance in recent memory associated with aging is a consequence of functional and structural impairment in the hippocampal formation. In the Fischer 344 rat, an experimental model of the human age-related memory disorder was developed. The majority of aged rats of this strain show impaired performance in the 8-arm radial maze in a manner typical of young rats with bilateral hippocampal lesions. Aged animals also exhibit rapid decay of LTP and slower kindling of the perforant path-dentate synapse. Furthermore, quantitative morphometric analysis of the hippocampal synaptic architecture revealed that aged, memory-impaired rats had a specific loss of perforated axospinous synapses in the middle third of the dentate gyrus molecular layer; the extent of loss was directly related to the degree of memory dysfunction. Most important was the fact that the electrophysiological and morphological abnormalities did not appear in equally old animals with good memory.     

Regulation of hippocampal synaptic plasticity by cyclic AMP-dependent protein kinases

Protein kinases critically regulate synaptic plasticity in the mammalian hippocampus. Cyclic-AMP dependent protein kinase (PKA) is a serine–threonine kinase that has been strongly implicated in the expression of specific forms of long-term potentiation (LTP), long-term depression (LTD), and hippocampal long-term memory. We review the roles of PKA in activity-dependent forms of hippocampal synaptic plasticity by highlighting particular themes that have emerged in ongoing research. These include the participation of distinct isoforms of PKA in specific types of synaptic plasticity, modification of the PKA-dependence of LTP by multiple factors such as distinct patterns of imposed activity, environmental enrichment, and genetic manipulation of signalling molecules, and presynaptic versus postsynaptic mechanisms for PKA-dependent LTP. We also discuss many of the substrates that have been implicated as targets for PKA’s actions in hippocampal synaptic plasticity, including CREB, protein phosphatases, and glutamatergic receptors. Future prospects for shedding light on the roles of PKA are also described from the perspective of specific aspects of synaptic physiology and brain function that are ripe for investigation using incisive genetic, cell biological, and electrophysiological approaches.