Restoration of long-term potentiation in middle-aged hippocampus after induction of brain-derived neurotrophic factor

Restoration of neuronal viability and synaptic plasticity through increased trophic support is widely regarded as a potential therapy for the cognitive declines that characterize aging. Previous studies have shown that in the hippocampal CA1 basal dendritic field deficits in the stabilization of long-term potentiation (LTP) are evident by middle age. The present study tested whether increasing endogenous brain-derived neurotrophic factor (BDNF) could reverse this age-related change. We report here that in middle-aged (8- to 10-mo-old) rats, in vivo treatments with a positive AMPA-type glutamate receptor modulator both increase BDNF protein levels in the cortical telencephalon and restore stabilization of basal dendritic LTP as assessed in acute hippocampal slices 18 h after the last drug treatment. These effects were not attributed to enhanced synaptic transmission or to facilitation of burst responses used to induce LTP. Increasing extracellular levels of BDNF by exogenous application to slices of middle-aged rats was also sufficient to rescue the stabilization of basal dendritic LTP. Finally, otherwise stable LTP in ampakine-treated middle-aged rats can be eliminated by infusion of the extracellular BDNF scavenger TrkB-Fc. Together these results indicate that increases in endogenous BDNF signaling can offset deficits in the postinduction processes that stabilize LTP.     

Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly

Daily restraint for 3 weeks was shown to atrophy dendrites of hippocampal pyramidal neurons in rats. Brain-derived neurotrophic factor (BDNF), which maintains neuronal survival and morphology, has been shown to decrease in response to acute stress. Plasma glucocorticoid (GC) and serotonergic projections from the raphe nuclei play major roles in reducing BDNF synthesis in the hippocampus. We investigated BDNF mRNA levels there, together with plasma GC levels, GC receptors in the hippocampus/hypothalamus and 5-HT synthesizing enzyme, tryptophan hydroxylase in the raphe nuclei, in animals chronically stressed for 1-3 weeks, using in situ hybridization and immunohistochemistry. In these animals, BDNF mRNA levels were significantly decreased in the hippocampus after 6 h of restraint, but the ability of restraint to reduce BDNF synthesis seemed less robust than that seen in acute stress models. HPA axis response to stress in these animals assessed by plasma GC levels was delayed and sustained, and the GC receptor in the paraventricular hypothalamic nucleus was increased at 1 week. Tryptophan hydroxylase immunoreactivity was increased in the median raphe nucleus at 2-3 weeks. Repetitive stress-induced reduction of BDNF may partly contribute to the neuronal atrophy/death and reduction of hippocampal volume observed both in animals and humans suffering chronic stress and/or depression.     

Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus

Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 h later. Finally, bilateral injections of BDNF (1 mug) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness.     

Preserved LTP and water maze learning in hyperglycaemic-hyperinsulinemic ZDF rats

Previous investigations have demonstrated that cognitive deficits as well as hippocampal dysfunctions are generated in animals presenting manifestations of Type 1 diabetes (T1D) mellitus. The present study examined whether such deficits can also be reproduced in the Zucker Diabetic Fatty (ZDF) rats after they developed symptoms of Type 2 diabetes (T2D). Learning and memory assessments were performed using the Morris water maze 5 weeks after the animals presented symptoms of Type 1 diabetes for Experiment 1 (Exp 1) and after 8 weeks for Experiment 2 (Exp 2). Testing in the water maze revealed that ZDF rats learned the task normally, although control rats were found to swim significantly faster after 5 or 8 weeks of untreated diabetes. From an electrophysiological perspective, we observed that the integrity of synaptic function was also preserved in ZDF rats as no alterations in long-term potentiation (LTP) were observed in the area CA1 of hippocampal slices. It is concluded that hyperglycaemia is not the only factor influencing water maze learning and LTP in this animal model of Type 2 diabetes (T2D). The experiments suggest that the resistance of ZDF rats to cognitive and electrophysiological dysfunctions might be related to the protective action of hyperinsulinemia. Indeed, measurements of the plasma insulin level at the end of testing were significantly superior in ZDF rats in comparison to control rats.     

Venlafaxine inhibits apoptosis of hippocampal neurons by up-regulating brain-derived neurotrophic factor in a rat depression model

Objective: To study the effect of venlafaxine on the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampal neurons, as well as its inhibitory effect on apoptosis of hippocampal neurons. Methods: Differences in behavioral ability between the depression model group and the Venlafaxine treatment group were observed using behavioral, sucrose-water and open field tests. The rat hippocampal tissue was sliced, stained and observed for BDNF distribution by immunohistochemistry. Apoptosis of hippocampal neurons was detected by TUNEL. BDNF expression in the hippocampal tissue was detected by Western blot. Injury and apoptosis of the hippocampal tissue were observed by electron microscopy. Results: Behavioral test showed that venlafaxine effectively improved the behavioral abilities of depressed rats. Immunohistochemistry showed that venlafaxine markedly increased the BDNF expression in the rat hippocampus. TUNEL showed that venlafaxine markedly inhibited apoptosis of hippocampal neurons, which was also confirmed by electron microscopic observation of the pathologic sections. Conclusion: Venlafaxine improved the expression of BDNF through working on PI3k/PKB/eNOS pathway and repressed the apoptosis of hippocampal neurons.     

Cocaine withdrawal enhances long-term potentiation in rat hippocampus via changing the activity of corticotropin-releasing factor receptor subtype 2

The neural plasticity mechanisms that underlie learning and memory may also be engaged when drug addiction occurs. It was reported that long-lasting neuroadaptations induced by cocaine use and withdrawal require the participation of hippocampus. However, the role of corticotrophin-releasing factor receptors in this process remains unclear. In the present study, the effects of chronic cocaine treatment (a 14-day cocaine administration, 20 mg/kg i.p., daily) and short-term cocaine withdrawal (a 3-day cocaine extinction following a 14-day cocaine administration) on long-term potentiation (LTP), one prominent cellular mechanism for learning and memory, were assessed in the CA1 region of the rat hippocampal slices. We found that cocaine withdrawal, but not the chronic cocaine administration itself, significantly enhanced the magnitude of LTP in hippocampal slices, as compared with that in saline controls. Selective blockade of corticotrophin-releasing factor receptor subtype 1 (CRF₁) with the specific antagonist NBI 27914 (100 nM in vitro) attenuated the magnitude of LTP in hippocampal slices from cocaine withdrawal rats, and intriguingly, also from saline control rats, while specific blockade of corticotrophin-releasing factor receptor subtype 2 (CRF₂) with astressin2-B (100 nM in vitro) selectively attenuated the magnitude of LTP in hippocampal slices from cocaine withdrawal rats. Our data suggest that short-term cocaine withdrawal treatment may cause synaptic plasticity in hippocampus partially via changing the activity of CRF₂ in the hippocampus.     

Chewing ameliorates stress-induced suppression of hippocampal long-term potentiation

Research has established that severe stress adversely affects hippocampal memory, and chewing has been suggested to restore impaired cognitive functions in the hippocampus. To address how chewing involves stress-attenuated hippocampal memory process, we measured the long-term potentiation (LTP) of hippocampal slices of adult male rats that had experienced restraint stress, including some rats that were allowed to chew a wooden stick during the stress period and other rats that were not. The three experimental conditions were: 1) restraint stress without chewing (ST), 2) restraint stress with chewing (SC), and 3) no treatment (CT). We prepared hippocampal slices and collected trunk blood from all experimental animals. For rats in the two stressed groups, we collected tissue and blood at one of three post-stress time points: immediately after, 24 h after, or 48 h after exposure to the stressor. We found that the magnitude of LTP in both group ST and SC was significantly attenuated immediately after stress exposure. However, within 24 h after the end of the stress period, LTP had returned to the control level in group SC whereas it remained low in group ST. At the same post-stress time point, we found that facilitation of N-methyl-d-aspartate (NMDA) receptors by bath-applied glycine had less effect on the magnitude of LTP in group SC than on group ST, suggesting that most NMDA receptors had already become functionally restored in group SC by that time. Plasma concentration of adrenocorticotropic hormone was significantly elevated only in group ST immediately after exposure to the stressor, reflecting the involvement of chewing in decreasing subsequent corticosterone secretion. Thus, the present study demonstrates that chewing ameliorates the stress-induced impairment of NMDA receptor-mediated LTP, suggesting chewing as a good strategy to cope with severe stress by suppressing excessive endocrine responses.     

Effects on serotonin of (-)nicotine and dimethylphenylpiperazinium in the dorsal raphe and nucleus accumbens of freely behaving rats

The aim of this study was to investigate the neurochemical mechanism underlying the effect of nicotine and dimethylphenylpiperazinium (DMPP) on 5-hydroxytryptamine (5-HT) release in the dorsal raphe nucleus and nucleus accumbens of freely behaving rats. For comparison, lobeline, cytisine and RJR-2403 were also investigated. It was found that all drugs, when infused locally, evoked an increase of 5-HT in the dorsal raphe nucleus. However, the magnitudes of the 5-HT increase were comparatively different between the drugs in the ranking of their potency: DMPP>RJR 2403>nicotine>lobeline>cytisine. Both methyllycaconitine, a nicotinic acetylcholine receptor (nAChR) antagonist and methyllycaconitine, a selective alpha7-containing nAChR antagonist blocked the effects of nicotine and DMPP, suggesting that alpha7 subunit mediated the increases in 5-HT. However, DMPP was reported to increase 5-HT using non-nAChR mechanism [Lendvai B, Sershen H, Lajtha A, Santha E, Baranyi M, Vizi ES (1996) Differential mechanisms involved in the effect of nicotinic agonists DMPP and lobeline to release [3H]5-HT from rat hippocampal slices. Neuropharmacology 35:1769-1777]. To test if 5-HT carriers were involved, a selective 5-HT reuptake inhibitor citalopram (1 microM) was infused into the dorsal raphe nucleus before administration of nicotine or DMPP. As a result, citalopram significantly blocked the effect of DMPP, whereas it had no influence on nicotine. Finally, the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was used to test whether the increases in 5-HT were depolarization-dependent. Administration of 8-OH-DPAT (0.1 mg/kg, s.c.) produced significant decreases in 5-HT in the animals treated with nicotine. In contrast, the effect of DMPP was not altered by 8-OH-DPAT, suggesting that the increases in 5-HT were independent of cell membrane depolarization. In conclusion, there are different mechanisms involved in nicotine- and DMPP-evoked increases in 5-HT. This is consistent with prior work suggesting DMPP may primarily act on 5-HT carriers.     

The intra-arterial injection of microglia protects hippocampal CA1 neurons against global ischemia-induced functional deficits in rats

In the present study, we have attempted to elucidate the effects of the intra-arterial injection of microglia on the global ischemia-induced functional and morphological deficits of hippocampal CA1 neurons. When PKH26-labeled immortalized microglial cells, GMIR1, were injected into the subclavian artery, these exogenous microglia were found to accumulate in the hippocampus at 24 h after ischemia. In hippocampal slices prepared from medium-injected rats subjected to ischemia 48 h earlier, synaptic dysfunctions including a significant reduction of synaptic responses and a marked reduction of long-term potentiation (LTP) of the CA3-CA1 Schaffer collateral synapses were observed. At this stage, however, neither significant neuronal degeneration nor gliosis was observed in the hippocampus. At 96 h after ischemia, there was a total loss of the synaptic activity and a marked neuronal death in the CA1 subfield. In contrast, the basal synaptic transmission and LTP of the CA3-CA1 synapses were well preserved after ischemia in the slices prepared from the microglia-injected animals. We also found the microglial-conditioned medium (MCM) to significantly increase the frequency of the spontaneous postsynaptic currents of CA1 neurons without affecting the amplitude, thus indicating that MCM increased the provability of the neurotransmitter release. The protective effect of the intra-arterial injected microglia against the ischemia-induced neuronal degeneration in the hippocampus was substantiated by immunohistochemical and immunoblot analyses. Furthermore, the arterial-injected microglia prevented the ischemia-induced decline of the brain-derived neurotrophic factor (BDNF) levels in CA1 neurons. These observations strongly suggest that the arterial-injection of microglia protected CA1 neurons against the ischemia-induced neuronal degeneration. The restoration of the ischemia-induced synaptic deficits and the resultant reduction of the BDNF levels in CA1 neurons, possibly by the release of diffusible factor(s), might thus contribute to the protective effect of the arterial-injection of microglia against ischemia-induced neuronal degeneration.     

Age-related deficits as working memory load increases: relationships with growth factors

Young and aged female rats were tested on a water radial-arm maze designed to measure performance as working memory load increased, followed by brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin 3 (NT3) protein assessments in hippocampus and frontal cortex. Aged rats showed deficiencies in both working and reference memory. There were also profound age-related working memory load effects. Aged rats made more errors as working memory load increased and showed learning only during early trials when memory load was low, while young rats exhibited learning over all trials. Neurotrophin assessment showed that frontal cortex NGF and BDNF levels were positively, and hippocampal NT3 negatively, correlated with number of errors made during specific trials in aged animals. Comparison to untested rats showed that testing increased NT3, but not BDNF or NGF, protein levels in both age groups. Findings suggest that young rats learn to handle a higher working memory load as testing progresses, while aged rats do not, and that frontal cortex and hippocampal neurotrophin levels may relate to working memory proficiency in aged female rats.     

Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents

Leptin is well known to be involved in the control of feeding, reproduction and neuroendocrine functions through its action on the hypothalamus. However, leptin receptors are found in brain regions other than the hypothalamus (including the hippocampus and cerebral cortex) suggesting extrahypothalamic functions. We investigated hippocampal long-term potentiation (LTP) and long-term depression (LTD), and the spatial-memory function in two leptin receptor-deficient rodents (Zucker rats and db/db mice). In brain slices, the CA1 hippocampal region of both strains showed impairments of LTP and LTD; leptin (10(-12) M) did not improve these impairments in either strain. These strains also showed lower basal levels of Ca(2+)/calmodulin-dependent protein kinase II activity in the CA1 region than the respective controls, and the levels did not respond to tetanic stimulation. These strains also showed impaired spatial memory in the Morris water-maze test (i.e. longer swim-path lengths during training sessions and less frequent crossings of the platform's original location in the probe test.From these results we suggest that the leptin receptor-deficient animals show impaired LTP in CA1 and poor spatial memory due, at least in part, to a deficiency in leptin receptors in the hippocampus.     

Spatial performance in a complex maze is associated with persistent long-term potentiation enhancement in mouse hippocampal slices at early training stages

Long-term potentiation (LTP) and long-term depression (LTD) are principal reflections of synaptic plasticity that have been implicated in learning and memory. We have previously shown that spatial learning in a newly validated complex maze is accompanied by depression of hippocampal CA1 synaptic activity in hippocampal slices of trained mice ("behavioral LTD"). In the present study, we investigated whether behavioral LTD is accompanied by alterations of subsequent LTP induced by high-frequency stimulation (HFS). Moreover, we were interested in the time course of such alterations in relation to training stage. Animals underwent 1, 2, and 8 days of spatial training in the complex maze, respectively. Hippocampal slices were taken 24 h after the last training session. We found a simultaneous decrease of basal synaptic response and increase of HFS induced LTP magnitude compared with slices of untrained animals. Synaptic plasticity was not influenced by repeated running wheel exercise in an additional control group without spatial learning. The mentioned alterations occurred already after day 2 of maze exploration parallel to the most pronounced improvement of behavioral performance but did not change thereafter until day 8 despite further learning progress. They were also found when animals were trained for 2 days and kept at rest for a subsequent 6 days. In conclusion, spatial learning may be reflected by distinct and persistent measurable alterations of synaptic plasticity in hippocampal CA1 neurons at early training stages.     

姜黄素对TNF-α损伤大鼠海马神经元的功能性保护作用及机制

目的:观察姜黄素对TNF-α损伤大鼠海马神经元的功能性保护作用并探讨其机制。方法:应用离体脑片记录技术,记录大鼠海马CA1区的兴奋性突触后电位(EPSP),给予Schaffer侧支高频刺激(HFS)诱发长时程增强(LTP),观察不同药物处理组EPSP起始斜率的变化情况。结果:与对照组相比,TNF-α和NMDA(N-甲基D-天冬氨酸)对大鼠海马脑片LTP产生明显的抑制作用(P0.05);而姜黄素可以部分拮抗TNF-α和NMDA对海马脑片LTP的抑制作用,与对照组相比无显著差异(P0.05);TNF-α、姜黄素和NMDA对大鼠海马神经元的基础突触传递没有显著影响。结论:姜黄素对TNF-α损伤的大鼠海马神经元有功能性保护作用,其机制可能是姜黄素部分拮抗TNF-α诱导的神经元细胞膜上的NMDA受体过度激活,维持神经元的长时程增强。     

Hyperinsulinemia in rats causes impairment of spatial memory and learning with defects in hippocampal synaptic plasticity by involvement of postsynaptic mechanisms

In addition to its peripheral metabolic functions, insulin acts as a central neuromodulator and affects synaptic plasticity of the hippocampal neurons. In this study, hyperinsulinemic obese zucker rats (OZR) with autosomal recessive mutation of the fa-gene were tested in water maze for learning and memory. The animals were then decapitated and hippocampal slices were prepared for electrophysiological examination. In the water maze test, the OZR performed less efficient than their counter lean control rats (LCR). The OZR showed prolonged latency and increased distance swam to reach a hidden platform. In the electrophysiological experiments, the hippocampal slices were examined for paired-pulse facilitation (PPF), long-term potentiation (LTP), and depression expression. The results showed that while the PPF (thus mainly the presynaptic mechanisms) was not affected, the LTP expression (169.9 ± 16.6 vs. 310.7 ± 2.4 %) and the synaptic plasticity range (69.2 vs. 211.2 %) were both reduced in the OZR animals compared to the LCR. It is concluded that hyperinsulinemia in the OZR resulted in defects in hippocampal synaptic plasticity associated with deterioration in spatial learning and memory functions.     

Suppression of hippocampal plasticity-related gene expression by sleep deprivation in rats

Previous work shows that sleep deprivation impairs hippocampal-dependent learning and long-term potentiation (LTP). Brain-derived neurotrophic factor (BDNF), cAMP response-element-binding (CREB) and calcium–calmodulin-dependent protein kinase II (CAMKII) are critical modulators of hippocampal-dependent learning and LTP. In the present study we compared the effects of short- (8 h) and intermediate-term (48 h) sleep deprivation ( SD ) on the expression of BDNF and its downstream targets, Synapsin I, CREB and CAMKII in the neocortex and the hippocampus. Rats were sleep deprived using an intermittent treadmill system which equated total movement in the SD and control treadmill animals (CT), but permitted sustained periods of rest in CT animals. Animals were divided into SD (treadmill schedule: 3 s on/12 s off) and two treadmill control groups, CT1 (15 min on/60 min off) and CT2 (30 min on/120 min off – permitting more sustained sleep). Real-time Taqman RT-PCR was used to measure changes in mRNA; BDNF protein levels were determined using ELISA . In the hippocampus, 8 h treatments reduced BDNF , Synapsin I, CREB and CAMKII gene expression in both SD and control groups. Following 48 h of experimental procedures, the expression of all these four molecular markers of plasticity was reduced in SD and CT1 groups compared to the CT2 and cage control groups. In the hippocampus, BDNF protein levels after 8 h and 48 h treatments paralleled the changes in mRNA. In neocortex, neither 8 h nor 48 h SD or control treatments had significant effects on BDNF , Synapsin I and CAMKII mRNA levels. Stepwise regression analysis suggested that loss of REM sleep underlies the effects of SD on hippocampal BDNF , Synapsin I and CREB mRNA levels, whereas loss of NREM sleep underlies the effects on CAMKII mRNA.     

Acute onset by 5-HT(6)-receptor activation on rat brain brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein mRNA expression

A number of previous studies have shown that chronic but not acute treatment with antidepressant drugs targeting the central 5-HT system, enhances mRNA expression for a number of genes including, brain-derived neurotrophic factor (BDNF) and the effector immediate early gene (IEG), activity-regulated, cytoskeletal-associated protein (Arc). The present study investigated the effects of 5-HT(6)-receptor activation on hippocampal and cortical levels of mRNA expression of BDNF and Arc in the rat. The selective 5-HT(6)-receptor agonist LY-586713 was administered acutely (0.1-10 mg/kg, s.c.) and mRNA levels of BDNF and Arc were measured 18 h later. Administration of LY-586713 caused a bell-shaped dose response on hippocampal BDNF mRNA expression, having no effect at 0.1 mg/kg, a significant up-regulation at 1 mg/kg and no effect at 10 mg/kg. The up-regulation in BDNF expression observed at 1 mg/kg was completely blocked by pre-treatment with the selective 5-HT(6)-receptor antagonist SB-271046 (10 mg/kg, s.c.). The effective dose (1 mg/kg) of LY-586713 on the induction of BDNF expression was also tested on Arc expression. Acute administration of LY-586713 at this dose caused marked increases of the Arc mRNA levels in cortical and hippocampal regions. These increases were also attenuated by SB-271046 (10 mg/kg) in all regions of the hippocampus, as well as the parietal cortex. However, in frontal cortical regions there was no attenuation by the antagonist. Moreover, SB-271046 alone increased Arc expression in these regions. The results presented here provide the first evidence for the involvement of the 5-HT(6) receptor in regulating BDNF and Arc mRNA expression, suggesting that LY-586713 has potential effects on neuronal plasticity. Overall, these findings suggest that, as opposed to more general 5-HT receptor activation by, for example, antidepressants, direct 5-HT(6)-receptor activation results in a more rapid rise in BDNF and Arc mRNA expression which does not require repeated administration.     

Allosteric modulation of the effects of the 5-HT reuptake inhibitor escitalopram on the rat hippocampal synaptic plasticity

The present in vivo electrophysiological studies in anesthetized rat were undertaken to assess the effects of the selective serotonin (5-HT) reuptake inhibitor (SSRI) escitalopram alone or in combination with the R-citalopram (the S- and R-enantiomers of citalopram), on both long-term potentiation (LTP) in the CA(1) region of dorsal hippocampus and spontaneous firing activity of dorsal raphe (DR) 5-HT neurons. At the postsynaptic level, neither escitalopram (10 mg/kg, i.p.) nor R-citalopram (20 mg/kg, i.p.) modified basal synaptic transmission but only escitalopram impaired LTP expression. Importantly, R-citalopram counteracted significantly the escitalopram-induced decrease of LTP. At the pre-synaptic level, escitalopram (25-75 microg/kg, i.v.) dose-dependently suppressed the spontaneous firing activity of DR 5-HT neurons and this suppressant effect was significantly prevented by a prior injection of R-citalopram (10 mg/kg, i.p.). These results support a role of allosteric binding sites of 5-HT transporter in the regulation of long-lasting CA(1) synaptic plasticity and DR 5-HT neuronal firing activity.     

Long-term potentiation induced in dendrites separated from rat's CA1 pyramidal somata does not establish a late phase

In 14 transversal hippocampal slices from rats the extracellular field-EPSP (excitatory postsynaptic potential) in the dendritic region of the CA1 subfield was recorded after isolating the apical dendrites from their somata by microsurgical cuts through the proximal stratum radiatum. Contrary to intact slices which, after tetanic stimulation of the Schaffer collaterals, showed long-term potentiation (LTP) until the end of registration after 8-10 h, LTP declined in the isolated dendrites to baseline values after 3 h. It is concluded that de-novo protein synthesis in postsynaptic cell bodies might be necessary for the maintenance of late phases of LTP.     

Modulation of hippocampal excitability by 5-HT4 receptor agonists persists in a transgenic model of Alzheimer's disease

5-HT(4) receptors are widely distributed in both peripheral and central nervous systems where they couple, via a G-protein, to the activation of adenylate cyclase. In the brain, the highest 5-HT(4) receptor densities are found in the limbic system, including the hippocampus and frontal cortex. It has been suggested that activation of these receptors may be of therapeutic benefit in diseases that produce cognitive deficits such as Alzheimer's disease (AD). Previous electrophysiological studies have shown that the 5-HT(4) agonist, Zacopride, can increase population spike amplitude recorded in region CA1 of rat hippocampal slices in a cyclic AMP (cAMP)/cAMP-dependent protein kinase A-dependent manner. We report here that the 5-HT(4) agonist, Prucalopride, and the 5-HT(4) partial agonist, SL65.0155, produce a similar effect in rat hippocampal slices and that the specific 5-HT(4) antagonist, GR113808, blocks these effects. To investigate the potential use of 5-HT(4) agonists in the treatment of AD, Prucalopride was applied to hippocampal slices from a transgenic mouse line that overexpresses the Abeta peptide. Despite the deficit in synaptic transmission present in these mice, the percentage increase of the CA1 population spike induced by Prucalopride was the same as that observed in wild-type mice. These data support 5-HT(4) receptors as a target for cognitive enhancement and suggest that a partial agonist would be sufficient to produce benefits, while reducing potential peripheral side effects. In addition, we show that 5-HT(4) receptors remain functional in the presence of excess Abeta peptide and may therefore be a useful target in AD.     

Aβ25-35伤害大鼠空间学习记忆和在体海马长时程增强的联合研究

目的:探讨海马内注射β-amyloid protein 25-35(Aβ25-35)所致Alzheizer’s病(AD)模型大鼠空间学习记忆功能障碍的海马突触可塑性长时程增强(LTP)机制,为联合开展AD动物行为学和在体电生理学研究提供实验证据。方法:在脑立体定位仪上给予大鼠双侧海马分别注射4 nmol/L Aβ25-35或等体积生理盐水每侧2μl,手术后恢复2周,每只大鼠依次进行行为学和电生理两部分实验。首先,利用Morris水迷宫进行空间学习、记忆功能测试;之后,进行在体海马CA1区场兴奋性突触后电位(fEPSP)引导记录实验,观察突触可塑性指标长时程增强(LTP)的改变。结果:与对照组相比,海马内注射Aβ25-35大鼠的空间学习记忆功能和在体海马突触可塑性LTP均有改变,其中:逃避潜伏期和逃避距离明显增加(P<0.01);目标象限内游泳时间和距离明显缩短(P<0.01);在体海马LTP幅度显著降低(P<0.01)。结论:海马内注射Aβ25-35可导致大鼠空间学习记忆功能障碍;联合实验中Aβ25-35同样可引起在体海马LTP改变。提示同批动物先后进行行为学和电生理学测试的方法是可行的,行为学实验不会影响后续LTP的实验结果。因此,本实验为行为学改变后进行在体LTP机制探讨提供了实验依据,为有效开展行为学和电生理学实验提供了思路。