Glycine facilitates induction of long-term potentiation of evoked potential in rat hippocampus

Effects of glycine were investigated in Schaffer/commissural-CA1 pyramidal cell synapses of the rat hippocampal slices. Perfusion of glycine (0.05 mM) did not change baseline population spikes evoked by test stimulation but significantly enhanced short-term potentiation induced by a single shorter tetanus (100 Hz, 11 impulses); the effects resulted in production of long-term potentiation (LTP). LTP produced by a longer tetanus (100 Hz, 100 impulses, 2 trains) was not significantly influenced. Higher concentration (0.5 mM) of glycine increased the baseline spike amplitude. All these effects of glycine were not observed in the presence of 10(-5) M 2-amino-5-phosphonovalerate, an N-methyl-D-aspartate (NMDA) antagonist. These results demonstrate that glycine can facilitate induction of LTP probably by activating NMDA receptor.     

Modulation of long-term potentiation induction in the hippocampus by N-methyl-D-aspartate-mediated presynaptic inhibition.

We investigated mechanisms involved in the modulation of long-term potentiation by low concentrations of N-methyl-D-aspartate in the CA1 region of rat hippocampal slices. When applied for 5 min prior to and during tetanic stimulation, 1 microM N-methyl-D-aspartate inhibited long-term potentiation induction. Studies examining paired-pulse facilitation of non-N-methyl-D-aspartate receptor-mediated synaptic responses suggest that the effects of N-methyl-D-aspartate result in part from a presynaptic mechanism. This conclusion is supported by the observation that 1 microM N-methyl-D-aspartate failed to diminish N-methyl-D-aspartate receptor-mediated synaptic currents and that agents that enhance glutamate release, including high extracellular concentrations of calcium and an adenosine A1 receptor antagonist, overcome the long-term potentiation inhibition. Furthermore, the calcineurin inhibitors, FK-506 and cyclosporin A, as well as the phosphatase 1 and 2A inhibitor, okadaic acid, blocked the effects of N-methyl-D-aspartate on long-term potentiation suggesting a role for phosphatase activation in modulating the induction of long-term potentiation. These results show that the inhibition of long-term potentiation by untimely N-methyl-D-aspartate receptor activation is reversed by treatments that enhance glutamate release and suggest that adenosine release and diminished calcium influx during tetanic stimulation coupled with phosphatase activation contribute to the modulation of synaptic plasticity.     

Thapsigargin blocks the induction of long-term potentiation in rat hippocampal slices.

Experiments were performed to investigate whether intact intracellular Ca2+ pools are necessary for long-term potentiation (LTP) in the CA1 region of rat hippocampal slices. Thapsigargin (1 microM), which depletes most intracellular Ca2+ pools by blocking ATP-dependent Ca2+ uptake into intracellular compartments, blocked the induction but not the expression of LTP. Thapsigargin had no effect on synaptic transmission or on responses mediated by N-methyl-D-aspartate (NMDA) receptor activation. These data suggest that Ca2+ release from intracellular stores is required for the induction of LTP.     

Genistein对HIV-1gp120抑制鼠LTP的实验研究

目的为了探讨酪氨酸蛋白激酶抑制剂Genistein对人类免疫缺陷病毒Ⅰ型(HIV1)的包膜糖蛋白gp120引起大鼠海马脑片CA1区的长时程增强效应(Longtermpotentiation,LTP)作用的影响。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,研究了Genistein对gp120引起的大鼠海马脑片CA1区的突触传递和可塑性变化的影响。结果gp120对高频电刺激(HFS,100Hz,1000ms×2,串间隔20s,共2次)Schaffer侧支引起的大鼠海马CA1区LTP产生抑制作用,而对PTP没有影响。酪氨酸蛋白激酶抑制剂Genistein可以反转这种抑制效应。结论gp120可能通过抑制海马CA1区LTP而参与艾滋病痴呆(HIV1associateddementia,HAD)的形成,且这种抑制作用可能与酪氨酸蛋白激酶抑制剂Genistein有关。     

Modulation of long-term potentiation in the rat hippocampus following cocaine self-administration

Long-lasting neuroadaptations that occur during drug use and remain after withdrawal are thought to contribute to the persisting and compulsive nature of drug addiction and relapse. At the molecular and cellular levels, mechanisms that have been implicated in the normal process of memory formation are increasingly being identified as potential contributors to the persistence of the addicted state. To investigate the effect of cocaine self-administration on synaptic plasticity, rats were allowed to self-administer 0.5 mg/kg/infusion cocaine or 0.9% NaCl during 90 min sessions for 15 consecutive days. These cocaine and saline self-administration subjects were then restricted to their home cages for 3, 30, or 100 days (3, 30, and 100 day cocaine/saline withdrawal groups) before the assessment of the induction and reversal of long-term potentiation (LTP) in the CA1 region of hippocampal slices. The magnitude of LTP was increased in the 3-day cocaine withdrawal group as compared with the 3-day saline withdrawal group, but this effect was short lived, as the 30-day cocaine and saline withdrawal groups exhibited similar LTP magnitudes. Interestingly, LTP was significantly decreased in the 100-day cocaine withdrawal group compared with the 100-day saline withdrawal group. These results support the hypothesis that the capacity for LTP is persistently altered after withdrawal from exposure to an addictive substance. In addition, this alteration can be differentially expressed such that depending upon the duration of the withdrawal period following the last drug exposure, LTP may be enhanced, unchanged, or suppressed.     

Calcium-induced long-term potentiation in the hippocampus

The effect of a transient increase in extracellular calcium concentration on the Schaffer collateral-commissural evoked excitatory postsynaptic potential and population spike responses of CAI pyramidal neurons was investigated using the rat in vitro hippocampal slice preparation. Brief exposure of slices (5-10 min) to twice the normal concentration of calcium (4 mM) induced a marked potentiation of both the excitatory postsynaptic potential and population spike that could persist for at least 3 h. No long-term changes were observed in either the presynaptic fiber volley of antidromically evoked CAI population spike, indicating that the potentiation could not be attributed to an increase in the number of fibers activated or a generalized increase in cellular excitability. The response of CAI pyramidal neurons to the iontophoretic application of L-glutamate in the apical dendritic zone was also unaffected after exposure to high calcium perfusate, suggesting a lack of alteration in membrane excitability or receptor sensitivity restricted to the region of synaptic input. In addition, total intracellular calcium content of individual slices, measured by atomic absorption spectrophotometry, was significantly increased for at least 1 h following return to the control medium. These data indicate that brief exposure of in vitro hippocampal slices to a high extracellular calcium concentration results in a long-term increase in synaptic efficacy which is similar in many respects to long-term potentiation induced by tetanic stimulation of hippocampal excitatory afferents. The results further suggest that the mechanisms underlying calcium-induced long-term potentiation may reside in presynaptic components and involve an enhanced transmitter release.     

Phorbol ester-induced synaptic potentiation differs from long-term potentiation in the guinea pig hippocampus in vitro

The relationship between the synaptic potentiations evoked by the protein kinase C activator phorbol-12,13-diacetate and by afferent tetanization has been examined in the CA1 region of the hippocampal slice preparation using extracellular recording. It has been found that the potentiation of the field excitatory postsynaptic potential produced by 1 microM phorbol ester does not affect the amount of long-term potentiation (LTP) that can be evoked by afferent tetanization, and vice versa. A dissociation between phorbol ester-induced and tetanus-induced potentiation is also indicated by the fact that only the former was associated with changes in paired-pulse facilitation. On the other hand, as previously described, higher concentrations (10 microM) of phorbol ester blocked the tetanus-induced potentiation. Since the total potentiation given by 10 microM phorbol ester and tetanization depended on the order of presentation of the potentiation-inducing stimuli, it appears that the blockade of LTP is, at least partly, independent of the phorbol ester-induced potentiation.     

HIV-1包膜糖蛋白V3环对大鼠海马长时程增强效应的影响

目的　探讨人免疫缺陷病毒Ⅰ型 (HIV 1)的包膜糖蛋白V3 环对大鼠海马脑片CA1区的突触传递及可塑性的影响。方法　应用离体脑片记录技术 ,记录大鼠海马CA1区的场兴奋性突触后电位 (fieldexcitatorypostsynapticpotentials,f EPSP) ,研究了V3 环对高频电刺激Schaffer侧支引起的鼠长时程增强效应 (long termpotentiation ,LTP)的影响。结果　V3 环对高频电刺激 (HFS ,10 0Hz,10 0 0ms× 2 ,串间隔 2 0s,共 2次 )Schaffer侧支引起的大鼠海马CA1区LTP产生抑制作用 ,而对其基础f EPSP没有影响。用浓度为 2 0 0pmol/L的V3 环灌流脑片 ,可引起LTP的维持发生抑制。这种抑制作用可被V3 环特异抗体V3 McAb(4 0ng/ml)所拮抗。结论　V3 环可能是通过抑制海马CA1区的LTP诱发和维持而参与艾滋病痴呆 (HIV 1associateddementia ,HAD)的形成     

The pro-inflammatory cytokine interleukin-18 impairs long-term potentiation and NMDA receptor-mediated transmission in the rat hippocampus in vitro.

The effects of the pro-inflammatory cytokine interleukin-18 (IL-18) were investigated on both normal and isolated N-methyl-D-aspartate (NMDA) receptor-mediated field excitatory post synaptic potentials (fEPSP) and on the induction of long-term potentiation (LTP) in the rat dentate gyrus in vitro. Bath perfusion with IL-18 (100 ng/ml) for 20 min prior to high-frequency stimulation had no significant effect on baseline synaptic transmission or paired pulse depression, but did impair the induction of LTP (115.7+/-8.8% versus 150.8+/-8.1% in vehicle control slices, n=6, P<0.05 at 60 min). Further analysis demonstrated that IL-18 significantly depressed the amplitude of pharmacologically isolated NMDA receptor-mediated fEPSP (NMDA-fEPSP; 77.4+/-4.3% of baseline compared to controls at 1 h; P<0.05, n=7), an effect that may underlie the impairment of LTP by IL-18. This action of IL-18 on LTP and NMDA-fEPSPs was attenuated in full by pretreatment of slices with exogenously applied IL-1 receptor antagonist (IL-1ra, 100 ng/ml), the naturally occurring antagonist of IL-1 type 1 receptors. This ability of IL-1ra to block the inhibitory effects of IL-18 is likely to be receptor-specific as no reversal of the tumour necrosis factor-alpha-induced inhibition of LTP was seen with IL-1ra administration (110.7+/-5.4% versus tumour necrosis factor-alpha-treated slices; 107.4+/-8.7%, P=0.6, n=6).These are the first experiments providing evidence of a direct neuromodulatory role for IL-18 in synaptic plasticity.     

Re-structuring of synapses 24 hours after induction of long-term potentiation in the dentate gyrus of the rat hippocampus in vivo

In male rats, long-term potentiation was induced unilaterally in the dentate gyrus, either by high frequency (200Hz) or theta rhythm stimulation. Structural synaptic changes were examined 24h after induction using quantitative electron microscopy. A disector technique was employed in order to estimate the density of synapses (using 70-80-nm sections) and of granule cell nuclei (using 2-microm sections) in the middle, and inner molecular layer in both hemispheres. Synaptic height and total lateral areas of synaptic active zones per unit tissue volume were assessed via assumption-free stereological techniques coupled with image analysis. The results obtained indicated that both synaptic density and number (corrected per neuron) of axo-spinous, but not axo-dendritic, synapses were approximately 40% higher in the middle, but not inner molecular layer of the potentiated hemisphere compared to the contralateral (control hemisphere). No significant inter-hemispheric difference was found in the volume densities of lateral areas of active zones.These data suggest that 24h after long-term potentiation induction, active zones of existing axo-spinous synapses either split forming separate contacts, or decrease in size while new synapses are formed.     

Release of proteins during long-term potentiation in the hippocampus of the anaesthetized rat

Using a push-pull device, the release of endogenous proteins in the extracellular space was investigated in the CA1 region of the hippocampus of anaesthetized rats. With low-frequency stimulation of the Schaffer collaterals, there was a relatively stable release of 5 proteins (64, 54, 48, 45 and 16 kDa). A train of high-frequency stimulation produced a long-lasting enhancement of the negative field EPSP and a delayed (90-120 min) enhancement of the release of these proteins. An additional 19 kDa protein was present only 90 min after the train. These observations raise the possibility that release of proteins might be involved in the maintenance of LTP.     

Thyrotropin-releasing hormone inhibits long-term potentiation in synaptic systems of rat hippocampus

The effects of thyrotropin-releasing hormone (TRH) on long-term potentiation of field responses in mossy fibers—CA3 and Shaffer collaterals—CA1 synaptic systems were studied on rat hippocampal slices. Incubation with micromolar concentrations of TRH inhibited the development of long-term potentiation in both synaptic systems. It is suggested that this phenomenon underlies the antiamnesic effect of TRH. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 12, pp. 690–693, December, 1999     

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.     

N-methyl-D-aspartate receptor-independent long-term potentiation in area CA1 of rat hippocampus: input-specific induction and preclusion in a non-tetanized pathway.

We previously reported that an N-methyl-D-aspartate receptor-independent component of long-term potentiation with an apparent delayed onset can be induced in area CA1 of the hippocampus. Here we show that some but not all of this delay in onset can be accounted for by a transient heterosynaptic depression. We also show that N-methyl-D-aspartate receptor-independent long-term potentiation is induced only in the input pathway tetanized, and not in a second pathway. However, prior induction of N-methyl-D-aspartate receptor-independent long-term potentiation in one pathway precludes later induction in an independent pathway. Calcium entry through dihydropyridine-sensitive Ca2+ channels may be a critical step for induction of N-methyl-D-aspartate receptor-independent long-term potentiation in area CA1 [Grover L. M. and Teyler T.J. (1990) Nature 347, 477-479]. Since the distribution [Westenbroek R. E. et al. (1990) Nature 347, 281-284] of dihydropyridine-sensitive Ca2+ channels in CA1 neuron dendrites does not suggest a basis for input-specific induction of long-term potentiation, an additional process may confer the specificity we observed. Tetanic stimulation of afferents into area CA1 can elicit several processes: a transient heterosynaptic depression, and a transient homosynaptic potentiation, as well as N-methyl-D-aspartate receptor-dependent and -independent long-term potentiation.     

4-Aminopyridine-mediated increase in long-term potentiation in CA1 of the rat hippocampus

The effect of 4-aminopyridine (4-AP) on long-term potentiation (LTP) was studied in the hippocampal slice preparation of the rat. Field excitatory postsynaptic potentials (EPSPs) were recorded and evoked in the stratum radiatum of the CA1. Both the low frequency EPSP and LTP of the EPSP were significantly increased by treatment with 4-AP. These effects were inhibited by increasing the magnesium concentration from 1 to 4 mM. Pretreatment with 20 microM DL-2-amino-5-phosphonovalerate antagonized only the increase in LTP produced by 4-AP. It is suggested that 4-AP enhances Ca influx either pre- or postsynaptically and thereby increases LTP.