Potentiation In Dentate Gyrus Research Articles

The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats

Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30–32days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25–30days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this impairment was largely reversed at 24-h. Animals in the high-dose NTP (20mg/kg/day) group were impaired at both short- and long-term intervals. Activity levels, used as an index of location memory during the ORT, demonstrated that rats receiving DMI were again impaired at retaining memory for location. DMI dose-dependently disrupts LTP in the dentate gyrus of anesthetized rats and also disrupts memory for tests of spatial memory when administered for long periods.

Modulation of the perforant path‐evoked potential in dentate gyrus as a function of intrahippocampal β‐adrenoceptor agonist concentration in urethane‐anesthetized rat

Backgroundβ-adrenoceptor activation in the hippocampus is sufficient to induce heterosynaptic long-term potentiation of perforant path input to the dentate gyrus. However, in vitro and in vivo studies suggest the plasticity effects of β-adrenoceptor activation may vary depending on the level of receptor activation.MethodsThe present experiments use an in vivo model concurrently infusing differing concentrations of the β-adrenoceptor agonist, isoproterenol (ISO; 0, 0.1, 1, 10, and 100 μmol/L in aCSF; 1 μL over 12.5 min) in the dentate gyrus, while monitoring changes in the perforant path-evoked potential at the same site.ResultsLong-term depression (LTD) of fEPSP slope was elicited by 0.1 μmol/L ISO. Higher doses did not alter fEPSP slope. Maximal long-term potentiation of the perforant path-evoked population spike (183% >3 h) occurred at 10 μmol/L ISO. Transient depression of spike amplitude occurred at 0.1 μmol/L ISO.ConclusionsThese data demonstrate concentration-dependent effects of β-adrenoceptor activation on the perforant path-evoked potential. Long-term depression and long-term potentiation of perforant path-evoked responses are variably elicited as a function of the degree of receptor activation.

Effects of intrahippocampal l-NAME treatment on the behavioral long-term potentiation in dentate gyrus

Using a combination of electrophysiological recordings, behavioral tests and local pharmacological administration in hippocampus, we investigated in the present study the effects of nitric oxide (NO) synthase inhibitor N-nitro-l-arginine methyl ester (l-NAME) on the behavioral long-term potentiation (LTP) and maze learning performance in freely moving rats. The results showed as follows: (1) intrahippocampal l-NAME administration led to a defect in maze learning performance of the animals; (2) l-NAME treatment also substantially impaired the induction of the behavioral LTP in perforant pathway to dentate gyrus (PP-DG) pathway induced by maze learning task, while it had no significant effects on basic synaptic transmission in PP-DG pathway; Collectively, these results indicate that NO synthesis may be critical for the behavioral LTP in PP-DG pathway and maze learning performance.

The psychostimulant modafinil facilitates water maze performance and augments synaptic potentiation in dentate gyrus

Modafinil is a psychostimulant drug used widely for the treatment of narcolepsy, which also has additional positive effects on cognition. Here, we investigate the effects of modafinil on behavioural performance and synaptic plasticity in rats. Improved acquisition in the water maze task was observed in animals that underwent chronic treatment with modafinil. We found that the distance traveled and escape latency were reduced after the first day in chronically-treated rats, compared to controls. Importantly, swim velocity was similar for both groups, excluding pharmacological effects on motor skills. We also found that modafinil increases synaptic plasticity in the dentate gyrus of urethane-anaesthetized rats; modafinil induced a robust augmentation of the population spike, evident after application of 2 bursts of 200 Hz high-frequency stimulation. Furthermore, the modafinil-dependent enhancement of postsynaptic potentials correlated selectively with theta rhythm augmentation. We propose that modafinil may facilitate hippocampal-associated spatial representation via increased theta-related hippocampal plasticity.

Estradiol enhances long term potentiation in hippocampal slices from aged apoE4‐TR mice

Hormone replacement therapy to treat or prevent Alzheimer Disease (AD) in postmenopausal women is controversial because it may pose other health risks such as cancer and thromboembolism. ApoE status is thought to influence the nootropic efficacy of hormone therapy, but findings are neither consistent nor well understood. We used a known in vitro memory model (long-term potentiation, LTP) in aged (24-27 month) female targeted replacement mice expressing human apoE3 or E4 to compare the effects of exogenous estradiol. Recording medial perforant path evoked field potentials in dentate gyrus of hippocampal slices, we found that both strains exhibited comparable basal synaptic transmission as assessed by input/output functions and paired pulse depression, and that these measures were not affected by estradiol. Vehicle-treated groups from both strains showed comparable LTP. Estradiol had no effect on LTP in apoE3-TR, but selectively increased LTP magnitude in apoE4-TR. The estradiol induced enhancement of LTP in aged female apoE4-TR is consistent with recent clinical observations that estrogen replacement decreases AD risk in some women with apoE4. Elucidating the mechanism of this selective enhancement may lead to more informed treatment decisions as well as to the development of safer alternatives to hormone therapy.

Opposite effects of shell or core stimulation of the nucleus accumbens on long-term potentiation in dentate gyrus of anesthetized rats

Hippocampal long-term potentiation (LTP) is a long-lasting increase in synaptic efficacy which is considered a cellular correlate of learning and memory. It has been shown that both, stimuli with emotional/motivational content and the electrical stimulation the basolateral amygdala, can modulate hippocampal LTP. The nucleus accumbens is part of the ventral striatum and is composed of two main regions: core and shell. Core and shell share a similar cellular composition, but differ in their connectivity with other brain areas. Considering that the nucleus accumbens is related to motivation and that it receives a strong projection from the basolateral amygdala, we have studied the effect of stimulating accumbens shell or core on medial perforant path-granule cells’ LTP in anesthetized male Wistar rats. We found that electrical stimulation of the shell enhances the magnitude of LTP while the stimulation of the core completely prevents LTP induction. The stimulation of the accumbens shell or core alone produced no apparent, direct field potential in dentate gyrus. Additionally, the co-stimulation of the shell or core with the medial perforant path does not modify the input–output curves obtained using stimulation of the perforant path only. These results demonstrate that electrical stimulation of the accumbens shell or core has a bidirectional effect on LTP induction at the dentate gyrus.

The effects of forced exercise on hippocampal plasticity in the rat: A comparison of LTP, spatial- and non-spatial learning

Physical activity may have the potential to improve cognitive function. Here we show that forced treadmill-running results in selective improvements in hippocampal plasticity. Rats that underwent exercise training demonstrated enhanced expression of long-term potentiation in dentate gyrus and enhanced object recognition learning. Spatial learning in the Morris watermaze was unaffected by exercise. These changes were associated with an increase in expression of brain-derived neurotrophic factor in the dentate gyrus.

Idazoxan increases perforant path-evoked EPSP slope paired pulse inhibition and reduces perforant path-evoked population spike paired pulse facilitation in rat dentate gyrus

Norepinephrine, acting via β-adrenoceptors, enhances the perforant path-evoked potential in dentate gyrus. Using systemic idazoxan to increase norepinephrine, and paired perforant path pulses to probe early inhibition, previous investigators reported that idazoxan increased initial spike amplitude and increased somatic feedback inhibition. Here, feedback inhibition was re-examined in idazoxan-treated (5 mg/kg) rats under urethane anesthesia. To control for initial increased spike amplitude after idazoxan, evoked potentials were matched, pre- and post-idazoxan, on initial population spike. Input–output current profiles were also compared pre- and post-idazoxan. Saline- and timolol-filled micropipettes permitted evaluation of a contribution of local β-adrenoceptors. As previously observed, initial spike amplitude was potentiated by idazoxan. Comparable spike potentiation was not seen on the timolol micropipette. Paired pulse inhibition of spike amplitude apparently increased, but input–output curve comparisons revealed a loss of feedback facilitation rather than an increase in feedback inhibition. Initial EPSP slopes were depressed after idazoxan in input–output curve data. EPSP slope feedback ratios were significantly reduced following idazoxan.These data suggest idazoxan has multiple effects on perforant path input to the dentate gyrus. Spike potentiation following idazoxan has previously been shown to depend on intact norepinephrine input. Here, the reduction in spike potentiation on the timolol pipette is consistent with other evidence that norepinephrine-mediated potentiation of the perforant path-evoked potential is dependent on local β-adrenoceptor activation. The input–output data suggest a decrease in feedback facilitation after idazoxan is likely to account for the apparent increase in feedback inhibition previously reported. Decreased EPSP slope ratios with similar paired pulse intervals have been reported in novel environments. Since exposure to novel environments activates locus coeruleus neurons, norepinephrine may mediate the change in EPSP slope inhibition reported in awake rats.In summary, these results are consistent with the hypothesis that idazoxan potentiates granule cell responses to perforant path input in the dentate gyrus via increases in norepinephrine that lead to β-adrenoceptor activation, and, further, that idazoxan reduces paired pulse feedback spike facilitation and enhances EPSP slope, but not spike, feedback inhibition.

17β-Estradiol potentiates field excitatory postsynaptic potentials within each subfield of the hippocampus with greatest potentiation of the associational/commissural afferents of CA3

We sought to determine the impact of 17β-estradiol throughout the hippocampal trisynaptic pathway and to investigate the afferent fiber systems within CA1 and CA3 in detail. To achieve this objective, we utilized multielectrode arrays to simultaneously record the field excitatory postsynaptic potentials from the CA1, dentate gyrus, and CA3 of rat hippocampal slices in the presence or absence of 100 pM 17β-estradiol. We confirmed our earlier findings in CA1, where 17β-estradiol significantly increased field excitatory postsynaptic potentials amplitude (20%±3%) and slope (22%±7%). 17β-Estradiol significantly potentiated the field excitatory postsynaptic potentials in dentate gyrus, amplitude (15%±4%) and slope (17%±5), and in CA3, amplitude (15%±4%) and slope (19%±5%). Using a high-density multielectrode array, we sought to determine the source of potentiation in CA1 and CA3 by determining the impact of 17β-estradiol on the apical afferents and the basal afferents within CA1 and on the mossy fibers and the associational/commissural fibers within CA3. In CA1, 17β-estradiol induced a modest increase in the amplitude (7%±2%) and slope (9%±3%) following apical stimulation with similar magnitude of increase following basal stimulation amplitude (10%±2%) and slope (12%±3%). In CA3, 17β-estradiol augmented the mossy fiber amplitude (15%±3%) and slope (18%±6%) and the associational/commissural fiber amplitude (31%±13%) and slope (40%±15%). These results indicate that 17β-estradiol potentiated synaptic transmission in each subfield of the hippocampal slice, with the greatest magnitude of potentiation at the associational/commissural fibers in CA3. 17β-Estradiol regulation of CA3 responses provides a novel site of 17β-estradiol action that corresponds to the density of estrogen receptors within the hippocampus. The implications of 17β-estradiol potentiation of the field potential in each of the hippocampal subfields and in particular CA3 associational/commissural fibers for memory function and clinical assessment are discussed.

Effect of galnon on induction of long-term potentiation in dentate gyrus of C57BL/6 mice

The impairment of cognitive performance by galanin administration in rodents indicates a possible modulating effect of this neuropeptide on long-term potentiation (LTP) induction in the hippocampal formation. Galnon is a non-peptide, systemically active galanin receptor agonist which has been tested in feeding, seizure and forced swim task in in vivo rodent experimental models. Similarly to galanin (1-29) (i.c.v.), galnon (i.p.) has exhibited anticonvulsant effects in rats. We have investigated the effect of galnon on the synaptic transmission and plasticity in hippocampal dentate gyrus (DG) of C57Bl/6 mice and compared the galnon effects to the effect of galanin (1-29) and galmic, a non-peptide galanin receptor agonist. Similarly to galanin (1-29) and galmic, superfusion of galnon did not alter the input-output responses in DG. Administration of galnon (1 microM) significantly attenuated the LTP induction by 85.5 +/- 1% by 51 min after high frequency trains stimulation. This result was very similar to the effect of galanin (1-29) and galmic, which caused an 80 +/- 1.5% and 94 +/- 2% reduction in the level of field potentiation, respectively. The PPF responses, however, were not altered due to galnon superfusion which is in contrast to the effect of galanin (1-29) or galmic. In summary, these data indicate that the systemically active, non-peptide galanin receptor agonist, galnon can exert similar effects to galanin (1-29) in attenuation of DG LTP in mice.

Long-term potentiation in aged rats is restored when the age-related decrease in polyunsaturated fatty acid concentration is reversed

Several age-related changes have been identified in rat hippocampus; among these are deficits in glutamate release and long-term potentiation in dentate gyrus. These deficits correlate with a decrease in the concentration of arachidonic acid in hippocampus. In this study, the effects of dietary supplementation for 8 weeks with ω -6 or ω -3 fatty acids were assessed in groups of aged and young rats. The data presented indicate that dietary supplementation in aged rats restored the concentrations of arachidonic acid and docosahexanoic acid in hippocampal preparations to those observed in tissue prepared from young rats. In parallel, aged rats which received the experimental diets sustained long-term potentiation in a manner indistinguishable from young rats. The evidence presented supports the view that an age-related increase in reactive oxygen species production is linked with the decrease in polyunsaturated fatty acids and that a diet enriched in eicosapentanoic acid has antioxidant properties which may play a key role in reversal of the observed age-related deficits.

Effects of intrahippocampal aniracetam treatment on Y-maze avoidance learning performance and behavioral long-term potentiation in dentate gyrus in rat

Effects of intrahippocampal treatment of aniracetam, a selective agonist for dl-α-amino-3-hydroxy-5-methyl-4-isoxazoleproionic acid (AMPA) receptors, on Y-maze avoidance learning task and behavioral long-term potentiation (LTP) in perforant path-dentate gyrus were studied in freely moving rats by using in vivo electrophysiology combined with behavioral tests. The results were as follows: (1) intrahippocampal treatment of aniracetam reversibly enhanced basal synaptic transmission in perforant path to dentate gyrus in a dosage dependent manner; (2) aniracetam produced improvement in Y-maze learning performance when administration occurred 5 min prior to maze learning; (3) aniracetam administration significantly facilitated behavioral LTP in dentate gyrus, while the maximal amplitude of LTP has no significant difference when compared to saline group. The present results indicate that hippocampal AMPA receptors are involved in learning and memory.

Long-term potentiation in dentate gyrus of the rat is inhibited by the phosphoinositide 3–kinase inhibitor, wortmannin

The pivotal role of inositol phospholipids in cell signalling has been placed centre-stage again with the recognition that phosphoinositide (PI) 3–kinase is implicated in several cellular processes. Stimulation of PI–3 kinase requires activation of the 85 kD regulatory subunit which relies on tyrosine phosphorylation, one consequence of which is activation of the 110 kD catalytic subunit. In this study, we have investigated the role of PI 3–kinase in the expression of long-term potentiation (LTP) in perforant path-granule cell synapses of the rat. We report that intracerebroventricular injection of wortmannin inhibited expression of LTP, though it did not affect the early change in the synaptic response. Activation of PI 3–kinase was enhanced in tetanized tissue prepared from dentate gyrus, compared with untetanized tissue, but this effect was inhibited in tissue prepared from wortmannin-pretreated rats. LTP was associated with increased glutamate release, as previously described, but this effect was also inhibited in tissue prepared from wortmannin-pretreated rats. The results presented demonstrate that wortmannin also exerted an inhibitory effect on KCl-stimulated glutamate release and calcium influx in hippocampal synaptosomes in vitro. The evidence presented is consistent with the hypothesis that PI 3–kinase activation, possibly by NGF, plays a role in expression of LTP in dentate gyrus.

Protein synthesis in entorhinal cortex and long-term potentiation in dentate gyrus.

Despite the concentration of effort in recent years, the mechanisms underlying the expression of long-term potentiation (LTP) in the hippocampus remain elusive, but amidst the uncertainty and sometimes controversy, one consistent finding is emerging; this is that late-phase LTP requires synthesis of proteins. This hypothesis was first proposed by a number of groups who reported that the more persistent components of LTP were blocked by protein synthesis inhibitors, and was supported by a significant literature which indicated that morphological changes accompanied LTP. Recent evidence indicated that the increase in protein synthesis may be cAMP-dependent and that subsequent activation of the transcription factor, CREB, represented one step in the cascade of events leading to protein synthesis. Whether protein synthesis occurs in presynaptic or postsynaptic neurons, or both, is still a subject of debate. Here we present evidence which suggests that LTP in perforant path-granule cell synapses is accompanied by protein synthesis, specifically synthesis of synaptic vesicle proteins, in the entorhinal cortex. We also show that protein synthesis is decreased in the entorhinal cortex of aged rats and a strain of rat which is genetically hypertensive, both of which exhibited impaired LTP. We propose that that the observed increase in protein synthesis in the entorhinal cortex, which accompanied LTP in the dentate gyrus, contributes to the reported changes in morphology in the presynaptic terminal.

Age-related changes in oxidative mechanisms and LTP are reversed by dietary manipulation

Aged rats exhibit an impaired ability to sustain long-term potentiation in dentate gyrus which correlates with a decrease in arachidonic acid concentration. Here we confirm the previous finding that dietary supplementation with arachidonic acid and its precursor, γ-linolenic acid, reversed the impairment in LTP in aged rats and report that there is a significant correlation between membrane arachidonic acid concentration and response to tetanic stimulation. We observed that age was associated with decreases in the concentration of vitamins C and E and increased activity of superoxide dismutase, indicative of a compromise in antioxidative defenses; these changes were paralleled by increases in interleukin-1β (IL-1β) concentration and lipid peroxidation. Dietary manipulation restored polyunsaturated fatty acid concentrations to values observed in tissue prepared from young rats and reversed the age-related changes in vitamins E and C, IL-1β concentration and superoxide dismutase activity. We propose that these changes reverse the increase in lipid peroxidation and thereby the age-related change in polyunsaturated fatty acids.

Intravenously administered cell-permeant calcium buffer decreases evoked synaptic potentials in rat dentate gyrus in vivo

We examined the effects of the neuroprotective cell-permeant Ca 2+ buffer, 2-aminophenol- N, N, O-triacetic acid acetoxymethyl ester (APTRA-AM, 20–40 mg/kg), on synaptically evoked potentials in the dentate gyrus of awake rats. Intravenous APTRA-AM (20 mg/kg) decreased the evoked potentials with peak effects ≈6 h after infusion, and recovery to control levels by 24 h. Peak decrease in the population spike (PS) amplitude was by 72±17% of control, and the excitatory postsynaptic potential (EPSP) slope was decreased by 31±12%. APTRA-AM (40 mg/kg), decreased the PS amplitude and EPSP slope by 58±7% and 31±6% of pre-drug levels, respectively. These effects were qualitatively similar to the presynaptically mediated decreases in synaptic potentials previously demonstrated in vitro with APTRA-AM. These results indicate that the cell-permeant Ca 2+ buffer, APTRA-AM, attenuates hippocampal excitability in vivo, most likely by decreasing synaptic neurotransmission.

Evidence for a role for synaptophysin in expression of long-term potentiation in rat dentate gyrus

Maintenance of long-term potentiation in perforant path-granule cell synapses is accompanied by increased glutamate release. Here we investigate the role of synaptophysin in release and in expression of long-term potentiation in dentate gyrus. We report that long-term potentiation was accompanied by increased endogenous glutamate release and increased tyrosine phosphorylation of synaptophysin, but these changes were attenuated when long-term potentiation was inhibited by the tyrosine kinase inhibitor tyrphostin AG879 or by the NMDA antagonist D-aminophosphonovalerate. In vitro analysis revealed that KCl-induced glutamate release was abolished in synaptosomes prepared in the presence of antisynaptophysin. The data suggest a role for synaptophysin in release and indicate that activation of tyrosine kinase and synaptophysin phosphorylation contribute to long-term potentiation perhaps by modulating glutamate release.

Effects of barium on stimulus-induced changes in [K +] o and field potentials in dentate gyrus and area CA1 of human epileptic hippocampus

The effects of barium on stimulus-induced rises in [K +] o were studied in the dentate gyrus (DG) and area CA1 of human hippocampal slices. Rises in [K +] o elicited by repetitive stimulation of the hilus, stratum moleculare, alveus, or stratum radiatum were dependent on stimulus intensity and frequency. Barium augmented rises in [K +] o in the DG by about 120% but failed to do so in area CA1. In both DG and area CA1 barium had no effects on population spikes whereas stimulus-induced slow field potentials were reduced. Since barium interferes with K + uptake and redistribution by blocking leak conductances and inwardly-rectifying currents in astrocytes, our findings suggest that glial cells in the sclerotic hippocampal area CA1 may contribute less to K + regulation.

Dietary Supplementation with Vitamin E Reverses the Age-related Deficit in Long Term Potentiation in Dentate Gyrus

Long term potentiation (LTP) in dentate gyrus is impaired in aged rats, and this has been associated with an age-related decrease in membrane arachidonic acid concentration. In this study, we considered whether the trigger for this age-related decrease in arachidonic acid might be increased lipid peroxidation stimulated by the proinflammatory cytokine, interleukin-1beta. Groups of aged and young rats were fed on a control diet or a diet supplemented with alpha-tocopherol and assessed for their ability to sustain LTP. Aged rats fed on the control diet exhibited an impaired ability to sustain LTP and analysis of tissue prepared from these rats exhibited increased interleukin-1beta, increased lipid peroxidation, and decreased membrane arachidonic acid concentration compared with young rats fed on either diet. Aged rats fed on the supplemented diet sustained LTP in a manner indistinguishable from young rats, and the age-related increases in interleukin-1beta and lipid peroxidation and the decrease in membrane arachidonic acid concentration were all reversed. We propose that interleukin-1beta may be the trigger that induces these age-related changes and may therefore be responsible for the deficit in long term potentiation in aged rats. The observation that alpha-tocopherol reverses these changes is consistent with the hypothesis that some age-related changes in hippocampus might derive from oxidative stress.

Intracerebroventricular norepinephrine potentiation of the perforant path-evoked potential in dentate gyrus of anesthetized and awake rats: A role for both α- and β-adrenoceptor activation

Norepinephrine (NE) applied iontophoretically to the dentate gyrus in vivo, and bath applied to hippocampal slices in vitro, produces potentiation of the perforant path-evoked potential. β-receptors mediate exogenous NE potentiation in vitro, while α-receptors are implicated in exogenous effects in vivo. The present study uses intracerebroventricular (i.c.v.) NE to mimic in vitro bath conditions in vivo. Short-term NE potentiation was reliably seen with 10 μg [±] NE in 2 μl of 0.9% saline i.c.v. Long-term potentiation occurred with higher doses of NE. The β-agonist isoproterenol and the α-agonist phenylephrine also produced potentiation. Long-term effects were common with isoproterenol. The β-antagonist metoprolol and the α-antagonist phentolamine attenuated NE potentiation. The results suggest that both α- and β-receptors could play a role in NE potentiation in dentate gyrus in vivo. In awake animals, 10 μg NE i.c.v. reproduced the potentiation pattern seen in anesthetized rats. NE potentiation in awake rats was independent of behavioral variation.