Long-term 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.

Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity

Excitatory amino acids play a key role in both adaptive and deleterious effects of stressors on the brain, and dysregulated glutamate homeostasis has been associated with psychiatric and neurological disorders. Here, we elucidate mechanisms of epigenetic plasticity in the hippocampus in the interactions between a history of chronic stress and familiar and novel acute stressors that alter expression of anxiety- and depressive-like behaviors. We demonstrate that acute restraint and acute forced swim stressors induce differential effects on these behaviors in naive mice and in mice with a history of chronic-restraint stress (CRS). They reveal a key role for epigenetic up- and down-regulation of the putative presynaptic type 2 metabotropic glutamate (mGlu2) receptors and the postsynaptic NR1/NMDA receptors in the hippocampus and particularly in the dentate gyrus (DG), a region of active neurogenesis and a target of antidepressant treatment. We show changes in DG long-term potentiation (LTP) that parallel behavioral responses, with habituation to the same acute restraint stressor and sensitization to a novel forced-swim stressor. In WT mice after CRS and in unstressed mice with a BDNF loss-of-function allele (BDNF Val66Met), we show that the epigenetic activator of histone acetylation, P300, plays a pivotal role in the dynamic up- and down-regulation of mGlu2 in hippocampus via histone-3-lysine-27-acetylation (H3K27Ac) when acute stressors are applied. These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.

Lentiviral silencing of GSK-3β in adult dentate gyrus impairs contextual fear memory and synaptic plasticity.

Attempts have been made to use glycogen synthase kinase-3 beta (GSK3β) inhibitors for prophylactic treatment of neurocognitive conditions. However the use of lithium, a non-specific inhibitor of GSK3β results in mild cognitive impairment in humans. The effects of global GSK3β inhibition or knockout on learning and memory in healthy adult mice are also inconclusive. Our study aims to better understand the role of GSK3β in learning and memory through a more regionally, targeted approach, specifically performing lentiviral-mediated knockdown of GSK3β within the dentate gyrus (DG). DG-GSK3β-silenced mice showed impaired contextual fear memory retrieval. However, cue fear memory, spatial memory, locomotor activity and anxiety levels were similar to control. These GSK3β-silenced mice also showed increased induction and maintenance of DG long-term potentiation (DG-LTP) compared to control animals. Thus, this region-specific, targeted knockdown of GSK3β in the DG provides better understanding on the role of GSK3β in learning and memory.

Excess influx of Zn2+ into dentate granule cells affects object recognition memory via attenuated LTP

The influx of extracellular Zn2+ into dentate granule cells is nonessential for dentate gyrus long-term potentiation (LTP) and the physiological significance of extracellular Zn2+ dynamics is unknown in the dentate gyrus. Excess increase in extracellular Zn2+ in the hippocampal CA1, which is induced with excitation of zincergic neurons, induces memory deficit via excess influx of Zn2+ into CA1 pyramidal cells. In the present study, it was examined whether extracellular Zn2+ induces object recognition memory deficit via excess influx of Zn2+ into dentate granule cells. KCl (100 mM, 2 µl) was locally injected into the dentate gyrus. The increase in intracellular Zn2+ in dentate granule cells induced with high K+ was blocked by co-injection of CaEDTA and CNQX, an extracellular Zn2+ chelator and an AMPA receptor antagonist, respectively, suggesting that high K+ increases the influx of Zn2+ into dentate granule cells via AMPA receptor activation. Dentate gyrus LTP induction was attenuated 1 h after KCl injection into the dentate gyrus and also attenuated when KCl was injected 5 min after the induction. Memory deficit was induced when training of object recognition test was performed 1 h after KCl injection into the dentate gyrus and also induced when KCl was injected 5 min after the training. High K+-induced impairments of LTP and memory were rescued by co-injection of CaEDTA. These results indicate that excess influx of Zn2+ into dentate granule cells via AMPA receptor activation affects object recognition memory via attenuated LTP induction. Even in the dentate gyrus where is scarcely innervated by zincergic neurons, it is likely that extracellular Zn2+ homeostasis is strictly regulated for cognition.

Amyloid β-mediated Zn2+ influx into dentate granule cells transiently induces a short-term cognitive deficit.

We examined an idea that short-term cognition is transiently affected by a state of confusion in Zn2+ transport system due to a local increase in amyloid-β (Aβ) concentration. A single injection of Aβ (25 pmol) into the dentate gyrus affected dentate gyrus long-term potentiation (LTP) 1 h after the injection, but not 4 h after the injection. Simultaneously, 1-h memory of object recognition was affected when the training was performed 1 h after the injection, but not 4 h after the injection. Aβ-mediated impairments of LTP and memory were rescued in the presence of zinc chelators, suggesting that Zn2+ is involved in Aβ action. When Aβ was injected into the dentate gyrus, intracellular Zn2+ levels were increased only in the injected area in the dentate gyrus, suggesting that Aβ induces the influx of Zn2+ into cells in the injected area. When Aβ was added to hippocampal slices, Aβ did not increase intracellular Zn2+ levels in the dentate granule cell layer in ACSF without Zn2+, but in ACSF containing Zn2+. The increase in intracellular Zn2+ levels was inhibited in the presence of CaEDTA, an extracellular zinc chelator, but not in the presence of CNQX, an AMPA receptor antagonist. The present study indicates that Aβ-mediated Zn2+ influx into dentate granule cells, which may occur without AMPA receptor activation, transiently induces a short-term cognitive deficit. Extracellular Zn2+ may play a key role for transiently Aβ-induced cognition deficits.

Two-Stage Translational Control of Dentate Gyrus LTP Consolidation Is Mediated by Sustained BDNF-TrkB Signaling to MNK

BDNF signaling contributes to protein-synthesis-dependent synaptic plasticity, but the dynamics of TrkB signaling and mechanisms of translation have not been defined. Here, we show that long-term potentiation (LTP) consolidation in the dentate gyrus of live rodents requires sustained (hours) BDNF-TrkB signaling. Surprisingly, this sustained activation maintains an otherwise labile signaling pathway from TrkB to MAP-kinase-interacting kinase (MNK). MNK activity promotes eIF4F translation initiation complex formation and protein synthesis in mechanistically distinct early and late stages. In early-stage translation, MNK triggers release of the CYFIP1/FMRP repressor complex from the 5'-mRNA cap. Inlate-stage translation, MNK regulates the canonical translational repressor 4E-BP2 in a synapse-compartment-specific manner. This late stage is coupled to MNK-dependent enhanced dendritic mRNA translation. We conclude that LTP consolidation in the dentate gyrus is mediated by sustained BDNF signaling to MNK and MNK-dependent regulation of translation in two functionally and mechanistically distinct stages.

Intracellular Zn(2+) signaling in the dentate gyrus is required for object recognition memory.

The role of perforant pathway-dentate granule cell synapses in cognitive behavior was examined focusing on synaptic Zn(2+) signaling in the dentate gyrus. Object recognition memory was transiently impaired when extracellular Zn(2+) levels were decreased by injection of clioquinol and N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylendediamine. To pursue the effect of the loss and/or blockade of Zn(2+) signaling in dentate granule cells, ZnAF-2DA (100 pmol, 0.1 mM/1 µl), an intracellular Zn(2+) chelator, was locally injected into the dentate molecular layer of rats. ZnAF-2DA injection, which was estimated to chelate intracellular Zn(2+) signaling only in the dentate gyrus, affected object recognition memory 1 h after training without affecting intracellular Ca(2+) signaling in the dentate molecular layer. In vivo dentate gyrus long-term potentiation (LTP) was affected under the local perfusion of the recording region (the dentate granule cell layer) with 0.1 mM ZnAF-2DA, but not with 1-10 mM CaEDTA, an extracellular Zn(2+) chelator, suggesting that the blockade of intracellular Zn(2+) signaling in dentate granule cells affects dentate gyrus LTP. The present study demonstrates that intracellular Zn(2+) signaling in the dentate gyrus is required for object recognition memory, probably via dentate gyrus LTP expression.

Differential effects of the histamine H(3) receptor agonist methimepip on dentate granule cell excitability, paired-pulse plasticity and long-term potentiation in prenatal alcohol-exposed rats.

We previously reported that prenatal alcohol-induced deficits in dentate gyrus (DG) long-term potentiation (LTP) are ameliorated by the histamine H3 receptor inverse agonist ABT-239. ABT-239 did not enhance LTP in control rats, suggesting that the possibility of a heightened H3 receptor-mediated inhibition of LTP in prenatal alcohol-exposed (PAE) offspring. To further investigate this mechanism, we examined the effect of methimepip, a selective histamine H3 receptor agonist, on DG granule cell responses and LTP in saccharin control and PAE rats. Long-Evans rat dams voluntarily consumed either a 0 or 5% ethanol solution 4 hours each day throughout gestation. Adult male offspring from these dams were anesthetized with urethane and electrodes implanted into the entorhinal cortical perforant path and the DG. In control offspring, methimepip reduced the coupling of fast excitatory postsynaptic field potentials to population spikes (E-S coupling), the probability of glutamate release, as measured by paired-pulse ratio (PPR) and diminished DG LTP. Similar reductions in E-S coupling and LTP were observed in saline-treated PAE offspring. In contrast to the control group, methimepip did not exacerbate PAE-induced reductions in E-S coupling or LTP. While the effects of methimepip in control offspring were consistent with speculation of a PAE-induced enhancement of H3 receptor-mediated inhibition of E-S coupling and LTP, the absence of an added effect of methimepip in PAE offspring could indicate either an inability to further inhibit these responses with methimepip in PAE rats or the presence of more complex regulatory neural interactions with in vivo recordings in PAE rats. Follow-up studies of H3 receptor-mediated responses in DG slice preparations are under way to provide clearer insights into the role of the H3 receptor regulation of excitatory transmission in PAE rats.

Advantageous effect of theanine intake on cognition

Theanine, γ-glutamylethylamide, is one of the major amino acid components in green tea. On the basis of the preventive effect of theanine intake after weaning on stress-induced impairment of recognition memory, the advantageous effect of theanine intake on recognition memory was examined in young rats, which were fed water containing 0.3% theanine for 3 weeks after weaning. The rats were subjected to object recognition test. Object recognition memory was maintained in theanine-administered rats 48 hours after the training, but not in the control rats. When in vivo dentate gyrus long-term potentiation (LTP) was induced, it was more greatly induced in theanine-administered rats than in the control rats. The levels of brain-derived neurotropic factor and nerve growth factor in the hippocampus were significantly higher in theanine-administered rats than in the control rats. The present study indicates the advantageous effect of theanine intake after weaning on recognition memory. It is likely that theanine intake is of advantage to the development of hippocampal function after weaning.

The effects of a reminder of underwater trauma on behaviour and memory-related mechanisms in the rat dentate gyrus

Intrusive re-experiencing is a core symptom in post-traumatic stress disorder (PTSD), often triggered by contextual cues associated with the trauma. It is not yet clear if intrusive re-experiencing is only the result, or whether it may contribute to the establishment of PTSD following acute stress. This study aimed at examining the impact of an underwater trauma (UWT) reminder on anxiety-like behaviour and on neuronal activity and plasticity in the hippocampus and the amygdala. Sprague-Dawley rats were exposed to UWT and 24h later were re-exposed to the context. The effects on behaviour, activation of the amygdala (BLA) and dentate gyrus (DG), and on long-term potentiation (LTP) and local circuit activity (frequency-dependent inhibition (FDI) and paired-pulse inhibition (PPI)) in the DG were assessed. The exposure to UWT by itself resulted in increased anxiety behaviour in the open field, together with increased PPI. Upon exposure to the UWT reminder, an additional increase in anxiety was also observed in the EPM and in FDI. Moreover, reminder exposure resulted in impaired DG LTP and a significant BLA extracellular-signal-regulated kinases (ERK) 2 activation. In conclusion, these observed effects of exposure to a trauma reminder, following the exposure to the initial trauma, might be associated with the progression of trauma-related pathologies and the development of related disorders.

Improvement in Memory and Brain Long-term Potentiation Deficits Due to Permanent Hypoperfusion/Ischemia by Grape Seed Extract in Rats.

Cerebral hypoperfusion/ischemia (CHI) is a neurological disease where impaired hippocampus electrical activity and cognition caused by a serial pathophysiological events. This study aimed to evaluate the effects of chronic oral administration of grape seed extract (GSE) on passive avoidance memory and long-term potentiation (LTP) after permanent bilateral common carotid arteries occlusion (2CCAO) in male adult rats. Thirty-two adult male Wistar rats were randomly divided into: 1) Sham+Veh, 2) Isch+Veh, 3) Sham+GSE, 4) Isch+GSE. In order to make 2CCAO as an animal model of CHI, carotid arteries were ligatured and then cut bilaterally. To evaluation of passive avoidance memory, step-down latency (STL) was measured and LTP was recorded from hippocampal dentate gyrus (DG) after high frequency stimulation (HFS) in all rats. We found that memory was significantly impaired in rats after CHI (P<0.001) concomitant with hippocampal LTP inhibition (P<0.05, P<0.01 for LTP1 and LTP48 respectively). GSE treatment significantly improved memory impairment and increased hippocampal LTP in rats with 2CCAO. Our results in present study suggest that GSE exhibits therapeutic potential for short-and long-term memories as well as LTP in DG, which is most likely related at least in part to its antioxidative and free radical scavenging actions.

Prenatal Ethanol (EtOH) Exposure Alters the Sensitivity of the Adult Dentate Gyrus to Acute EtOH Exposure

Prenatal ethanol (EtOH) exposure results in a spectrum of structural, cognitive, and behavioral abnormalities, collectively termed "fetal alcohol spectrum disorders" (FASDs). The hippocampal formation, an area of the brain strongly linked with learning and memory, is particularly vulnerable to the teratogenic effects of EtOH. Prenatal EtOH exposure can lead to long-lasting impairments in the ability to process spatial information, as well as produce long-lasting deficits in the ability of animals to exhibit long-term potentiation (LTP), a biological model of learning and memory processing. These deficits also have the ability to facilitate EtOH and/or other drug abuse later in life. This study sought to determine prenatal EtOH exposure altered the effects of acute EtOH application on synaptic plasticity. Prenatal EtOH exposure was modeled using a liquid diet where dams were given 1 of 3 diets: (i) a liquid diet containing EtOH (35.5% EtOH-derived calories), (ii) a liquid diet, isocaloric to the EtOH diet, but with maltose-dextrin substituting for the EtOH-derived calories, and (iii) an ad libitum diet of standard rat chow. Extracellular recordings from transverse brain slices (350μm) prepared from 50- to 70-day-old rats, following prenatal EtOH exposure (gestational day 1 to 21). LTP was examined in the dentate gyrus following acute EtOH exposure (0, 20, or 50mM) in these slices. Prenatal EtOH exposure attenuated LTP in the adult dentate gyrus. In control offspring, acute application of EtOH in adulthood attenuated (20mM) or blocked (50mM) LTP. Conversely, the effect of acute EtOH application on LTP was not as pronounced in prenatal EtOH offspring. Prenatal EtOH exposure alters the sensitivity of the adult dentate gyrus to acute EtOH application producing a long-lasting tolerance to the inhibitory effects of EtOH. This decreased sensitivity may provide a mechanism promoting the formation of drug-associated memories and help explain the increased likelihood of developing an alcohol dependency often observed in individuals with FASDs.

Effects of Ethanol Exposure during Distinct Periods of Brain Development on Hippocampal Synaptic Plasticity.

Fetal alcohol spectrum disorders occur when a mother drinks during pregnancy and can greatly influence synaptic plasticity and cognition in the offspring. In this study we determined whether there are periods during brain development that are more susceptible to the effects of ethanol exposure on hippocampal synaptic plasticity. In particular, we evaluated how the ability to elicit long-term potentiation (LTP) in the hippocampal dentate gyrus (DG) was affected in young adult rats that were exposed to ethanol during either the 1st, 2nd, or 3rd trimester equivalent. As expected, the effects of ethanol on young adult DG LTP were less severe when exposure was limited to a particular trimester equivalent when compared to exposure throughout gestation. In males, ethanol exposure during the 1st, 2nd or 3rd trimester equivalent did not significantly reduce LTP in the DG. In females, ethanol exposure during either the 1st or 2nd trimester equivalents did not impact LTP in early adulthood, but following exposure during the 3rd trimester equivalent alone, LTP was significantly increased in the female DG. These results further exemplify the disparate effects between the ability to elicit LTP in the male and female brain following perinatal ethanol exposure (PNEE).

Priming stimulation of basal but not lateral amygdala affects long-term potentiation in the rat dentate gyrus in vivo

The amygdaloid complex, or amygdala, has been implicated in assigning emotional significance to sensory information and producing appropriate behavioral responses to external stimuli. The lateral and basal nuclei (lateral and basal amygdala), which are termed together as basolateral amygdala, play a critical role in emotional and motivational learning and memory. It has been established that the basolateral amygdala activation by behavioral manipulations or direct electrical stimulation can modulate hippocampal long-term potentiation (LTP), a putative cellular mechanism of memory. However, the specific functional role of each subnucleus in the modulation of hippocampal LTP has not been studied yet, even though studies have shown cytoarchitectural differences between the basal and lateral amygdala and differences in the connections of each one of them to other brain areas. In this study we have tested the effects of lateral or basal amygdala pre-stimulation on hippocampal dentate gyrus LTP, induced by theta burst stimulation of the perforant path, in anesthetized rats. We found that while priming stimulation of the lateral amygdala did not affect LTP of the dentate gyrus, priming stimulation of the basal amygdala enhanced the LTP response when the priming stimulation was relatively weak, but impaired it when it was relatively strong. These results show that the basal and lateral nuclei of the amygdala, which have been already shown to differ in their anatomy and connectivity, may also have different functional roles. These findings raise the possibility that the lateral and basal amygdala differentially modulate memory processes in the hippocampus under emotional and motivational situations.

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.

Methionine-enriched diet decreases hippocampal antioxidant defences and impairs spontaneous behaviour and long-term potentiation in rats

Diets high in methionine lead to elevation of plasma homocysteine levels which are possibly linked to neurodegenerative diseases and oxidative stress. In the present study, we investigated the effects of methionine-enriched diet on antioxidant defences, on rat spontaneous behaviour and on the ability to sustain long-term potentiation in the dentate gyrus (DG).Sprague-Dawley rats were fed either a standard laboratory diet or a methionine enriched-diet (1% or 5% methionine in drinking water) for 8 weeks. After the 8 weeks, the animals were tested for spontaneous motor activity and habituation in an open field maze, for anxiety-like behaviour in an elevated plus maze and for the ability to sustain long-term potentiation (LTP) induced in the dentate gyrus under urethane anaesthesia. The brains were then removed and histochemically stained for superoxide dismutase (SOD) activity.Rats fed on 5% methionine significantly reduced total distance travelled during the open field test and exhibited no habituation with respect to the other two groups. Rats fed on 5% methionine also showed a significant increase of the anxiety level. Moreover, in this group, the ability to induce LTP in DG was impaired. SOD activity was significantly increased in the cerebral cortex of the rats fed on 1% and 5% methionine with respect to the control group.In conclusion, 5% methionine in drinking water led to evident impairment of locomotor skills and of synaptic plasticity. SOD activity in the cortex was increased in both the groups fed on 1% and 5% methionine, thus suggesting that metabolic adjustments, triggered by the methionine-enriched diet, are likely mediated by reactive oxygen species.

β-Estradiol unmasks metabotropic receptor-mediated metaplasticity of NMDA receptor transmission in the female rat dentate gyrus

Loss of estrogen in women following menopause is associated with increased risk for cognitive decline, dementia and depression, all of which can be prevented by estradiol replacement. The dentate gyrus plays an important role in cognition, learning and memory. The gatekeeping function of the dentate gyrus to filter incoming activity into the hippocampus is modulated by estradiol in a frequency-dependent manner and involves activation of metabotropic glutamate receptors (mGluR). In the present study, we investigated whether estradiol (EB) modulates the metaplastic effect of inducing synaptic long-term potentiation (LTP) on subsequent propensity for expression of LTP in the dentate gyrus. At medial perforant path-dentate granule cell synapses in hippocampal slices of ovariectomized female rats, EB replacement was critical for an initial induction of LTP to enhance the magnitude of subsequent LTP elicited by a second high-frequency stimulation, metaplasticity, which was not present in slices from oil-treated control animals. EB enhanced expression of group I mGluRs, and the metaplastic effect of EB on LTP required activation of group I mGluRs that led to Src-family tyrosine kinase-mediated phosphorylation of NR2B subunits of N-methyl-d-aspartate receptors (NMDAR) that enhanced the magnitude of NMDAR-dependent LTP. Our data show that EB effects on LTP in the hippocampal dentate gyrus require activation of group I mGluRs, which in turn leads to functional metaplastic regulation of NR2B subunit-containing NMDARs, as opposed to direct effects of EB on NMDARs.

Transient increases in dendritic spine density contribute to dentate gyrus long‐term potentiation

Dendritic spines are the primary sites for excitatory neurotransmission in the adult brain and exhibit changes in their number and morphology with experience. The relationship between spine formation and synaptic activity has been best characterized along the apical dendrites of pyramidal neurons in the hippocampal CA1 subfield. However, less is known about the structural mechanisms at the spine that mediate plasticity in other hippocampal subfields. The dentate gyrus is the predominant point of entry for synaptic input to the hippocampus, and dentate granule cells differ from CA1 pyramidal neurons in terms of their morphology and biophysical properties. In order to understand the structural mechanisms for plasticity in the dentate gyrus, we measured dendritic spine density in hippocampal slice preparations at different intervals following synaptic stimulation. We observed that transient increases in dendritic spine density are detectable 30 min after induction of long-term potentiation (LTP). By 60 min poststimulation, dendritic spine density has returned to basal levels. Both early LTP and enhancements in dendritic spine density could be blocked by destabilizing actin filaments, but not by inhibitors of transcription or protein synthesis. These results indicate that spine formation is a transient event that is required for dentate gyrus LTP.

Polygalasaponin F induces long-term potentiation in adult rat hippocampus via NMDA receptor activation

To investigate the effect and underlying mechanisms of polygalasaponin F (PGSF), a triterpenoid saponin isolated from Polygala japonica, on long-term potentiation (LTP) in hippocampus dentate gyrus (DG) of anesthetized rats. Population spike (PS) of hippocampal DG was recorded in anesthetized male Wistar rats. PGSF, the NMDAR inhibitor MK801 and the CaMKII inhibitor KN93 were intracerebroventricularly administered. Western blotting analysis was used to examine the phosphorylation expressions of NMDA receptor subunit 2B (NR2B), Ca(2+)/calmodulin-dependent kinase II (CaMKII), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB). Intracerebroventricular administration of PGSF (1 and 10 μmol/L) produced long-lasting increase of PS amplitude in hippocampal DG in a dose-dependent manner. Pre-injection of MK801 (100 μmol/L) or KN93 (100 μmol/L) completely blocked PGSF-induced LTP. Furthermore, the phosphorylation of NR2B, CaMKII, ERK, and CREB in hippocampus was significantly increased 5-60 min after LTP induction. The up-regulation of p-CaMKII expression could be completely abolished by pre-injection of MK801. The up-regulation of p-ERK and p-CREB expressions could be partially blocked by pre-injection of KN93. PGSF could induce LTP in hippocampal DG in anesthetized rats via NMDAR activation mediated by CaMKII, ERK and CREB signaling pathway.

Stimulus intensity-dependent modulations of hippocampal long-term potentiation by basolateral amygdala priming

There is growing realization that the relationship between memory and stress/emotionality is complicated, and may include both memory enhancing and memory impairing aspects. It has been suggested that the underlying mechanisms involve amygdala modulation of hippocampal synaptic plasticity, such as long-term potentiation (LTP). We recently reported that while in CA1 basolateral amygdala (BLA) priming impaired theta stimulation induced LTP, it enhanced LTP in the dentate gyrus (DG). However, emotional and stressfull experiences were found to activate synaptic plasticity within the BLA, raising the possibility that BLA modulation of other brain regions may be altered as well, as it may depend on the way the BLA is activated or is responding. In previous studies BLA priming stimulation was relatively weak (1 V, 50 μs pulse duration). In the present study we assessed the effects of two stronger levels of BLA priming stimulation (1 V or 2 V, 100 μs pulse duration) on LTP induction in hippocampal DG and CA1, in anesthetized rats. Results show that 1V-BLA priming stimulation enhanced but 2V-BLA priming stimulation impaired DG LTP; however, both levels of BLA priming stimulation impaired CA1 LTP, suggesting that modulation of hippocampal synaptic plasticity by amygdala is dependent on the degree of amygdala activation. These findings suggest that plasticity-induced within the amygdala, by stressful experiences induces a form of metaplasticity that would alter the way the amygdala may modulate memory-related processes in other brain areas, such as the hippocampus.