Long-term Potentiation In Rats Research Articles

Enriched environment rescues neonatal pain induced cognitive deficits and the impaired hippocampal synaptic plasticity later in life.

Although extensive and untreated pain that occurs during a critical developmental window may impair cognition later in life, environmental interventions early in life might promote cognition. However, the underlying mechanism is poorly understood. Our current study utilized a rat model of "repetitive needle pricks" from the day of birth (P0) to postnatal day 7 (P7) to mimic the painful experience of preterm neonates in the neonatal intensive care unit. Enriched environment (EE) during development period (from P15 to P70) was implemented as a nonpharmacological intervention approach. Electrophysiological recording, behavioral tests, and biochemical analysis were performed after the end of EE (between P71 and P80). The results showed neonatal repetitive pain resulted in a reduction in mechanical withdrawal thresholds by the von Frey test in P70 (p<.001). Furthermore, neonatal repetitive pain impaired spatial learning and memory (p<.05) and even led to dysfunction in fear memory (p<.01). In contrast, EE rescued neonatal pain-induced cognitive deficits and normalized hippocampal long-term potentiation in rats exposed to neonatal pain (p <<.05). The beneficial effect of EE might be the improvements in hippocampal synaptic plasticity via upregulating neurotrophic factors and N-methyl-d-aspartate (NMDA) receptors in the hippocampus. Our findings provide evidence that early environmental intervention might be a safe strategy to overcome neurodevelopmental abnormalities in preterm infants who experienced multiple procedural painful events during the early critical period.

Activation of 5-HT1 receptor in lateral habenula impaired contextual fear memory and hippocampal LTP in rat

Serotonin (5-hydroxytraptamine, 5-HT) is a neurotransmitter plays important roles in emotion and motivation. The action of 5-HT varies across nucleus and the receptor sub-types. Lateral habenula (LHb) in a brain area reciprocally connects with raphe nucleus and plays important roles in emotion and depression. In this study, we aimed to study the role of 5-HT1 receptor in LHb on fear learning. 15 min before or immediate after the fear conditioning, 5-Carboxyamidotrypamine maleate salt (5-CT), an agonist of 5-HT1 receptor, was bilaterally delivered into LHb (1 μg/μl, 1 μl/side) in rats. We found that activation of 5-HT1 receptor in LHb impaired the acquisition but not consolidation of fear memory in rats, which was accompanied by impaired long-term potentiation (LTP) and decreased phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at the Ser845 site in hippocampus. In addition, 5-CT decreased the time spent in center area of the open field and time spent in open arm in elevated plus maze. These results suggest that activation of 5-HT1 receptor in LHb impaired acquisition of hippocampal dependent fear memory and increased anxiety- like behavior in rats.

Losartan improved hippocampal long-term potentiation impairment induced by repeated LPS injection in rats.

Cognitive impairment has been known as a common consequence of brain inflammation. Long‐term potentiation (LTP), the generally accepted cellular mechanism for memory formation in the mammalian brain, has been shown to be suppressed by inflammation. Studies have shown that angiotensin II (Ang II) through the Ang II type 1 receptor (AT1R) has a role in brain and peripheral immune system communication and brain inflammation. Here, the effect of AT1R blockade on hippocampal LTP in rats undergoing repeated lipopolysaccharide (LPS) injection was investigated. Rats received intraperitoneal (ip) injections of LPS (250 μg kg−1 day−1) for seven days. Treatment with losartan (ip; 3 mg kg−1 day−1) was started 3 days before LPS injection and continued during the LPS injections. Rats were anesthetized, and field excitatory postsynaptic potential (fEPSP) was recorded from the stratum radiatum of the CA1 area of the hippocampus in response to stimulation of the Schaffer collateral pathway. Results showed that LTP was suppressed in the LPS‐injected rats as no significant differences were found in the fEPSP slope and amplitude before and after the LTP induction. AT1R blockade by losartan restored fEPSP to the control levels. These findings indicate that Ang II, through AT1R, has a role in LTP suppression induced by systemic inflammation.

Effects of the hydroalcoholic extract of Rosa damascena on hippocampal long-term potentiation in rats fed high-fat diet

High-fat diets (HFDs) and obesity can cause serious health problems, such as neurodegenerative diseases and cognitive impairments. Consumption of HFD is associated with reduction in hippocampal synaptic plasticity. Rosa damascena (R. damascena) is traditionally used as a dietary supplement for many disorders. This study was carried out to determine the beneficial effect of hydroalcoholic extract of R. damascena on in vivo hippocampal synaptic plasticity (long-term potentiation, LTP) in the perforant pathway (PP)—dentate gyrus (DG) pathway in rats fed with an HFD. Male Wistar rats were randomly assigned to four groups: Control, R. damascena extract (1 g/kg bw daily for 30 days), HFD (for 90 days) and HFD + extract. The population spike (PS) amplitude and slope of excitatory post-synaptic potentials (EPSP) were measured in DG area in response to stimulation applied to the PP. Serum oxidative stress biomarkers [total thiol group (TTG) and superoxide dismutase (SOD)] were measured. The results showed the HFD impaired LTP induction in the PP-DG synapses. This conclusion is supported by decreased EPSP slope and PS amplitude of LTP. R. damascena supplementation in HFD animals enhanced EPSP slope and PS amplitude of LTP in the granular cell of DG. Consumption of HFD decreased TTG and SOD. R. damascena extract consumption in the HFD animals enhanced TTG and SOD. These data indicate that R. damascena dietary supplementation can ameliorate HFD-induced alteration of synaptic plasticity, probably through its significant antioxidant effects and activate signalling pathways, which are critical in controlling synaptic plasticity.

Experimental Preeclampsia Causes Persistent Impairment of Hippocampal‐Dependent Memory and Network Function that is Exacerbated by Status Convulsions

Preeclampsia (PE) is a hypertensive disorder of pregnancy involving hyperlipidemia and widespread maternal endothelial dysfunction that can cause spontaneous seizures including status convulsions known as eclampsia. Further, PE increases the risk of cardiovascular disease and cognitive impairment later in life. This study investigated long‐lasting effects of PE without and with status convulsions on the hippocampus, a brain region involved in memory and cognition. Sprague Dawley rats that were either normal pregnant or with experimental PE (ePE) induced by a high cholesterol diet starting d7 of gestation were used. Acute status convulsions were induced on day 19 of a 22‐day gestation via multiple i.p. injections of the chemoconvulsant pentylenetetrazol or saline (no‐seizure controls). Five weeks after status convulsions, an object recognition task was used to quantify the percent of time spent investigating a novel object as a measure of long‐term memory function (n = 8/group). After which, hippocampal network function was assessed by evoking long‐term potentiation (LTP), a well‐accepted cellular model for learning and memory, in the Schaffer Collateral to CA1 (Sch‐CA1) pathway of hippocampal slices. Synaptically evoked field excitatory post‐synaptic potentials (fEPSPs) were collected from the Sch–CA1 area of the hippocampus at a rate of 0.05 Hz. A 20 min stable baseline period was established before delivering a 40 pulse theta burst stimulation (TBS). Increase in fEPSP slope 60 min after TBS was analyzed as a measure of synaptic LTP. Data are mean ± SEM and comparisons made via a two‐way ANOVA to determine the interaction between two independent variables (ePE and status convulsions) with a post‐hoc Tukey test.There were significant interactions between the effects of ePE and status convulsions on memory function (F (1, 18) = 9.469; p = 0.007) as well as LTP (F (1, 19) = 9.991; p = 0.005). Object recognition was reduced in rats that had ePE compared to those that had a normal pregnancy, as formerly ePE rats spent 55 ± 3 % of the time investigating the novel object, much less than the 73 ± 3 % in rats that had a healthy pregnancy (Fig 1). Status convulsions impaired memory in rats that had a normal pregnancy, but not in the ePE group likely due to memory already being impaired (Fig 1). Further, LTP was impaired in rats that had ePE, with the slope of fEPSPs increasing to only 132 ± 7 % of baseline in slices from ePE rats compared to 157 ± 4 % in rats that had a healthy pregnancy (Fig 2). Status convulsions impaired LTP in rats that had ePE and those that had a normal pregnancy, with the slope of fEPSPs increasing to only 114 ± 5 % of baseline in formerly ePE rats and 106 ± 5 % in rats that had seizures during normal pregnancy (Fig 2).Overall, these findings suggest that PE and eclampsia cause permanent memory dysfunction by impairing LTP in the hippocampus, and highlight the importance of seizure prevention to maternal cognitive health. Further, understanding mechanisms of impaired hippocampal plasticity after PE and/or eclampsia may lead to novel therapeutic approaches to minimize the cognitive burden associated with PE and eclampsia later in life.Support or Funding InformationNIH NINDS R01 NS045940NIH NINDS R01 NS108455Long‐term memory as measured via a novel object recognition task. **p<0.01.Figure 1LTP of hippocampal slices. *p<0.05 and **p<0.01.Figure 2

The Effects of Probiotic Lactobacillus and Bifidobacterium Strains on Memory and Learning Behavior, Long-Term Potentiation (LTP), and Some Biochemical Parameters in β-Amyloid-Induced Rat's Model of Alzheimer's Disease.

This study assessed the effects of probiotic supplementation on spatial learning and memory, long-term potentiation (LTP), paired-pulse facilitation (PPF) ratios, nitric oxide (NO) concentrations, and lipid profiles in a rat model of amyloid beta (Aβ)(1–42)-induced Alzheimer’s disease (AD). Forty rats were randomly divided into 4 groups. The sham (control and prevention) group received intracerebroventricular (ICV) injections of artificial cerebrospinal fluid, the Alzheimer group received ICV injection of Aβ(1–42), and the probiotic+Alzheimer group received 500 mg probiotics daily (15×109 colony-forming unit) by gavage for 4 weeks before and 2 weeks after injection of Aβ(1–42). The Morris water maze test was performed for evaluation of spatial learning and memory. LTP and PPF ratios were measured to evaluate longterm synaptic plasticity and pre-synaptic mechanisms, respectively. The results showed that probiotic supplementation significantly improved learning, but not memory impairment, and increased PPF ratios compared to those in the Alzheimer group. Both Aβ(1–42) injection and probiotic supplementation alone did not significantly effect plasma level of NO. Probiotic supplementation of rats in the probiotic (6 weeks)+Alzheimer group decreased serum levels of total cholesterol, triglyceride, and very low-density lipoprotein-cholesterol significantly compared to the Alzheimer group. The results of this study suggest that probiotic supplementation may positively impact learning capacity and LTP in rats with AD, most likely via the release of neurotransmitters via presynaptic mechanisms or via a protective effect on serum lipid profiles.

A C-terminal peptide from secreted amyloid precursor protein-α enhances long-term potentiation in rats and a transgenic mouse model of Alzheimer's disease

Processing of the amyloid precursor protein by alternative secretases results in ectodomain shedding of either secreted amyloid precursor protein-α (sAPPα) or its counterpart secreted amyloid precursor protein-β (sAPPβ). Although sAPPα contains only 16 additional amino acids at its C-terminus compared to sAPPβ, it displays significantly greater potency in neuroprotection, neurotrophism and enhancement of long-term potentiation (LTP). In the current study, this 16 amino acid peptide sequence (CTα16) was characterised for its ability to replicate the synaptic plasticity-enhancing properties of sAPPα. An N-acetylated version of CTα16 produced concentration-dependent increases in the induction and persistence of LTP at Schaffer collateral/commissural synapses in area CA1 of young adult rat hippocampal slices. A scrambled peptide had no effect. CTα16 significantly enhanced de novo protein synthesis, and correspondingly its enhancement of LTP was blocked by the protein synthesis inhibitor cycloheximide, as well as by the α7-nicotinic receptor blocker α-bungarotoxin. The impaired LTP of 14–16 month old APPswe/PS1dE9 transgenic mice, a mouse model of Alzheimer's disease, was completely restored to the wild-type level by CTα16. These results indicate that the CTα16 peptide fragment of sAPPα mimics the larger protein's functionality with respect to LTP, stimulation of protein synthesis and activation of α7-nAChRs, and thus like sAPPα may have potential as a therapeutic agent against the plasticity and cognitive deficits observed in AD and other neurological disorders.

Short erythropoietin-derived peptide enhances memory, improves long-term potentiation, and counteracts amyloid beta–induced pathology

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the irreversible neuronal loss and memory impairment, and current treatments are merely symptomatic. Erythropoietin (EPO) has been shown to possess neurotrophic, neuroprotective, anti-inflammatory, and memory-enhancing effects, which could be therapeutically beneficial in the different aspects of AD. However, the hematopoietic effect of EPO has hampered its potential as a neuroprotective and procognitive agent. In this study, we characterized a novel small peptide, NL100, derived from a conserved C-helix region of EPO. NL100 was shown to bind to the EPO receptor, induce neuritogenesis, and protect hippocampal neurons from oxidative- and Aβ25-35-induced neurodegeneration in vitro. Importantly, long-term NL100 treatment did not induce hematopoiesis, overcoming this challenge associated with EPO. Memory-enhancing effects were demonstrated after NL100 treatment in social recognition test for short-term memory, in both healthy rats and rats challenged centrally with Aβ25-35 peptide, and in the Morris water maze test for spatial memory. Moreover, NL100 was shown to reverse Aβ25-35-induced hippocampal degeneration and gliosis as well as pilocarpine-induced suppression of long-term potentiation in rats. In conclusion, NL100 is a novel EPO-derived nonhematopoietic peptide with neuroprotective and memory-enhancing effects and could therefore be a potential candidate for the development of new treatments for neurodegenerative disorders and dementia.

Sodium valproate suppresses abnormal neurogenesis induced by convulsive status epilepticus.

Status epilepticus has been shown to activate the proliferation of neural stem cells in the hippocampus of the brain, while also causing a large amount of neuronal death, especially in the subgranular zone of the dentate gyrus and the subventricular zone. Simultaneously, proliferating stem cells tend to migrate to areas with obvious damage. Our previous studies have clearly confirmed the effect of sodium valproate on cognitive function in rats with convulsive status epilepticus. However, whether neurogenesis can play a role in the antiepileptic effect of sodium valproate remains unknown. A model of convulsive status epilepticus was established in Wistar rats by intraperitoneal injection of 3 mEq/kg lithium chloride, and intraperitoneal injection of pilocarpine 40 mg/kg after 18-20 hours. Sodium valproate (100, 200, 300, 400, 500, or 600 mg/kg) was intragastrically administered six times every day (4-hour intervals) for 5 days. To determine the best dosage, sodium valproate concentration was measured from the plasma. The effective concentration of sodium valproate in the plasma of the rats that received the 300-mg/kg intervention was 82.26 ± 11.23 μg/mL. Thus, 300 mg/kg was subsequently used as the intervention concentration of sodium valproate. The following changes were seen: Recording excitatory postsynaptic potentials in the CA1 region revealed high-frequency stimulation-induced long-term potentiation. Immunohistochemical staining for BrdU-positive cells in the brain revealed that sodium valproate intervention markedly increased the success rate and the duration of induced long-term potentiation in rats with convulsive status epilepticus. The intervention also reduced the number of newborn neurons in the subgranular area of the hippocampus and subventricular zone and inhibited the migration of newborn neurons to the dentate gyrus. These results indicate that sodium valproate can effectively inhibit the abnormal proliferation and migration of neural stem cells and newborn neurons after convulsive status epilepticus, and improve learning and memory ability.

Effect of garlic powder on hippocampal long-term potentiation in rats fed high fat diet: an in vivo study.

The objective of this study was to determine the relation between the chronic consumption of garlic powder in combination with high-fat diet (HFD) on long term potentiation (LTP) in the dentate gyrus (DG) of rat hippocampus. Male rats were divided to 4 groups, control with the standard diet, control with a standard diet plus garlic, high-fat diet (HFD) group and high-fat diet with garlic. Following 6months of controlled dietary in each experimental group, the rats were anesthetized with i.p. injection of ketamine and xylazin (100 and 2.5mg/kg, respectively), and placed into a stereotaxic apparatus for surgery, electrode implantation and field potential recording. The population spike (PS) amplitude and slope of excitatory post synaptic potentials (EPSP) were measured in the DG area of adult rats in response to stimulation applied to the perforant path (PP) (by 400Hz tetanization). The results showed that garlic increased EPSP slope and PS amplitude respect to HFD group. It was suggested that the garlic powder administration could attenuate the deteriorating effect of HFD on in vivo hippocampal LTP in the granular cells of the DG.

Low frequency electrical stimulation has time dependent improving effect on kindling-induced impairment in long-term potentiation in rats

Application of low-frequency stimulation (LFS) can improve learning and memory in kindled animals (Ghafouri et al., 2016). Considering the important role of long-term potentiation (LTP) in learning and memory, in the present study the effectiveness of LFS on kindling-induced impairment in LTP induction was investigated in hippocampal CA1 area at different times post kindling stimulations. Animals were kindled via electrical stimulation of hippocampal CA1 area in a semi-rapid manner (12 stimulations per day). One group of animals received four trials of LFS at 30s, 6h, 24h, and 30h following the last kindling stimulation. Each LFS consisted of 4 packages at 5min intervals; each package contained 200 monophasic square wave pulses of 0.1ms duration at 1Hz. The kindled, kindled+LFS and LFS groups were divided into four subgroups in which hippocampal slices were prepared at 48h, 1week, 2weeks, and 1month following the last kindling stimulation respectively. Extracellular evoked field excitatory postsynaptic potentials (fEPSPs) were recorded in the stratum radiatum of the CA1 area of the slice. Obtained results showed that LTP was not induced in kindled animals. However, application of LFS overcame the kindling-induced impairment in LTP generation in CA1 area of the hippocampus. This improving effect remained up to one week after the last kindling stimulation and extended to one month by increasing the number of applied LFS packages.

The interactive role of CB1 receptors and L-type calcium channels in hippocampal long-term potentiation in rats

Long-term potentiation (LTP) of synaptic responses is a widely researched model of synaptic plasticity that occurs during learning and memory. The cannabinoid system is an endogenous system that modulate this kind of synaptic plasticity. In addition, voltage dependent calcium channels is essential for induction of LTP at some synapses in the hippocampus. However, there is currently debate over the interaction between L-type calcium channels and cannabinoid system on the synaptic plasticity. In this study, we examined the effects of an acute administration of the cannabinoid antagonist AM251 following a chronic administration of the Ca2+ channel blocker verapamil on LTP induction in the hippocampal dentate gyrus(DG) of rats. Male Wistar rats were administered verapamil(10,25,50mg/kg) or saline intraperitoneally(IP) daily for 13days(n=10/group). After this treatment period, animals were anesthetized with an IP injection of urethane; the recording and stimulating electrodes were positioned in the DG and the perforant pathway. After obtaining a steady state baseline response, a single IP injection of saline or AM251(1 or 5mg/kg) was administered. LTP was induced by high-frequency stimulation(HFS). The population spike(PS) amplitude and the slope of excitatory postsynaptic potentials(EPSP) were compared between the experimental groups. The acute administration of the CB1 antagonist AM251 increased LTP induction. The EPSP slopes and PS amplitude in the verapamil and AM251 groups differed after HFS, such that AM251 increased LTP, whereas verapamil decreased LTP induction. These findings suggest that there are functional interactions between the L-type calcium channels and cannabinoid system in this model of synaptic plasticity in the hippocampus.

Co-injection of Aβ1-40 and ApoE4 impaired spatial memory and hippocampal long-term potentiation in rats

Apolipoprotein E4 (APOE4) allele located on chromosome 19 is a major genetic risk factor for developing Alzheimer’s disease (AD). However, the direct effects of ApoE4 on the cognitive function and long-term synaptic plasticity have not fully investigated. At the same time, although amyloid beta protein (Aβ)-ApoE complexes are principal components of AD-associated brain damage, there is still lack of in vivo study on the effects of co-existed Aβ1-40 and ApoE4. In the present study, we examined the effects of ApoE4 on the spatial memory and hippocampal long term potentiation (LTP) by using Morris water maze test and in vivo field potential recording, compared the neurotoxicity of Aβ1-40 and ApoE4, and investigated the effects of co-application of Aβ1-40 and ApoE4 on cognitive behavior and synaptic plasticity. The results showed that intracerebrovenrticular (i.c.v.) injection of Aβ1-40 or ApoE4 significantly and similarly impaired spatial learning and memory, and depressed the high-frequency stimulus (HFS) induced LTP. Importantly, compared to the effects of Aβ1-40 or ApoE4 alone, co-injection of Aβ1-40 and ApoE4 produced much heavier damages in cognitive behaviors and long term synaptic plasticity. These results demonstrated that ApoE4 not only exerted direct neurotoxicity but also enhanced the neurotoxicity of Aβ1-40 on spatial cognitive function and hippocampal LTP, which maybe partly elucidates the mechanism by which APOE4 allele exerted negative effects as a major genetic risk factor for developing AD.

Protective Effects of Enriched Environment Against Transient Cerebral Ischemia-Induced Impairment of Passive Avoidance Memory and Long-Term Potentiation in Rats.

Introduction:Enriched Environment (EE), a complex novel environment, has been demonstrated to improve synaptic plasticity in both injured and intact animals. The present study investigated the capacity of an early environmental intervention to normalize the impairment of passive avoidance memory and Long-Term Potentiation (LTP) induced by transient bilateral common carotid artery occlusion (2-vessel occlusion, 2VO) in rats.Methods:After weaning, young Wistar rats (22 days old) were housed in EE or Standard Environment (SE) for 40 days. Transient (30-min) incomplete forebrain ischemia was induced 4 days before the passive avoidance memory test and LTP induction.Results:The transient forebrain ischemia led to impairment of passive avoidance memory and LTP induction in the Perforant Path-Dentate Gyrus (PP-DG) synapses. Interestingly, housing and growing in EE prior to 2VO was found to significantly reverse 2VO-induced cognitive and LTP impairments.Conclusion:Our results suggest that early housing and growing in EE exhibits therapeutic potential to normalize cognitive and LTP abnormalities induced by 2VO ischemic model in rats.

Acute Effect of Electroacupuncture on Hippocampal Long-term Potentiation of Rats in Vivo

Acute Effect of Electroacupuncture on Hippocampal Long-term Potentiation of Rats in Vivo

Inducible nitric oxide inhibitor aminoguanidine, ameliorates deleterious effects of lipopolysaccharide on memory and long term potentiation in rat

AimAn interaction between nitric oxide (NO) and neuro-inflammation has been considered to modulate learning and memory. In the present study, the effect of an inducible NO synthase (iNOS) inhibitor, aminoguanidine (AG) on lipopolysaccharide (LPS)-induced memory impairment was evaluated. Materials and methodsThe rats were divided and treated: Control (Saline), LPS, AG - LPS and AG, before behavioral and electrophysiological experiments. ResultsThe escape latency in Morris water maze (MWM) test and the latency to enter the dark compartment in Passive avoidance (PA) test in LPS group were significantly higher than in control (P<0.001) whereas, in AG-LPS group they were shorter than LPS group (P<0.001). The amplitude and slope of field excitatory post synaptic potential (fEPSP) decreased in LPS group compared to control group (P<0.05 and P<0.01) whereas, in AG-LPS group they were higher than LPS group (P<0.05). Malondialdehyde (MDA) and NO metabolites concentrations in the hippocampus and serum TNFα level of LPS group were higher than control group (P<0.001, P<0.05 and 0.01 respectively) while, in AG- LPS group they were lower than LPS group (P<0.001and P<0.01 respectively). The thiol content and the activities of superoxide dismutase (SOD) and catalase (CAT) in the hippocampus of LPS group reduced compared to control group (P<0.001 and P<0.05 respectively) while, in AG - LPS group they enhanced compared to LPS (P<0.001 and P<0.05 respectively). ConclusionIt is suggested that increased NO has a role in LPS-induced learning and LTP impairments and the brain tissues oxidative damage which are preventable by iNOS inhibitor aminoguanidine.

Neuroprotective effects of metformin against Aβ-mediated inhibition of long-term potentiation in rats fed a high-fat diet

Metformin (Met) is used to treat neurodegenerative disorders such as Alzheimer's disease (AD). Conversely, high-fat diets (HFD) have been shown to increase AD risk. In this study, we investigated the neuroprotective effects of Met on β-amyloid (Aβ)-induced impairments in hippocampal synaptic plasticity in AD model rats that were fed a HFD. In this study, 32 adult male Wistar rats were randomly assigned to four groups: group I (control group, regular diet); group II (HFD+vehicle); group III (HFD+Aβ); or group IV (Met+HFD+Aβ). Rats fed a HFD were injected with Aβ to induce AD, allowed to recover, and treated with Met for 8 weeks. The rats were then anesthetized with intraperitoneal injections of urethane and placed in a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In vivo electrophysiological recordings were then performed to measure population spike (PS) amplitude and excitatory postsynaptic potential (EPSP) slope in the hippocampal dentate gyrus. Long-term potentiation (LTP) was induced by high-frequency stimulation of the perforant pathway. Blood samples were then collected to measure plasma levels of triglycerides, low-density lipoproteins, very low-density lipoprotein, and cholesterol. After induction of LTP, PS amplitude and EPSP slope were significantly decreased in Aβ-injected rats fed a HFD compared to vehicle-injected animals or untreated animals that were fed a normal diet. Met treatment of Aβ-injected rats significantly attenuated these decreases, suggesting that Met decreased the effects of Aβ on LTP. These findings suggest that Met treatment is neuroprotective against the detrimental effects of Aβ and HFDs on hippocampal synaptic plasticity.

Caspase-3 is Involved in Aluminum-Induced Impairment of Long-Term Potentiation in Rats Through the Akt/GSK-3β Pathway.

A number of studies have indicated that aluminum (Al) exposure can impair learning and memory function. The ability of Al to inhibit hippocampal long-term potentiation (LTP) suggests the possibility of Al impairing synaptic plasticity. LTP is dependent on the externalization of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPAR). The protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β) signaling pathway has been demonstrated to mediate AMPAR delivery. A mechanism by which caspase-3 cleaves Akt is involved in synaptic plasticity, but the underlying molecular mechanism involved has still not been elucidated. The purpose of this study was to investigate the mechanism of LTP impairment and the related signaling pathway disturbance induced by Al exposure. Our results reveal that Al treatment produces a dose-dependent suppression of LTP and decreases in the AMPAR subunits GluR1 and GluR2, in both membrane and total cell extracts. Al caused increased accumulation of active caspase-3 and a gradual decrease in Akt and pGSK-3β. Interestingly, Al depressed LTP and AMPAR protein concentration. N-benzyloxycarbonyl-Asp(OMe)-Glu(OMe)-Val-Asp(OMe)-fluoromethyl ketone (a caspase-3 inhibitor) reversed the Al-induced LTP inhibition, increased levels of active caspase-3, and decreased AMPAR levels in both total and membrane-enriched extracts. It also decreased Akt and pGSK-3β. The molecular mechanism of Al-induced LTP impairment might be related to the activation of caspase-3, cleavage of Akt, activation of GSK-3β, and inhibition of the externalization of AMPAR.

Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats

β-Amyloid (Aβ) is the main component of amyloid plaques developed in the brain of patients with Alzheimer's disease (AD). The increasing burden of Aβ in the cortex and hippocampus is closely correlated with memory loss and cognition deficits in AD. Recently, leptin, a 16kD peptide derived mainly from white adipocyte tissue, has been appreciated for its neuroprotective function, although less is known about the effects of leptin on spatial memory and synaptic plasticity. The present study investigated the neuroprotective effects of leptin against Aβ-induced deficits in spatial memory and in vivo hippocampal late-phase long-term potentiation (L-LTP) in rats. Y maze spontaneous alternation was used to assess short term working memory, and the Morris water maze task was used to assess long term reference memory. Hippocampal field potential recordings were performed to observe changes in L-LTP. We found that chronically intracerebroventricular injection of leptin (1μg) effectively alleviated Aβ1–42 (20μg)-induced spatial memory impairments of Y maze spontaneous alternation and Morris water maze. In addition, chronic administration of leptin also reversed Aβ1–42-induced suppression of in vivo hippocampal L-LTP in rats. Together, these results suggest that chronic leptin treatments reversed Aβ-induced deficits in learning and memory and the maintenance of L-LTP.

Acute pentobarbital treatment impairs spatial learning and memory and hippocampal long-term potentiation in rats

Reports of the effects of pentobarbital on learning and memory are contradictory. Some studies have not shown any interference with learning and memory, whereas others have shown that pentobarbital impairs memory and that these impairments can last for long periods. However, it is unclear whether acute local microinjections of pentobarbital affect learning and memory, and if so, the potential mechanisms are also unclear. Here, we reported that the intra-hippocampal infusion of pentobarbital (8.0mM, 1μl per side) significantly impaired hippocampus-dependent spatial learning and memory retrieval. Moreover, in vitro electrophysiological recordings revealed that these behavioral changes were accompanied by impaired hippocampal CA1 long-term potentiation (LTP) and suppressed neuronal excitability as reflected by a decrease in the number of action potentials (APs). These results suggest that acute pentobarbital application causes spatial learning and memory deficits that might be attributable to the suppression of synaptic plasticity and neuronal excitability.