Population Spike Amplitude Research Articles

Continuous exercise training rescues hippocampal long-term potentiation in the VPA rat model of Autism: Uncovering sex-specific effects

Long‐term potentiation (LTP) impairment has been reported in many studies of autistic models. The aim of the present study was to investigate the effects of interval training (IT) and continuous training (CT) exercises on LTP in the hippocampal dentate gyrus (DG) neurons of valproic acid (VPA) rat model of autism. To induce an autism-like model, pregnant rats were injected 500 mg/kg NaVPA (intraperitoneal) on the embryonic day 12.5. IT and CT aerobic exercises started on postnatal day 56 in the offspring. Four weeks after IT and/or CT exercises, the offspring were urethane-anesthetized and placed into a stereotaxic apparatus for surgery, electrode implantation, and field potential recording. In the DG region, excitatory post synaptic potentials (EPSP) slope and population spike (PS) amplitude were measured. Sex differences in LTP were evident for control rats but not for VPA-exposed offspring. LTP was significantly smaller in VPA-exposed male offspring compared with control male rats. In contrast to males, there was no difference between VPA-exposed female offspring and control female rats. Interestingly, we observed a sex difference in the response to exercise between VPA-exposed male and female offspring. CT exercise training (but not IT) increased LTP in VPA-exposed male offspring. Both IT and CT exercise trainings had no effect on intact LTP in VPA-exposed female offspring. Our work suggests that there may be differences in the benefits of exercise interventions based on sex, and CT exercise training could be more beneficial for LTP improvements.

Cacao consumption improves passive avoidance memory impairment in a rat model of Alzheimer's disease: the role of hippocampal synaptic plasticity and oxidative stress.

Introduction: Alzheimer's disease (AD) causes progressive loss of cognitive function and synaptic plasticity, which is the most common form of dementia. The present study was designed to scrutinize the effects of cacao on passive avoidance memory function and to identify the roles of hippocampal synaptic plasticity and oxidative stress in an AD rat model induced by unilateral intracerebroventricular (UICV) injection of amyloid-beta (Aβ). Methods: Oral administration of cacao (500 mg/kg/ day) was given for 2 consecutive months. A memory retention test was conducted 24 h after passive avoidance training was completed. Subsequently, the amplitude of population spike (PS) and slope of field excitatory postsynaptic potentials (fEPSPs) were assessed at hippocampal long-term potentiation (LTP) in perforant pathway-dentate gyrus (PP-DG) synapses. Moreover, total thiol group (TTG) and malondialdehyde (MDA) concentrations were evaluated in the plasma. Furthermore, compact Aβ plaques were detected in the hippocampal DG by performing Congo red staining. Results: As a result of AD induction, passive avoidance memory was impaired; also, reduced fEPSP slopes, PS amplitudes, and content of TTG, and increase in MDA levels in the rats were observed. In contrast, cacao treatment ameliorated passive avoidance memory impairment, improved hippocampal LTP impairment, modulated oxidative-antioxidative status, and delayed Aβ plaques production in AD rats. Disscussion: Conclusively, cacao alleviates Aβ-induced cognitive deficit, probably by the amelioration of hippocampal LTP impairment, modulation of oxidative-antioxidative status, and inhibition of Aβ plaque accumulation.

Coenzyme Q10 and exercise training reinstate middle cerebral artery occlusion-induced behavioral deficits and hippocampal long-term potentiation suppression in aging rats.

Patients experience post-stroke cognitive impairment during aging. To date, no specific treatment solution has been reported for this disorder. The purpose of this study was to evaluate the effects of exercise training and coenzyme Q10 supplementation on middle cerebral artery occlusion (MCAO) induced behavioral impairment, long-term potentiation inhibition and cerebral infarction size in aging rats. Fifty aging male rats underwent MCAO surgery and were randomly distributed in to the following groups: 1-Sham, 2- control, 3- Coenzyme Q10, 4- Exercise training and 5- Exercise training with Q10 supplementation (Ex + Q10). Aerobic training groups were allowed to run on a treadmill for 12 weeks. Q10 (50mg/kg) was administered intragastrically by gavage. Morris water maze, shuttle box and elevated plus maze tests were used to evaluate cognitive function. The population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) in the dentate gyrus area were recorded as a result of perforant pathway electrical stimulation. Our study showed that Q10 and aerobic training alone ameliorate spatial memory in the acquisition phase, but have no effect on spatial memory in the retention phase. Q10 and exercise training synergistically promoted spatial memory in the retention phase. Q10 and exercise training separately and simultaneously mitigated cerebral ischemia-induced passive avoidance memory impairment in acquisition and retention phases. The EPSP did not differ between the groups, but exercise training and Q10 ameliorate the PS amplitude in hippocampal responses to perforant path stimulation. Exercising and Q10 simultaneously reduced the cerebral infarction volume. Collectively, the findings of the present study imply that 12 weeks of aerobic training and Q10 supplementation alone can simultaneously reverse cerebral ischemia induced neurobehavioral deficits via amelioration of synaptic plasticity and a reduction in cerebral infarction volume in senescent rats.

Memory loss induced by lisdexamfetamine in the rat: A behavioral, electrophysiological, and histopathological Study

Lisdexamfetamine (LDX) is one of the drugs commonly used to treat attention deficit hyperactivity disorder (ADHD). However, its neurological side effects, particularly on cognition, are not fully understood. The present study focused on memory in rats treated with four weeks of LDX injection. We compared LDX-treated rats with control ones, using several methods to evaluate the behavioral responses and electrophysiological, molecular, and histological properties in the hippocampus. Our findings demonstrated that subchronic administration of LDX impaired behavioral performance in all memory assessment tests (Y maze, Morris Water Maze, and Shuttle box). Although LDX did not alter population spike (PS) amplitude, it increased the field excitatory postsynaptic potential (fEPSP) slope of evoked potentials of LTP components. Also, in addition to an increase in expression of caspase-3 in the hippocampus, which indicates the susceptibility to apoptosis in LDX-treated rats, the number of microglia and astrocytes went up significantly in the LDX group. Moreover, Sholl's analysis showed an increase in the soma size and total process length in both hippocampal astrocytes and microglia. Overall, because of these destructive effects of LDX on the hippocampus, which is one of the critical memory-related areas of the brain, the findings of this investigation provide evidence to show the disruption of memory-related variables following the LDX. However, more research is needed to clarify it.

The Expression of Neurodegeneration-Related Genes in the Hippocampus of Hypothyroid Rats Following Long-Term Potentiation.

In our research, we examined how the induction of long-term potentiation (LTP) in the hippocampus of hypothyroid rats afects the mRNA levels of several proteins involved with neurodegeneration, including Gsk3, Cdk5, Akt1, Mapt, P35 (Anxa), Capn1, Bace1, and Psen2. Wistar-albino rats, consisting of 12 males, were used in the research, and they were separated into 2 groups: control (n=6) and hypothyroidism (n=6). To induce hypothyroidism, propylthiouracil was added to drinking water at a dosage of 20 mg/kg/day. The test stimulus intensity was calculated, basal recordings were acquired, and LTP was induced by administering 100 Hz high-frequency stimulation (HFS) for 1 second with a 5-minute delay when the rats were aged 60 days. The population spike (PS) amplitude and excitatory postsynaptic potential (EPSP) slope were measured in the granule cell layer of the dentate gyrus. Using reverse transcription polymerase chain reaction, the mRNA levels of neurodegenerative genes were assessed in induced hippocampal tissues after the LTP protocol. The free T4 levels in plasma were measured using a plate reader with the commercial ELISA kit. Following HFS, LTP was solely induced in the EPSP slope and PS amplitude in the control group. The impaired LTP response of the hypothyroidism group was accompanied by an increase in Akt1-mRNA expression and a decrease in Gsk3ß expression, whereas the value genes' mRNA expression levels did not difer significantly from those of the control group. The hypothyroidism-related LTP impairment could be caused by a reduction in PI3K/AKT signaling. Further investigation of this path is required to elucidate the pathophysiology of impaired synaptic plasticity in hypothyroidism.

Hyperthyroidism-Induced Upregulation of Neurodegeneration-Related Gene Expression in Metaplasticity-Induced Hippocampus

Introduction: Thyroid hormones, which produce critical changes in our bodies even when their physiological levels alter slightly, are crucial hormones that influence gene transcription. Neuronal plasticity, on the other hand, requires both the activation of local proteins as well as protein translation and transcription in response to external signals. So far, no study has examined metaplastic long-term potentiation (LTP) and related gene expression levels in a hyperthyroid experimental model. Methods: The Wistar male rats were administered 0.2 mg/kg/day of <sc>l</sc>-thyroxine for 21 days to induce hyperthyroidism. Perforant path was primed with 1-Hz low-frequency stimuli (LFS) for 900 s to investigate metaplasticity responses. The LFS was followed by high-frequency stimuli (HFS, 100 Hz) after 5 min. Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude were recorded from the granule cell layer of the dentate gyrus. The mRNA levels of genes related to neurodegeneration (Gsk-3β, Cdk5, Akt1, Mapt, p35, Capn1, Bace1, and Psen2) were measured using the RT-PCR method for the stimulated hippocampus. Results: Similar to euthyroid rats, hyperthyroid animals had a lower EPSP slope and PS after LFS. Depression of EPSP prevented subsequently induced EPSP-LTP, although HFS was able to elicit PS-LTP despite depression of PS amplitude in both groups. Despite similarities in metaplastic LTP responses, these electrophysiological findings were accompanied by increased Akt, Bace1, Cdk5, and p35-mRNA expressions and decreased Gsk-3β mRNA expression in hyperthyroid rats’ hippocampus. Conclusion: These data support the view that in thyroid hormone excess, the mechanism that keeps synaptic efficacy within a dynamic range occurs concurrently with increased mRNA expression of neurodegeneration-related genes. Our study encourages further examination of the increased risk of neurodegenerative disease in hyperthyroidism.

The Effects of the Fraction Isolated from Iranian Buthotus shach Scorpion Venom on Synaptic Plasticity, Learning, Memory, and Seizure Susceptibility.

Epilepsy, as a neurological disease, can be defined as frequent seizure attacks. Further, it affects many other aspects of patients' mental activities, such as learning and memory. Scorpion venoms have gained notice as compounds with potential antiepileptic properties. Among them, Buthotus schach (BS) is one of the Iranian scorpions studied by Aboutorabi et al., who fractionated, characterized, and tested this compound using electrophysiological techniques in brain slices (patch-clamp recording). In the present study, the fraction obtained from gel electrophoresis was investigated through behavioral and electrophysiological assays. At first, ventricular cannulation was performed in rats, and then the active fraction (i.e., F3), carbamazepine, and the vehicle were microinjected into the brain before seizure induction by the subcutaneous (SC) injection of pentylenetetrazol (PTZ). Seizure behaviors were scaled according to Racine stages. Memory and learning were evaluated using the Y-maze and passive avoidance tests. Other groups entered evoked field potential recording after microinjection and seizure induction. Population spike (PS) and field excitatory postsynaptic potential (fEPSP) were measured. The F3 fraction could prevent the fifth stage and postpone the third stage of seizure compared to the control (carbamazepine) group. There was no significant improvement in memory and learning in the group treated with the F3 fraction. Also, PS amplitude and fEPSP slope increased significantly, and long-term potentiation was successfully formed after the high-frequency stimulation of the performant pathway. Our results support the antiepileptic effects of the F3 fraction of BS venom, evidenced by behavioral and electrophysiological studies. However, the effects of this fraction on memory and learning were not in the same direction, suggesting the involvement of two different pathways.

Effect of Suanzaoren Decoction on expression of ionotropic glutamate receptors and synaptic plasticity in hippocampus of anxiety rats

This study investigated the effect of Suanzaoren Decoction on the expression of N-methyl-D-aspartate receptors(NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors(AMPAR) in the hippocampus and synaptic plasticity in rats with conditioned fear-induced anxiety. The effect of Suanzaoren Decoction on rat behaviors were evaluated through open field experiment, elevated plus maze experiment, and light/dark box experiment. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of glutamate(Glu) and γ-aminobutyric acid(GABA) in the rat hippocampus. Real-time fluorescence quantitative PCR(qRT-PCR) and Western blot were employed to assess the gene and protein expression of ionotropic glutamate receptors in the hippocampal region. Transmission electron microscopy was utilized to observe the changes in the ultrastructure of synaptic neurons in the hippocampal region. Long-term potentiation(LTP) detection technique was employed to record the changes in population spike(PS) amplitude in the hippocampal region of mice in each group. The behavioral results showed that compared with the model group, the Suanzaoren Decoction group effectively increased the number of entries into open arms, time spent in open arms, percentage of time spent in open arms out of total movement time, number of entries into open arms out of total entries into both arms(P&lt;0.01), and significantly increased the time spent in the light box and the number of shuttle crossings(P&lt;0.01). There was an increasing trend in the number of grid crossings, entries into the center grid, and time spent in the center grid, indicating a significant anxiolytic effect. ELISA results showed that compared with the model group, the Suanzaoren Decoction group exhibited significantly reduced levels of Glu, Glu/GABA ratio(P&lt;0.01), and significantly increased levels of GABA(P&lt;0.01) in the rat hippocampus. Furthermore, Suanzaoren Decoction significantly decreased the gene and protein expression of NMDAR(GluN2B and GluN2A) and AMPAR(GluA1 and GluA2) compared with the model group. Transmission electron microscopy results demonstrated improvements in synapses, neuronal cells, and organelles in the hippocampal region of the Suanzaoren Decoction group compared with the model group. LTP detection results showed a significant increase in the PS amplitude changes in the hippocampal region of Suanzaoren Decoction group from 5 to 35 min compared with the model group(P&lt;0.05, P&lt;0.01). In conclusion, Suanzaoren Decoction exhibits significant anxiolytic effects, which may be attributed to the reduction in NMDAR and AMPAR expression levels and the improvement of synaptic plasticity.

Interactions between cathodic- and anodic-pulses during high-frequency stimulations with the monophasic-pulses alternating in polarity at axons—experiment and simulation studies

Background. Electrical neuromodulation therapies commonly utilize high-frequency stimulations (HFS) of biphasic-pulses to treat neurological disorders. The biphasic pulse consists of a leading cathodic-phase to activate neurons and a lagging anodic-phase to balance electrical charges. Because both monophasic cathodic- and anodic-pulses can depolarize neuronal membranes, splitting biphasic-pulses into alternate cathodic- and anodic-pulses could be a feasible strategy to improve stimulation efficiency. Objective. We speculated that neurons in the volume initially activated by both polarity pulses could change to be activated only by anodic-pulses during sustained HFS of alternate monophasic-pulses. To verify the hypothesis, we investigated the interactions of the monophasic pulses during HFS and revealed possible underlying mechanisms. Approach. Different types of pulse stimulations were applied at the alvear fibers (i.e. the axons of CA1 pyramidal neurons) to antidromically activate the neuronal cell bodies in the hippocampal CA1 region of anesthetized rats in-vivo. Sequences of antidromic HFS (A-HFS) were applied with alternate monophasic-pulses or biphasic-pulses. The pulse frequency in the A-HFS sequences was 50 or 100 Hz. The A-HFS duration was 120 s. The amplitude of antidromically-evoked population spike was measured to evaluate the neuronal firing induced by each pulse. A computational model of axon was used to explore the possible mechanisms of neuronal modulations. The changes of model variables during sustained A-HFS were analyzed. Main results. In rat experiments, with a same pulse intensity, the activation volume of a cathodic-pulse was greater than that of an anodic-pulse. In paired-pulse tests, a preceding cathodic-pulse was able to prevent a following anodic-pulse from activating neurons due to refractory period. This indicated that the activation volume of a cathodic-pulse covered that of an anodic-pulse. However, during sustained A-HFS of alternate monophasic-pulses, the anodic-pulses were able to prevail over the cathodic-pulses in activating neurons in the overlapped activation volume. Model simulation results show the mechanisms of the activation failures of cathodic-pulses. They include the excessive membrane depolarization caused by an accumulation of potassium ions, the obstacle of hyperpolarization in the conduction pathway and the interactions from anodic-pulses. Significance. The study firstly showed the domination of anodic-pulses over cathodic-pulses in their competitions to activate neurons during sustained HFS. The finding provides new clues for designing HFS paradigms to improve the efficiency of neuromodulation therapies.

The effects of carvacrol and p-cymene on Aβ1-42 -induced long-term potentiation deficit in male rats.

Alzheimer's disease (AD) is the most common type of dementia in which oxidative stress plays an important role. In this disease, learning and memory and the cellular mechanism associated with it, long-term potentiation (LTP), are impaired. Considering the beneficial effects of carvacrol (CAR) and p-cymene against AD, their effect was assessed on in vivo hippocampal LTP in the perforant pathway (PP)-dentate gyrus (DG) pathway in an Aβ1-42 -induced rat model of AD. Male Wistar rats were randomly assigned to five groups: sham: intracerebroventricular (ICV) injection of phosphate-buffered saline, Aβ: ICV Aβ1-42 injections, Aβ + CAR (50 mg/kg), Aβ + p-cymene (50 mg/kg), and Aβ + CAR + p-cymene. Administration of CAR and p-cymene was done by gavage daily 4 weeks before and 4 weeks after the Aβ injection. The population spike (PS) amplitude and field excitatory postsynaptic potentials (fEPSP) slope were determined in DG against the applied stimulation to the PP. Aβ-treated rats exhibited impaired LTP induction in the PP-DG synapses, resulting in significant reduction in both fEPSP slope and PS amplitude compared to the sham animals. Aβ-treated rats consumed either CAR or p-cymene separately (but not their combination), and showed an enhancement in fEPSP slope and PS amplitude of the DG granular cells. These data indicate that CAR or p-cymene can ameliorate Aβ-associated changes in synaptic plasticity. Surprisingly, the combination of CAR and p-cymene did not yield the same effect, suggesting a potential interaction between the two substances.

Insulin-induced long-term potentiation in the dentate gyrus of hippocampal formation

The discovery that brain areas involving in learning and memory express receptors for insulin hormone, led to the idea that insulin signaling may have a role in regulating cognitive function. Although previous studies have shown a role for insulin in regulation of the threshold of plasticity induction, no study has addressed whether insulin can induce a chemical plasticity per se. Young-adult male rats that are fed with standard diets with or without carbohydrate syrup (sucrose or high-fructose corn syrups) were enrolled in this study. Extracellular field potentials were recorded from the dentate gyrus in response to perforant pathway stimulation at 0.033 Hz in anesthetized rats. The slope of field excitatory postsynaptic potentials (fEPSPs) and the amplitude of population spike (PS) were measured 15 min after a 60-min infusion of insulin (500 nM), NT157 (an IRS inhibitor, 6 μM), alone or together, or physiological saline. mRNA expressions of insulin signaling proteins were measured by rt-PCR in the whole hippocampus. We did not observe any appreciable change in the fEPSP slope and the PS amplitude before and after saline infusion. However, intra-hippocampal insulin application results in the induction of LTP of fEPSP and of PS in the dentate gyrus. Insulin infusion together with NT157 inhibited fEPSP-LTP, but not PS-LTP, and rats that are fed with carbohydrate syrup did not express synaptic LTP. In rats that additional carbohydrate syrup is not given, insulin-induced LTP was accompanied with an increase in PI3K-mRNA, AKT-mRNA, and GSK-3β-mRNA which was not observed when co-administered with NT157. The GSK-3β-mRNA and IRS1-mRNA levels were found to be lower in rats that received supplemental carbohydrate and that not express insulin-induced synaptic LTP, compared to the rats expressing synaptic LTP and fed by standard diet. The results obtained provide a mechanistic link between insulin and synaptic plasticity. We concluded that insulin not only functions as a modulator of synaptic plasticity but also acts as a chemical inducer of LTP.

Acute adolescent morphine exposure improves dark avoidance memory and enhances long-term potentiation of ventral hippocampal CA1 during adulthood in rats.

Adolescence represents a distinctive vulnerable period when exposure to stressful situations including opioid exposure can entail lasting effects on brain and can change neural mechanisms involved in memory formation for drug-associated cues, possibly increasing vulnerability of adolescents to addiction. Herein, the effects of acute adolescent morphine exposure (AAME, two injections of 2.5mg/kg SC morphine on PND 31) were therefore investigated 6 weeks later (adulthood) on avoidance memory and hippocampal long-term potentiation (LTP) at Schaffer collateral-CA1 synapses in transvers slices from the ventral hippocampus in adult male rats using field recordings technique. Animal body weight was measured from PND 31 throughout PND 40 and also in four time points with 1 week intervals from adolescence to adulthood (PNDs 48, 55, 62 and 69) to evaluate the effect of AAME on the weight gain. We showed that there were no effects on body weight, anxiety-like behaviour and locomotor activity, even until adulthood. There was an improved dark avoidance memory during adulthood. Finally, AAME had no effects on baseline synaptic responses and resulted in a decrease in the mean values of the field excitatory postsynaptic potential slopes required to evoke the half-maximal population spike amplitude and an enhancement of LTP magnitude (%) in the ventral CA1 during adulthood. Briefly, our results suggest long-lasting effects of acute adolescent morphine exposure on the ventral hippocampus, which begin the enhancing of synaptic plasticity and the improving of emotional memory in adulthood.

Conditional deletion of KCC2 impairs synaptic plasticity and both spatial and nonspatial memory.

The postsynaptic inhibition through GABAA receptors (GABAAR) relies on two mechanisms, a shunting effect due to an increase in the postsynaptic membrane conductance and, in mature neurons, a hyperpolarization effect due to an entry of chloride into postsynaptic neurons. The second effect requires the action of the K+-Cl- cotransporter KCC2 which extrudes Cl- from the cell and maintains its cytosolic concentration very low. Neuronal chloride equilibrium seems to be dysregulated in several neurological and psychiatric conditions such as epilepsy, anxiety, schizophrenia, Down syndrome, or Alzheimer's disease. In the present study, we used the KCC2 Cre-lox knockdown system to investigate the role of KCC2 in synaptic plasticity and memory formation in adult mice. Tamoxifen-induced conditional deletion of KCC2 in glutamatergic neurons of the forebrain was performed at 3 months of age and resulted in spatial and nonspatial learning impairment. On brain slices, the stimulation of Schaffer collaterals by a theta burst induced long-term potentiation (LTP). The lack of KCC2 did not affect potentiation of field excitatory postsynaptic potentials (fEPSP) measured in the stratum radiatum (dendrites) but increased population spike (PS) amplitudes measured in the CA1 somatic layer, suggesting a reinforcement of the EPSP-PS potentiation, i.e., an increased ability of EPSPs to generate action potentials. At the cellular level, KCC2 deletion induced a positive shift in the reversal potential of GABAAR-driven Cl- currents (EGABA), suggesting an intracellular accumulation of chloride subsequent to the downregulation of KCC2. After treatment with bumetanide, an antagonist of the Na+-K+-Cl- cotransporter NKCC1, spatial memory impairment, chloride accumulation, and EPSP-PS potentiation were rescued in mice lacking KCC2. The presented results emphasize the importance of chloride equilibrium and GABA-inhibiting ability in synaptic plasticity and memory formation.

Geraniol improves passive avoidance memory and hippocampal synaptic plasticity deficits in a rat model of Alzheimer's disease

Alzheimer's disease (AD) is the most progressive and irreversible neurodegenerative disease that leads to synaptic loss and cognitive decline. The present study was designed to evaluate the effects of geraniol (GR), a valuable acyclic monoterpene alcohol, with protective and therapeutic effects, on passive avoidance memory, hippocampal synaptic plasticity, and amyloid-beta (Aβ) plaques formation in an AD rat model induced by intracerebroventricular (ICV) microinjection of Aβ1-40. Seventy male Wistar rats were randomly into sham, control, control-GR (100 mg/kg; P.O. (orally), AD, GR-AD (100 mg/kg; P.O.; pretreatment), AD-GR (100 mg/kg; P.O.; treatment), and GR-AD-GR (100 mg/kg; P.O.; pretreatment & treatment). Administration of GR was continued for four consecutive weeks. Training for the passive avoidance test was carried out on the 36th day and a memory retention test was performed 24 h later. On day 38, hippocampal synaptic plasticity (long-term potentiation; LTP) was recorded in perforant path-dentate gyrus (PP-DG) synapses to assess field excitatory postsynaptic potentials (fEPSPs) slope and population spike (PS) amplitude. Subsequently, Aβ plaques were identified in the hippocampus by Congo red staining. The results showed that Aβ microinjection increased passive avoidance memory impairment, suppressed of hippocampal LTP induction, and enhanced of Aβ plaque formation in the hippocampus. Interestingly, oral administration of GR improved passive avoidance memory deficit, ameliorated hippocampal LTP impairment, and reduced Aβ plaque accumulation in the Aβ-infused rats. The results suggest that GR mitigates Aβ-induced passive avoidance memory impairment, possibly through alleviation of hippocampal synaptic dysfunction and inhibition of Aβ plaque formation.

Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer’s disease

BackgroundVinpocetine (Vin) is known as a phosphodiesterase 1 inhibitor (PDE1-I) drug with multilateral effects, including antioxidant and anti-inflammatory activity. In this research, we investigated the neuroprotective and therapeutic effects of Vin through hippocampal synaptic plasticity on a rat’s model of Alzheimer’s disease (AD) induced by an intracerebroventricular (ICV) injection of beta-amyloid (Aβ).MethodsSixty adult male Wistar rats were randomly divided into six groups: 1. control, 2. sham, 3. Aβ, 4. pretreatment (Vin + Aβ): Vin (4 mg/kg, gavage) for 30 days and then, inducing an AD model by an ICV injection of Aβ(1–42), 5. treatment (Aβ + Vin): inducing an AD model and then receiving Vin for 30 days by gavage, and 7. pretreatment + treatment (Vin + Aβ + Vin): receiving Vin by gavage for 30 days before and 30 days after the induction of an AD model. After these procedures, via stereotaxic surgery, the stimulating electrodes were placed at the perforant pathway (PP) and the recording electrodes were implanted in the dentate gyrus.ResultsExcitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the Aβ group meaningfully diminished compared to the control group after the induction of long-term potentiation (LTP).ConclusionsVin could significantly prevent the Aβ effects on LTP. It can be concluded that pretreatment and treatment with Vin can be neuroprotective against harmful consequences of Aβ on hippocampal synaptic plasticity.

Effects of sesamin on Aβ1-42-induced oxidative stress and LTP impairment in a rat model of Alzheimer's disease.

The present study examined the protective effect of sesamin (Ses) on β-amyloid (Aβ)-induced long-term potentiation (LTP) impairment at the PP-DG synapses in male rats. Wistar rats were randomly assigned to seven groups: control, sham, Aβ; ICV Aβ1-42 microinjection, Ses, Aβ + Ses; first, ICV Aβ injections and then receiving Ses, Ses + Aβ: four weeks of pretreatment with Ses and then Aβ injection, and Ses + Aβ + Ses: pre (four weeks) and post (four weeks) treatment with Ses. Ses-treated groups received 30mg/kg of Ses once a day by oral gavage for four weeks. After the treatment period, the animals were positioned in a stereotaxic device for surgery and field potential recording. The population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were evaluated in the DG region. Serum oxidative stress biomarkers (total oxidant status (TOS) and total antioxidant capacity (TAC)) were measured. Aβ impaired LTP induction at the PP-DG synapses evidenced by a decrease in EPSP slope and PS amplitude of LTP. In Aβ rats, Ses increased EPSP slope and PS amplitude of LTP in the DG granular cells. Also, an increase in TOS and a reduction in TAC caused by Aβ were significantly corrected by Ses. Ses could prevent Aβ-induced LTP impairment at the PP-DG synapses in male rats, which can be due to its preventive effects on oxidative stress.

Anti-glutamatergic Effects of Three Lignan Compounds: Arctigenin, Matairesinol and Trachelogenin - An ex vivo Study on Rat Brain Slices.

Arctigenin is a bioactive dibenzylbutyrolactone-type lignan exhibiting various pharmacological activities. The neuroprotective effects of arctigenin were demonstrated to be mediated via inhibition of AMPA and KA type glutamate receptors in the somatosensory cortex of the rat brain. The aim of this study was to compare the effects of arctigenin with matairesinol and trachelogenin on synaptic activity in ex vivo rat brain slices. Arctigenin, matairesinol and trachelogenin were isolated from Arctium lappa, Centaurea scabiosa and Cirsium arvense, respectively, and applied on brain slices via perfusion medium at the concentration range of 0.5 - 40 µM. The effects of the lignans were examined in the CA1 hippocampus and the somatosensory cortex by recording electrically evoked field potentials. Arctigenin and trachelogenin caused a significant dose-dependent decrease in the amplitude of hippocampal population spikes (POPS) and the slope of excitatory postsynaptic potentials (EPSPs), whereas matairesinol (1 µM and 10 µM) decreased EPSP slope but had no effect on POPS amplitude. Trachelogenin effect (0.5 µM, 10 µM, 20 µM) was comparable to arctigenin (1 µM, 20 µM, 40 µM) (p > 0.05). In the neocortex, arctigenin (10 µM, 20 µM) and trachelogenin (10 µM) significantly decreased the amplitude of evoked potential early component, while matairesinol (1 µM and 10 µM) had no significant effect (p > 0.05). The results suggest that trachelogenin and arctigenin act via inhibition of AMPA and KA receptors in the brain and trachelogenin has a higher potency than arctigenin. Thus, trachelogenin and arctigenin could serve as lead compounds in the development of neuroprotective drugs.

Policosanol protects against Alzheimer's disease-associated spatial cognitive decline in male rats: possible involved mechanisms.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by cognitive decline and synaptic failure. The present study was designed to explore the possible protective effects of policosanol (PCO) on spatial cognitive capacity, long-term potentiation (LTP) induction, oxidant/antioxidant status, and Aβ plaques formation in an AD rat model induced by intracerebroventricular (ICV) injection of Aβ1-40. Healthy adult male Wistar rats were randomly divided into control, sham (ICV injection of 5µl phosphate-buffered saline), AG (50mg/kg; P.O., as PCO vehicle), PCO (50mg/kg; P.O.), AD model (ICV injection of 5µl Aβ), AD + AG (50mg/kg; P.O.), and AD + PCO (50mg/kg; P.O.). Treatments were performed for eight consecutive weeks. At the end of the treatment course, spatial learning and memory functions, hippocampal long-term potentiation (LTP) induction, malondialdehyde (MDA), and total thiol group (TTG) levels, as well as the formation of Aβ plaques, were examined. The results showed that injection of Aβ reduced spatial learning and memory abilities in the Barnes maze test, which was accompanied by decreases in field excitatory postsynaptic potential (fEPSP) slope, population spike (PS) amplitude, and TTG level and increases in Aβ plaque accumulation and MDA content. In contrast, PCO treatment improved all the above-mentioned changes in the Aβ-infused rats. The results suggest that amelioration of hippocampal synaptic plasticity impairment, modulation of oxidant/antioxidant status, and inhibition of Aβ plaque formation by PCO may be the mechanisms behind its protective effect against AD-associated spatial cognitive decline.

Curcumin attenuates memory impairments and long-term potentiation deficits by damping hippocampal inflammatory cytokines in lipopolysaccharide-challenged rats.

Neuroinflammation is a key pathological event triggering neurodegenerative process, resulting in neurologic sequelae. Curcumin (cur) has recently received increasing attention due to its anti-inflammatory properties. Therefore, we investigated the protective effects of curcumin on lipopolysaccharide (LPS)-induced memory impairments, long-term potentiation (LTP) deficits, hippocampal inflammatory cytokines, and neuronal loss in male rats. Rats were randomly divided into four groups as follows: (1) Vehicle; (2) cur; (3) LPS; and (4) cur/LPS. Following curcumin pretreatment (50mg/kg, per oral via gavage, 14 consecutive days), animals received a single dose of LPS (1mg/kg, intraperitoneally) or saline. Twenty-four hours after LPS/or saline administration, passive avoidance test (PAT), hippocampal LTP, inflammatory cytokines (TNFα, IL-1β), and neuronal loss were assessed in hippocampal tissue of rats. Our results indicated that pretreatment with curcumin in LPS-challenged rats attenuates memory impairment in PAT, which was accompanied by significant increase in the field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude. Hence, pretreatment with curcumin in LPS-treated rats decreased hippocampal concentration of tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), as well as reduced neuronal loss in the hippocampal tissue. This study provide evidence that pretreatment with curcumin attenuates LPS-induced memory impairment and LTP deficiency, which may be partly related to the amelioration of inflammatory cytokines and neuronal loss in the hippocampal tissue.

Underlying mechanisms of long-term potentiation during the inhibition of the cannabinoid CB1 and GABAB receptors in the dentate gyrus of hippocampus

BackgroundThe release of various neurotransmitters and thereby the excitability of neuronal circuits are regulated by the endocannabinoid system in an activity-dependent manner. Hippocampal long-term potentiation (LTP) is augmented in cannabinoid type 1 (CB1) receptor-deficient mice. CB1 receptors exist on GABAergic axon terminals in the hippocampus. In our previous work, we showed that CB1 antagonists increased the population spike (PS) amplitude, field excitatory post-synaptic potential (fEPSP), and the LTP induction in the dentate gyrus (DG) of the rat hippocampus while the GABAB antagonist decreased these parameters. Determining the underlying mechanisms of the pre- and/or postsynaptic locus of LTP expression is of great importance. In this study, we investigated whether LTP alteration acutely caused by CB1 and GABAB receptor antagonists (AM251 and CGP55845, respectively) happens at the postsynaptic or presynaptic regions, or at both. Therefore, the paired-pulse ratio (PPR) was assessed prior to and following the LTP induction in the studied groups.MethodsMale Wistar rats were randomly assigned to the groups of control, AM251, CGP55845, CGP55845 + AM251. A high-frequency stimulation (HFS) of the perforant path (PP) was used to induce LTP in the DG region.ResultsStatistical analysis revealed that AM251 produced significant increase in excitatory postsynaptic potential (EPSP) slope and amplitude of PS. Conversely, administration of CGP55845 produced decrease in slope of EPSP. The current results indicated that the PPR was not influenced by LTP induction in the presence of AM251 or CGP55845 either alone or their combination.ConclusionsIt can be concluded that the site causing LTP expression is, at least in part, the postsynaptic site because PPR was not influenced by LTP induction in the presence of AM251 or CGP55845 either alone or their combination.