Long-term Potentiation Of Population Spike Research Articles

Effect of intrahippocampal microinjection of VU0155041, a positive allosteric modulator of mGluR4, on long term potentiation in a valproic acid-induced autistic male rat model

The precise cause of autism spectrum disorder (ASD) is not fully understood. Despite the involvement of glutamatergic dysregulation in autism, the specific contribution of mGlu4 receptors to synaptic plasticity remains unclear. Using the positive allosteric modulator VU0155041, we aimed to restore long-term potentiation (LTP) in the perforant path-dentate gyrus (PP-DG) pathway in VPA-induced autistic rat model. High-frequency stimulation was applied to the PP-DG synapse to induce LTP, while the VU0155041 was administered into the DG. Unexpectedly, VU0155041 failed to alleviate the observed LTP reduction in VPA-exposed rats, further resulting in a significant decrease in population spike LTP. This unexpected outcome prompts discussion on the complex nature of mGlu4 receptor modulation, highlighting potential interference with physiological processes underlying synaptic plasticity.

Neurodegeneration-related genes are differentially expressed in middle-aged rats compared to young-adult rats having equal performance on long-term memory and synaptic plasticity

The present study is concerned with assessing differences in plasticity-induced neurodegeneration-related gene expressions and tau phosphorylation between young-aged and middle-aged rats. The experiments were carried out in vivo under urethane anesthesia on adult male Wistar rats between the ages of 2-3 months and 11-12 months. Field potentials, composed of a field of excitatory-postsynaptic potential (fEPSP) and a population-spike (PS), were recorded from granule cells of the dentate gyrus. Plasticity was induced by high-frequency (HFS) or low frequency stimulation (LFS). mRNA of neurodegeneration-related genes and total-and phosphorylated-tau were measured in HFS-and LFS-induced hippocampus by using quantitative rt-PCR and Western blotting. In addition, naive rats (unstimulated) were tested for spatial learning and memory with a 5-day Morris water maze (MWM). HFS-induced LTP of PS had attenuated in middle-aged rats, but there were no gross differences in baseline synaptic function, HFS-induced fEPSP and LFS-induced fEPSP, and PS plasticity between young-aged and middle-aged rats. Relative to young-aged rats, in middle-aged rats, HFS-induced MAPT, CDK5, and AKT1 genes were more up regulated, while LFS-induced Bace1, PSEN2, CAPN1, ANXA, CDK5, and GSK-3β genes were more down-regulated. Tau and p-tauThr231 were increased by HFS/LFS in the hippocampus of middle-aged rats compared to those of young-aged rats. In MWM, despite the difference in searching strategy of both age groups of rats, memory was not affected by age. Impaired long-term potentiation (LTP) and accompanying changes in intracellular biological markers may underlie in neurodegenerative disease characterized by dementia that occurs gradually later ages. However, these changes were not reflected in behavioral spatial memory.

Comparison of the subsequent LTP in hippocampal synapses primed by low frequency stimulations ranging from 0.5 to 5 Hz: An in vivo study

According to the Bienenstock,Cooper, andMunro’s (BCM) model, the level of afferent activity regulates the point of crossover from long-term depression (LTD) to long-term potentiation (LTP) of the active synapses. Although experimental results from the hippocampus and visual cortex have supported the BCM theory, it remains unclear whether previous activity of synapses regulates the output of neuron populations in vivo, as expected from the theory. In the present study, we studied the effects of priming stimulations at different frequencies (LFS, 0.5, 1, 2 and 5 Hz) on the magnitude of LTP at synaptic and somatic levels in the dentate gyrus of hippocampal formation. LTP in the dentate gyrus (DG) of LFS-primed or unprimed hippocampal formation was induced by delivering of tetanic stimulation to the perforant pathway (PP) in anesthetized rats. The field excitatory postsynaptic potential (fEPSP) slope and the population spike (PS) amplitude were evaluated to measure the magnitude of LTP. 1 Hz- and 5 Hz- (not 0.5 Hz and 2 Hz) stimulation of the PP led to an early LTD of fEPSP. The LTP of fEPSP was completely inhibited by previously delivering 0.5 Hz and 2 Hz LFS, but instead converted to LTD by 1 Hz LFS. However, none of the frequencies used was able to inhibit the LTP of PS. These results suggest that temporal dynamics which are critical to determine the direction of synaptic plasticity has no impact on the plasticity of neuronal output. We concluded that it is needed to explain why neuronal output does not behave within the framework of the BCM theory.

Synaptic plasticity in area CA1 of rat hippocampal slices following intraventricular application of albumin

Epileptogenesis following insults to the brain may be triggered by a dysfunctional blood-brain barrier (BBB) associated with albumin extravasation and activation of astrocytes. Using ex vivo recordings from the BBB-disrupted hippocampus after neocortical photothrombotic stroke, we previously demonstrated abnormal activity-dependent accumulation of extracellular potassium with facilitated generation of seizure like events and spreading depolarizations. Similar changes could be observed after intracerebroventricular (icv) application of albumin. We hypothesized that alterations in extracellular potassium and glutamate homeostasis might lead to alterations in synaptic interactions. We therefore assessed the effects of icv albumin on homo- and heterosynaptic plasticity in hippocampal CA1, 24h after a single injection or 7days after continuous infusion of icv albumin. We demonstrate alterations in both homo- and heterosynaptic plasticity compared to control conditions in ex vivo slice studies. Albumin-treated tissue reveals (1) reduced long-term depression following low-frequency stimulation; (2) increased long-term potentiation of population spikes in response to 20Hz stimulation; (3) potentiated responses to Schaffer collateral stimulation following high-frequency stimulation of the direct cortical input and low-frequency stimulation of alveus and finally, (4) TGFβ receptor II (TGFβR-II) involvement in albumin-induced homosynaptic plasticity changes. We conclude that albumin-induced network hyperexcitability is associated with abnormal homo- and heterosynaptic plasticity that could partly be reversed by interference with TGFβR-II-mediated signaling and therefore it might be an important factor in the process of epileptogenesis.

Intraperitoneal Administration of Low Dose Aluminium in The Rat: How Good is It to Produce a Model for Alzheimer Disease.

Since neurotoxicity of aluminium (Al) resembles the progressive neurodegeneration observed in Alzheimer Disease (AD), Al administration in several ways has been used to produce AD model. Intraperitoneal (ip) low dose (4.2 mg/ kg) Al injection in rats for long periods is the preferred method by some researchers. In this paper, the efficiency of this method for producing an AD model was evaluated. In this study, we looked at the neuropathology of Al and the characteristic lesions of AD by histological and immunohistochemical techniques and determined oxidative stress markers in the brains of Al-treated and control rats. We also made electrophysiological recordings at the hippocampus and evaluated possible behavioural changes by Morris water maze test. However, no pathologic changes occurred in the animals except for an impairment in long-term potentiation (LTP) in the hippocampus (e.g. the LTPs of population spike (PS) amplitude at 15 min post-tetanus were measured as 217±27% in Al-treated rats and as 240±42% in sham-treated rats, of baseline PS amplitude). According to the findings of the present study, low dose of ip Al in rats is not sufficient to produce a good AD model. Higher doses (≥10 mg/kg) should be used.

Intraperitoneal Administration of Low Dose Aluminium in The Rat: How Good is It to Produce a Model for Alzheimer Disease.

Since neurotoxicity of aluminium (Al) resembles the progressive neurodegeneration observed in Alzheimer Disease (AD), Al administration in several ways has been used to produce AD model. Intraperitoneal (ip) low dose (4.2 mg/ kg) Al injection in rats for long periods is the preferred method by some researchers. In this paper, the efficiency of this method for producing an AD model was evaluated. In this study, we looked at the neuropathology of Al and the characteristic lesions of AD by histological and immunohistochemical techniques and determined oxidative stress markers in the brains of Al-treated and control rats. We also made electrophysiological recordings at the hippocampus and evaluated possible behavioural changes by Morris water maze test. However, no pathologic changes occurred in the animals except for an impairment in long-term potentiation (LTP) in the hippocampus (e.g. the LTPs of population spike (PS) amplitude at 15 min post-tetanus were measured as 217±27% in Al-treated rats and as 240±42% in sham-treated rats, of baseline PS amplitude). According to the findings of the present study, low dose of ip Al in rats is not sufficient to produce a good AD model. Higher doses (≥10 mg/kg) should be used.

Chronic sodium salicylate administration enhances population spike long-term potentiation following a combination of theta frequency primed-burst stimulation and the transient application of pentylenetetrazol in rat CA1 hippocampal neurons

The effect of chronic administration of sodium salicylate (NaSal) on the excitability and synaptic plasticity of the rodent hippocampus was investigated. Repeated systemic treatment with NaSal reliably induced tolerance to the anti-nociceptive effect of NaSal (one i.p. injection per day for 6 consecutive days). Following chronic NaSal or vehicle treatment, a series of electrophysiological experiments on acute hippocampal slices (focusing on the CA1 circuitry) were tested whether tolerance to NaSal would augment pentylenetetrazol (PTZ)-induced long-term potentiation (LTP) and /or epileptic activity, and whether the augmentation was the same after priming activity with a natural stimulus pattern prior to PTZ. We noted an altered synaptic input-to-spike transformation, such that neuronal firing increased after a given synaptic drive. Population spike-LTP (PS-LTP) was increased in the NaSal-tolerant animals, but only when it was induced via a combination of electrical stimulation (theta pattern primed-burst stimulation) and the transient application of PTZ. Identifying and understanding these changes in neuronal excitability and synaptic plasticity following chronic salicylate treatment could prove useful in the clinical diagnosis or treatment of chronic aspirin-induced, or even idiopathic, seizure activity.

Effects of voluntary exercise on hippocampal long-term potentiation in morphine-dependent rats

This study was designed to examine the effect of voluntary exercise on hippocampal long-term potentiation (LTP) in morphine-dependent rats. The rats were randomly distributed into the saline–sedentary (Sal/Sed), the dependent–sedentary, the saline–exercise (Sal/Exc), and the dependent–exercise (D/Exc) groups. The Sal/Exc and the D/Exc groups were allowed to freely exercise in a running wheel for 10days. The Sal/Sed and the morphine–sedentary groups were kept sedentary for the same extent of time. Morphine (10mg/kg) was injected bi-daily (12h interval) during 10days of voluntary exercise. On day 11, 2h after the morphine injection, the in vivo LTP in the dentate gyrus of the hippocampus was examined. The theta frequency primed bursts were delivered to the perforant path for induction of LTP. Population spike (PS) amplitude and the field excitatory post-synaptic potentials (fEPSP) slope were measured as indices of increase in synaptic efficacy. Chronic morphine increased the mean basal EPSP, and augmented PS–LTP. Exercise significantly increased the mean baseline EPSP and PS responses, and augmented PS–LTP in both saline and morphine-treated groups. Moreover, the increase of PS–LTP in the morphine–exercise group was greater (22.5%), but not statistically significant, than that of the Sal/Exc group. These results may imply an additive effect between exercise and morphine on mechanisms of synaptic plasticity. Such an interaction between exercise and chronic morphine may influence cognitive functions in opiate addicts.

The timing of maternal separation affects morris water maze performance and long‐term potentiation in male rats

The increasing evidences showed that adverse early life events have profound long lasting consequences in adult rats including neural, behavioral, and cognitive effects. Early maternal separation was one of the models of adverse early life stress, but which period acts critically was unknown until now. The purpose of this paper was to explore the effects of maternal separation in different periods, that is, postnatal Day 2-9 and postnatal Day 14-21, on spatial learning and memory and long-term potentiation (LTP) in hippocampus of adolescent rats. Rat pups were assigned to three groups: early maternal separation from postnatal Day 2-9 (EMS2-9), separation from postnatal Day 14-21 (EMS14-21), and control (Con)--rats stayed with their mother all the time before weaning. Morris water maze test (MWM) and electrophysiological test were performed at 40-50 days of age. The results indicated that EMS14-21 impaired spatial learning and memory ability. For the excitatory postsynaptic potential long-term potentiation (EPSP LTP), both the two maternal separation groups showed decreased values compared to control group. In terms of population spike long-term potentiation (PS LTP), both the two maternal separation groups also showed lower values compared with control group, but only EMS14-21 group had significant difference compared with control group. In conclusion, our results revealed that EMS14-21 showed worst in both escape latency in Morris Water Maze test and LTP compared to control group and EMS2-9 group.

Donepezil in a Narrow Concentration Range Augments Control and Impaired by Beta-Amyloid Peptide Hippocampal LTP in NMDAR-Independent Manner

Acetylcholinesterase (AChE) inhibitor donepezil is widely used for the treatment of Alzheimer's disease (AD). The mechanisms of therapeutic effects of the drug are not well understood. The ability of donepezil to reverse a known pathogenic effect of β-amyloid peptide (Abeta), namely, the impairment of hippocampal long-term potentiation (LTP), was not studied yet. The goal of the present study was to study the influence of donepezil in 0.1-10 μM concentrations on control and Abeta-impaired hippocampal LTP. Possible involvement of N-methyl-D: -aspartate receptors (NMDARs) into mechanisms of donepezil action was also studied. LTP of population spike (PS) was studied in the CA1 region of rat hippocampal slices. Change of LTP by donepezil treatment had a bell-shaped dose-response curve. The drug in concentrations of 0.1 and 1 μM did not change LTP while in concentration of 0.5 μM significantly increased it, and in concentration of 5 and 10 μM suppressed LTP partially or completely. Abeta (200 nM) markedly suppressed LTP. Addition of 0.1, 0.5 or 1 μM donepezil to Abeta solution caused a restoration of LTP. N-methyl-D: -aspartate (NMDA) currents were studied in acutely isolated pyramidal neurons from CA1 region of rat hippocampus. Neither Abeta, nor 0.5 μM donepezil were found to change NMDA currents, while 10 μM donepezil rapidly and reversibly depressed it. Results suggest that donepezil augments control and impaired by Abeta hippocampal LTP in NMDAR-independent manner. In general, our findings extend the understanding of mechanisms of therapeutic action of donepezil, especially at an early stage of AD, and maybe taken into account while considering the possibility of donepezil overdose.

Theta pulse stimulation: A natural stimulus pattern can trigger long-term depression but fails to reverse long-term potentiation in morphine withdrawn hippocampus area CA1

The effects of chronic morphine exposure on synaptic plasticity in the CA1 region of the hippocampal slice preparation using extracellular recordings of the population spike (PS) evoked in response to Schaffer collateral stimulation were studied. High frequency stimulation (HFS; 1X100 Hz) and theta pulse stimulation (TPS; 5 Hz trains for 3 min) were used as patterned activities. The results showed that in rats chronically treated with morphine (dependent group), TPS induced long-term depression (LTD) of PS in CA1 in the absence of in vitro morphine. This TPS-induced PS LTD was blocked in the presence of either AP5 (NMDAR antagonist) or CPX (A1 adenosine receptor antagonist) alone, but was not blocked when AP5 and CPX were co-applied. This TPS-induced PS LTD was also blocked in the presence of either 8-PT (a selective A1 adenosine receptor antagonist) or MRS1220 (a specific A3 receptor antagonist). Additionally, when TPS was applied prior to HFS, PS long-term potentiation (LTP) was blocked. However, when TPS was applied after HFS, there was no reversal of PS LTP in slices from dependent rats in contrast to controls which displayed reversal of LTP. Both the PS LTD and the absence of PS LTP reversal were blocked by in vitro application of morphine. It is concluded that morphine withdrawal was associated with greater depression of CA1 PS elicited by natural stimulus induced activity pattern. This effect was associated with changes in NMDA and adenosine receptors due to chronic morphine administration. Such an in vitro preparation could provide a novel paradigm to investigate withdrawal effects on synaptic plasticity.

Impaired in vivo synaptic plasticity in dentate gyrus and spatial memory in juvenile rats induced by prenatal morphine exposure

Prenatal morphine exposure induces neurobiological changes, including deficits in learning and memory, in juvenile rat offspring. However the effects of this exposure on hippocampal plasticity, which is critical for learning and memory processes, are not well understood. The present study investigates the alterations of spatial memory and in vivo hippocampal synaptic plasticity in juvenile rats prenatally exposed to morphine. On gestation days 11-18, pregnant rats were randomly chosen to be injected twice daily with morphine or saline. Each juvenile offspring (postnatal day 22-31) performed one two-trial Y-maze task to evaluate spatial memory. Afterwards, the in vivo field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded in the perforant path dentate gyrus (DG) pathway in the hippocampus. Prenatal morphine exposure reduced depotentiation (DP), but not long-term potentiation (LTP), of the EPSP slope. However, both LTP and DP of the EPSP slope were depressed in prenatal morphine-exposed juvenile offspring. The morphine group also showed poorer performance for the Y-maze task than the control group. Depressed PS LTP, but not EPSP LTP, in the morphine group suggested that prenatal morphine exposure changed GABAergic inhibition, which mediates EPSP-spike potentiation. Then a loss of GABA-containing neurons in the DG area of the morphine group was observed using immunohistochemistry. Taken together, our results suggest that prenatal morphine exposure impairs the juvenile offspring's dentate synaptic plasticity and spatial memory, and that decreased GABAergic inhibition may play a role in these effects. These findings might contribute to an explanation for the cognitive deficits in children whose mothers abuse opiates during pregnancy.

Corticosterone disrupts glucose-, but not lactate-supported hippocampal PS-LTP

We previously reported that acute exposure of rat hippocampal brain slices to stress levels of corticosterone aggravated ischemic neuronal damage. The present study examined whether or not an acute stress level corticosterone exposure interferes with expression of rat hippocampal CA1 population spike long-term potentiation (PS-LTP) in slices supplemented either with glucose or lactate. Exposure of glucose-supplemented (5mM) slices to corticosterone (1microM) for 90min significantly diminished their ability to generate and maintain PS-LTP compared to equicaloric lactate-supplemented (10mM) slices (p<0.05). Moreover, this diminished expression of LTP in glucose-supplemented slices was ameliorated by either treatment with RU38486 (5microM), a potent corticosterone receptor antagonist or with10mM glucose. These results suggest that lactate may serve as an effective alternate energy substrate during exposure to elevated levels of corticosterone, allowing maintenance of glucocorticoid-sensitive neuronal functions such as synaptic potentiation during metabolically critical periods when glucose utilization is compromised.

Effects of sub-chronic lithium treatment on synaptic plasticity in the dentate gyrus of rat hippocampal slices

Although it has long been suggested that lithium has robust neuroplastic actions, and these actions lead to an enhancement on synaptic plasticity, the effects of lithium treatment on synaptic plasticity have been rarely studied. This study examined the effects of sub-chronic lithium treatment on synaptic plasticity in the dentate gyrus (DG) of hippocampal slices in the rats. Young adult rats were intraperitoneally administered a daily dose of 1 mgEq LiCl or saline-vehicle for 14 days. Twelve hours after the last injections, the input/output (I/0) responses of field excitatory postsynaptic potentials (fEPSP) and the long-term potentiation (LTP) of fEPSP and population spikes (PS) were determined in the DG of hippocampal slices prepared from the animals treated with lithium or vehicle. Treatment of lithium for 14 days significantly increased the I/O responses of fEPSP and the LTP of fEPSP and PS. These results indicate that sub-chronic treatment of lithium increases the excitatory postsynaptic responses, synaptic strength and the cell firing of the granule cells in the DG of the hippocampus.

NMDA-induced preconditioning attenuates synaptic plasticity in the rat hippocampus

It was recently demonstrated that glutamate could precondition hippocampal slices against the damaging effects of hypoxia, and we have now extended this observation by investigating (i) the ability of glutamate receptor agonists to act as preconditioning agents and (ii) the effects of preconditioning on synaptic plasticity. Using rat hippocampal slices, 15 μM NMDA applied for 10 min (chemical insult) caused abolition of the population spike potentials (PS) followed by approximately 33% recovery at 60 min post-insult. In comparison, a 5 min preconditioning exposure of 10 μM NMDA given 30 min prior to the insult significantly improved the recovery to 69%. Preconditioning did not alter paired pulse facilitation; however, it significantly enhanced paired pulse depression and reduced population spike long-term potentiation (PS-LTP) and LTP in field recordings. This effect on PS-LTP appeared to be NMDA receptor dependent and was blocked by the nitric oxide synthase inhibitors nitro- l-arginine methyl ester ( l-NAME) and 7-nitro indazole (7-NI) but not by the adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). We conclude that preconditioning by NMDA can improve recovery following acute insults but may have deleterious effects on neuronal plasticity.

Eugenol depresses synaptic transmission but does not prevent the induction of long-term potentiation in the CA1 region of rat hippocampal slices

Using field potential recording in the CA1 region of the rat hippocampal slices, the effects of eugenol on synaptic transmission and long-term potentiation (LTP) were investigated. Population spikes (PS) were recorded in the stratum pyramidal following stimulation of stratum fibers. To induce LTP, eight episodes of theta pattern primed-bursts (PBs) were delivered. Eugenol decreased the amplitude of PS in a concentration-dependent manner. The effect was fast and completely reversible. Eugenol had no effect on PBs-induced LTP of PS. It is concluded that while eugenol depresses synaptic transmission it does not affect the ability of CA1 synapses for tetanus-induced LTP and plasticity.

Impairment in Short-Term but Enhanced Long-Term Synaptic Potentiation and ERK Activation in Adult Hippocampal Area CA1 Following Developmental Thyroid Hormone Insufficiency*

Thyroid hormones are critical for the development and maturation of the central nervous system. Insufficiency of thyroid hormones during development impairs performance on tasks of learning and memory that rely upon the hippocampus and impairs synaptic function in young hypothyroid animals. The present study was designed to determine if perturbations in synaptic function persist in adult euthyroid animals exposed developmentally to insufficient levels of hormone. Pre- and postnatal thyroid hormone insufficiency was induced by administration of 3 or 10 ppm propylthiouracil (PTU) to pregnant and lactating dams via the drinking water from gestation day (GD) 6 until postnatal day (PN) 30. This regimen produced a graded level of hormonal insufficiency in the dam and the offspring. Population spike and population excitatory postsynaptic potentials (EPSP) were recorded at the pyramidal cell layer and the stratum radiatum, respectively, in area CA1 of hippocampal slices from adult male offspring. PTU exposure increased baseline synaptic transmission, reduced paired-pulse facilitation, and increased the magnitude of the population spike long-term potentiation (LTP). Phosphorylation of the extracellular signal-regulated kinases (ERK1 and ERK2) was increased as a function of LTP stimulation in slices from PTU-exposed adult animals. On the other hand, no differences in the basal levels of synaptic proteins implicated in synaptic plasticity (total ERK, synapsin, growth-associated protein-43, and neurogranin) were detected. These results reinforce previous findings of persistent changes in synaptic function and, importantly extend these observations to moderate levels of thyroid hormone insufficiency that do not induce significant toxicity to the dams or the offspring. Such alterations in hippocampal synaptic function may contribute to persistent behavioral deficits associated with developmental hypothyroidism.

Repeated administration of group I mGluR antagonists prevents seizure-induced long-term aberrations in hippocampal synaptic plasticity

Kindling induced by repeated application of the convulsant pentylenetetrazole (PTZ) is a validated model of epilepsy and epilepsy-related neuromorphological, neurophysiological and behavioural alterations. In this study, we examined whether kindling-induced long-term aberrations in hippocampal synaptic plasticity can be prevented by application of group I mGluR antagonists. Kindling resulted in a higher magnitude of long-term potentiation (LTP) induced by a strong high-frequency stimulation in the hippocampal CA1 region in vitro. When the specific mGluR1 antagonist LY 367385 (0.40 μMol) or the specific mGluR5 inhibitor MPEP (0.06 μMol) were given 30 min prior to PTZ, this kindling-induced enhancement of LTP was almost completely prevented. In addition, application of MPEP led to an impaired maintenance of population spike LTP in kindled animals. LY 367385 applied to unkindled control animals caused a reduction of the initial magnitude of population spike LTP. MPEP, in contrast, left the initial magnitude untouched but resulted in a faster decay of potentiation. A single administration of LY 367385 (200 μM) and MPEP (50 μM), respectively, directly into the bath had almost no effect. Our data suggest that the long-lasting aberrations of hippocampal synaptic plasticity induced by the repeated occurrence of generalized epileptic seizures ultimately require a concurrent operation of mGluR1 and mGluR5.

Effect of intermittent hypoxia on long-term potentiation in rat hippocampal slices

Intermittent hypoxia (IH) during sleep has been shown to induce apoptosis in a time-dependent manner and spatial learning deficits in adult rats. Recently, we have demonstrated that IH induced significant decreases in Ser-133-phosphorylated cAMP-response element-binding protein (pCREB) without changes in total CREB. The expression of cleaved caspase 3 in the hippocampal CA1, a marker of apoptosis, peaked at 3 days of IH and returned to normoxic values at 14 days of IH. In addition, biphasic changes in spatial task learning were correlated with the CREB phosphorylation time course. In the present study, the rat hippocampal slice preparation was used to evaluate the ability to induce and maintain a CA1 population spike long-term potentiation (PS-LTP) in room air (RA)-maintained and IH-exposed rats. A significant decrease in the ability to sustain PS-LTP for 15 min in slices prepared from IH-exposed rats for either 3 days (34% of total) or 7 days (51% of total) as compared to slices prepared from RA-maintained rats (76% of total) was observed. These results suggest that the diminishment in the ability of neuronal tissue to express and sustain PS-LTP is correlated with previously reported biphasic changes in CREB phosphorylation and programmed cell death.

Role of adenosine receptors and protein phosphatases in the reversal of pentylenetetrazol-induced potentiation phenomenon by theta pulse stimulation in the CA1 region of rat hippocampal slices

The effect of theta pulse stimulation (TPS) on pentylenetetrazol (PTZ)-induced long-term potentiation of population spikes (PS) was studied in the hippocampal CA1 in vitro. A transient PTZ application produced a long-lasting enhancement of PS amplitude. A 3-min episode of TPS delivered at a higher intensity produced complete reversal of the PTZ potentiation when delivered during the last minutes of PTZ application. Prior application of high-intensity TPS also decreased the amount of PTZ potentiation, whereas it had no long-lasting effect on baseline synaptic responses. High-intensity TPS induced reversal was blocked by adenosine A1 receptor antagonist and, furthermore, was reduced by protein phosphatase 1 inhibitor. The results suggest that mechanism of PTZ-induced LTP reversal involves activation of adenosine receptors and protein phosphatases.