Long-term Potentiation Recording Research Articles

The effects of choline supplementation in mothers with hypothyroidism on the alteration of cognitive-behavioral, long-term potentiation, morphology, and apoptosis in the hippocampus of pre-pubertal offspring rats.

The mother's thyroid hormone status during gestation and the first few months after delivery can play a crucial role in maturation during the brain development of the child. Transient abnormalities in thyroid function at birth indicate developmental and cognitive disorders in adulthood. Choline supplementation during gestation and the perinatal period in rats causes long-lasting memory improvement in the offspring. However, it remains unclear whether choline is able to restore the deficits in rats with maternal hypothyroidism. The aim of this study was to evaluate the effects of choline supplementation on the alteration of cognitive-behavioral function, long-term potentiation (LTP), and morphological changes as well as apoptosis in pre-pubertal offspring rats. To induce hypothyroidism, 6-propyl-2-thiouracil was added to the drinking water from the 6th day of gestation to the 21st postnatal day (PND). Choline treatment was started twice a day on the first day of the gestation until PND 21 via gavage. LTP recording and Morris water maze (MWM) test were conducted at PND 28. Then, the rats were sacrificed to assess their brains. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP (both: P < 0.001). Choline treatment alleviated LTP (P < 0.001), as well as learning and memory deficits (P < 0.01) in both male and female hypothyroid rats. However, no significant changes were observed in the number of caspase-3 stained cells in choline-receiving hypothyroid groups. The results revealed that developmental thyroid hormone deficiency impaired spatial learning and memory and reduced LTP. Choline treatment alleviated LTP, as well as learning and memory deficits in both male and female hypothyroid rats.

The Effect of Sub-chronic Administration of Brewed Coffee on Long-term Potentiation in a Rat Model of Alzheimer's Disease

Background: Alzheimer's disease (AD) is a neurodegenerative illness that causes memory loss and cognitive impairment. For neurodegenerative illnesses, the therapeutic properties and healthy advantages of brewed coffee (BC) intake have been widely explored. Objectives: This research aimed to look into the findings of sub-chronic BC administration on long-term potentiation (LTP) as a model of synaptic plasticity that supports memory function in the hippocampus in rat models of AD. Methods: In this study, 32 male Wistar rats were utilized as test subjects. The animals were randomly divided into four groups with eight rats in each group as follows: (1) Sham (animals that received normal saline (NS)), (2) streptozotocin (STZ), (3) BC, and (4) BC-STZ. Animals were treated for three weeks. Results: The amplitude of excitatory postsynaptic potentials (EPSPs) in the BC + STZ (164.23 ± 11.33%; n = 8) group significantly increased compared to the STZ group at 0.25 h after HFS (P = 0.0330). Also, it significantly increased in the BC + STZ group at 0.5, 0.75, 1, 1.25, 1.5, 1.75, and 2 h (P = 0.4481, P = 0.4609, P = 0.1239, P = 0.0017, P = 0.0413, P = 0.0851, P = 0.1323) after HFS. Moreover, the slope of EPSPs in the BC-STZ group showed an overall improvement compared to the STZ group at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, and 2 h (P = 0.1511, P = 0.0004, P = 0.0394, P = 0.0038, P = 0.0002, P = 0.0059, P = 0.0245, and P = 0.4126, respectively) after HFS during LTP recording time. Conclusions: In conclusion, the present study found that BC consumption improved synaptic plasticity and memory in rat models of AD induced by STZ. However, more studies are needed to elucidate BC's neuroprotective mechanisms.

Hippocampal LTP modulation and glutamatergic receptors following vestibular loss.

Vestibular dysfunction strongly impairs hippocampus-dependent spatial memory performance and place cell function. However, the hippocampal encoding of vestibular information at the synaptic level, remains sparsely explored and controversial. We investigated changes in in vivo long-term potentiation (LTP) and NMDA glutamate receptor (NMDAr) density and distribution after bilateral vestibular lesions (BVL) in adult rats. At day 30 (D30) post-BVL, the LTP of the population spike recorded in the dentate gyrus (DG) was higher in BVL rats, for the entire 3h of LTP recording, while no difference was observed in the fEPSP slope. However, there was an increase in EPSP-spike (E-S) potentiation in lesioned rats. NMDArs were upregulated at D7 and D30 predominantly within the DG and CA1. At D30, we observed a higher NMDAr density in the left hippocampus. NMDArs were overexpressed on both neurons and non-neuronal cells, suggesting a decrease of the entorhinal glutamatergic inputs to the hippocampus following BVL. The EPSP-spike (E-S) potentiation increase was consistent with the dorsal hippocampus NMDAr upregulation. Such an increase could reflect a non-specific enhancement of synaptic efficacy, leading to a disruption of memory encoding, and therefore might underlie the memory deficits previously reported in rats and humans following vestibular loss.

Coexistence of Multiple Types of Synaptic Plasticity in Individual Hippocampal CA1 Pyramidal Neurons.

Understanding learning and memory mechanisms is an important goal in neuroscience. To gain insights into the underlying cellular mechanisms for memory formation, synaptic plasticity processes are studied with various techniques in different brain regions. A valid model to scrutinize different ways to enhance or decrease synaptic transmission is recording of long-term potentiation (LTP) or long-term depression (LTD). At the single cell level, spike timing-dependent plasticity (STDP) protocols have emerged as a powerful tool to investigate synaptic plasticity with stimulation paradigms that also likely occur during memory formation in vivo. Such kind of plasticity can be induced by different STDP paradigms with multiple repeat numbers and stimulation patterns. They subsequently recruit or activate different molecular pathways and neuromodulators for induction and expression of STDP. Dopamine (DA) and brain-derived neurotrophic factor (BDNF) have been recently shown to be important modulators for hippocampal STDP at Schaffer collateral (SC)-CA1 synapses and are activated exclusively by distinguishable STDP paradigms. Distinct types of parallel synaptic plasticity in a given neuron depend on specific subcellular molecular prerequisites. Since the basal and apical dendrites of CA1 pyramidal neurons are known to be heterogeneous, and distance-dependent dendritic gradients for specific receptors and ion channels are described, the dendrites might provide domain specific locations for multiple types of synaptic plasticity in the same neuron. In addition to the distinct signaling and expression mechanisms of various types of LTP and LTD, activation of these different types of plasticity might depend on background brain activity states. In this article, we will discuss some ideas why multiple forms of synaptic plasticity can simultaneously and independently coexist and can contribute so effectively to increasing the efficacy of memory storage and processing capacity of the brain. We hypothesize that resolving the subcellular location of t-LTP and t-LTD mechanisms that are regulated by distinct neuromodulator systems will be essential to reach a more cohesive understanding of synaptic plasticity in memory formation.

The RAS/PI3K Pathway is Involved in the Impairment of Long-term Potentiation Induced by Acute Aluminum Treatment in Rats

ObjectiveTo explore the role of RAS/PI3K pathway in the impairment of long-term potentiation (LTP) induced by acute aluminum (Al) treatment in rats in vivo. MethodsFirst, different dosages of aluminum-maltolate complex [Al(mal)3] were given to rats via acute intracerebroventricular (i.c.v.) injection. Following Al exposure, the RAS activity of rat hippocampus were detected by ELISA assay after the hippocampal LTP recording by field potentiation technique in vivo. Second, the antagonism on the aluminum-induced suppression of hippocampal LTP was observed after the treatment of the RAS activator epidermal growth factor (EGF). Finally, the antagonism on the downstream molecules (PKB activity and the phosphorylation of GluR1 S831 and S845) were tested by ELISA and West-blot assays at the same time. ResultsWith the increasing aluminum dosage, a gradually decreasing in RAS activity of the rat hippocampus was produced after a gradually suppressing on LTP. The aluminum-induced early suppression of hippocampal LTP was antagonized by the RAS activator epidermal growth factor (EGF). And the EGF treatment produced changes similar to those observed for LTP between the groups on PKB activity as well as the phosphorylation of GluR1 S831 and S845. ConclusionThe RAS→PI3K/PKB→GluR1 S831 and S845 signal transduction pathway may be involved in the inhibition of hippocampal LTP by aluminum exposure in rats. However, the mechanisms underlying this observation need further investigation.

MICRORNA-138 IMPAIRS LEARNING AND MEMORY BY TARGETING ANK1

Alzheimer's disease (AD) is characterized by brain deposition of the amyloid beta-protein (A β) and Tau hyperphosphorylation that are associated with cognitive impairment and dementia. Many factors are involved in the pathologies of AD, like protein kinase, transcriptional factors, etc. While some evidence has been found for understanding the genetic and molecular mechanisms of AD, the role of small noncoding RNAs in occurrence and development of AD remains to be investigated. Using the Morris water maze, contextual fear conditioning, long-term potentiation recording in extracorporeal hippocampus slices, and Golgi staining, we report the roles of mir-138 in C57BL/6J mice and AD mice. Using real-time polymerase chain reaction, dual luciferase reporter assay and western blotting experiments, we further determined the target of the mir-138. Overexpression of mir-138 induces Tau hyperphosphorylation and decreases the number of dendrite spines in control mice model. In contrast, inhibition of mir-138 ameliorates these changes in AD mice. Furthermore, we confirm that ankyrin 1 (ANK1) is a direct target of miR-138, and supplement of ANK1 substantially reduces tau phosphorylation induced by miR-138. small noncoding RNAs, like mir-138, may be a therapeutic potential target for reversing cognitive impairments of AD.

Electrophysiological properties of hippocampal–cortical neural networks, role in the processes of learning and memory in rats

The recording of hippocampal and cortical long-term potentiation (LTP) in rats in vivo is an appropriate and commonly used method to describe changes in cellular mechanisms underlying synaptic plasticity. Recently, we introduced a method for the simultaneous recording of LTP in bilateral CA1 regions and parietal association cortex (PtA), and observed differences between the Schaffer collateral-CA1 pathway (SC), Schaffer collateral/associational commissural pathway (SAC) and Schaffer collateral/associational commissural-cortex pathway (SACC). In this study, we found that (1) synaptic transmission of the SAC and SACC pathways depended on hippocampal commissural fibers [dorsal and ventral hippocampal commissural fibers, the medial septum (MS) and hippocampal CA3 commissural fibers], (2) nerve conduction velocity of the SACC pathway might be higher than that of the SAC pathway, (3) the input/output (I/O) curve of the SC pathway was shifted to the left side, compared to that of the SAC and SACC pathways, (4) all three pathways could induce stable LTP; however, LTP of the SAC and SACC pathways was much stronger than that of the SC pathway, (5) the degree of paired-pulse facilitation (PPF) was weaker in the SC pathway than that in the SAC and SACC pathways, (6) after cutting off the corpus callosum and commissural fibers, spatial learning and memory were impaired, and the ability to explore the novel environment and spontaneous locomotor activity were weakened. Taken together, our results suggested that hippocampal commissural fibers were very important for exchanging information between hemispheres, and basic differences in electrophysiological properties of hippocampal-cortical neural networks play a vital role in the processes of learning and memory.

Magnesium L-threonate Prevents and Restores Memory Deficits Associated with Neuropathic Pain by Inhibition of TNF-α

Background: Clinical studies have shown that about two-thirds of patients with chronic pain suffer from short-term memory (STM) deficits and an effective drug for treatment of the neurological disorder is lacking at present. Objective: We tested whether chronic oral application of magnesium L-threonate (MgT), which has been shown to improve memory in normal and aging animals by elevating Mg2+ in the brain, could prevent or restore the STM deficits induced by spared nerve injury (SNI), an animal model of chronic neuropathic pain. The mechanisms underlying the effect of MgT on STM deficits were also investigated. Study Design: The experiments were conducted in a random and double-blind fashion in adult male rats. MgT was administrated via drinking water at a dose of 609 mg/kg/d for 2 weeks, starting either one week before SNI (preventative group) or one week after SNI (therapeutic group), and water without the drug served as control. Methods: STM was accessed with a novel object recognition test (NORT), followed by recording of long-term potentiation (LTP) in the hippocampus in vivo and the measurement of the expression of tumor necrosis factor-α (TNF-α) with Western Blot or Immunohistochemistrical staining. α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptor (NMDAR) currents were recorded with patch clamp in CA1 neurons in acute and cultured hippocampal slices. Result: We found that chronic oral application of MgT was able to prevent and restore the deficits of STM and of LTP at CA3-CA1 synapses in the hippocampus induced by SNI. Furthermore, both preventative and therapeutic chronic oral application of MgT blocked the up-regulation of TNF-α in the hippocampus, which has been previously shown to be critical for memory deficits. SNI reduced NMDAR current and the effect was dramatically attenuated by elevating extracellular Mg2+ concentration ([Mg2+]o). In cultured hippocampal slices, chronic application of recombinant rat TNF-α (rrTNF-α) for 3 days reduced NMDAR current in a concentration-dependent manner and the effect was again blocked by elevating [Mg2+]o. Limitations: We showed that oral application of MgT inhibited the over-expression of TNF-α and rescued the dysfunction of the NMDAR, but the causal relationship between them remains elusive. Conclusions: Our data suggested that oral application of MgT was able to prevent and restore the STM deficits in an animal model of chronic neuropathic pain by reversing the dysfunction of the NMDAR, and normalization of TNF-α expression may play a role in the effect. Oral application of MgT may be a simple and potent means for handling this form of memory deficit. Key words: Magnesium L-threonate, short-term memory, tumor necrosis factor-α, NMDA receptor, neuropathic pain

Environmental Novelty Activates β2-Adrenergic Signaling to Prevent the Impairment of Hippocampal LTP by Aβ Oligomers

A central question about human brain aging is whether cognitive enrichment slows the development of Alzheimer changes. Here, we show that prolonged exposure to an enriched environment (EE) facilitated signaling in the hippocampus of wild-type mice that promoted long-term potentiation. Akey feature of the EE effect was activation of β2-adrenergic receptors and downstream cAMP/PKA signaling. This EE pathway prevented LTP inhibition by soluble oligomers of amyloid β-protein (Aβ) isolated from AD cortex. Protection by EE occurred in both young and middle-aged wild-type mice. Exposure to novelty afforded greater protection than did aerobic exercise. Mice chronically fed a β-adrenergic agonist without EE were protected from hippocampal impairment by Aβ oligomers. Thus, EE enhances hippocampal synaptic plasticity by activating β-adrenoceptor signaling and mitigating synaptotoxicity of human Aβ oligomers. These mechanistic insights support using prolonged exposure to cognitive novelty and/or oral β-adrenergic agonists to lessen the effects of Aβ accumulation during aging.

Cytokines induced by long-term potentiation (LTP) recording: A potential explanation for the lack of correspondence between learning/memory performance and LTP

The relationship between learning/memory performance and long-term potentiation (LTP) induction is ambiguous. Although a large body of data supports a strong correspondence between learning/memory performance and LTP, many studies have also provided evidence to the contrary. In this study, we found that 2-month-old senescence-accelerated mice/prone 8 (SAMP8 mice) displayed both impaired performance in a Morris Water Maze (MWM) and enhanced LTP compared to senescence-accelerated mice/resistance 1 (SAMR1). BALB/c mice challenged with Complete Freund’s Adjuvant (CFA) performed better in the shuttle-box test but displayed impaired LTP compared to intact animals. It is interesting that BALB/c mice challenged with Incomplete Freund’s Adjuvant (IFA) performed better than intact animals, with no LTP impairment. Cytokine analysis showed no significant differences between the interleukin-6 (IL-6), interleukin-10 (IL-10) or TNF-α content in the intact hippocampal tissues of either the SAMR1 and SAMP8 mice or the immune-challenged BALB/c and intact animals. Further analysis demonstrated that the increase in cytokine content was higher in the hippocampal tissues used for LTP recording in the SAMR1 and CFA-challenged animals compared to the SAMP8 and intact BALB/c mice. A correlation analysis demonstrated that pro-inflammatory cytokines (IL-6 and TNF-α) displayed a negative correlation with LTP, while an anti-inflammatory cytokine (IL-10) displayed a positive correlation with LTP. These results suggest that pro-inflammatory cytokines induced by LTP manipulation in experiments (e.g., via tissue injury caused by electrode insertion) may be one of the factors contributing to the observed lack of correspondence between memory/learning ability and LTP.

Chronic Stress Accelerates and Intensifies Aß-induced Alzheimer’s-disease-like Pathogenesis in Rat Models

Apart from genetic factors, environmental factors such as stress may also play a critical role in the manifestation of Alzheimer’s disease (AD). We studied the impact of chronic psychosocial stress in two amyloid-beta (Aβ) rat models of AD by three approaches: learning and memory tests in the radial arm water maze, electrophysiological recordings of long-term potentiation (LTP) in anesthetized rats, and immunoblot analysis of synaptic plasticity- and cognition-related signaling molecules. The first Aβ rat model, representing established AD, was induced by continuous intracerebroventricular (ICV) infusion of a pathogenic dose of Aβ peptides via a 14-day osmotic pump. In this AD model, chronic stress intensified cognitive deficits, produced more depression of LTP, and accentuated the reduction of signaling molecule levels compared with the established model alone. The second model represents subjects that are clinically normal but are at risk for AD, and was induced by ICV infusion of a sub-threshold (sub-Aβ) dose of Aβ peptides. Chronic psychosocial stress was induced using a rat intruder model. Various tests showed that sub-Aβ rats were not significantly different from control rats. However, chronically stressed sub-Aβ rats showed more significant impairment of cognitive functions and early-phase LTP than that caused by stress alone. Molecular analysis revealed marked disturbances in the levels of essential signaling molecules in the stressed AD at-risk rats. These findings suggest that chronic stress may profoundly accelerate and intensify the impairment of cognition and synaptic plasticity in individuals at risk for AD and those with established AD, respectively. Possible mechanisms for the effect of chronic stress are discussed.

Effects of Chronic Administration of Melatonin on Spatial Learning Ability and Long-term Potentiation in Lead-exposed and Control Rats

To explore the changes in spatial learning performance and long-term potentiation (LTP) which is recognized as a component of the cellular basis of learning and memory in normal and lead-exposed rats after administration of melatonin (MT) for two months. Experiment was performed in adult male Wistar rats (12 controls, 12 exposed to melatonin treatment, 10 exposed to lead and 10 exposed to lead and melatonin treatment). The lead-exposed rats received 0.2% lead acetate solution from their birth day while the control rats drank tap water. Melatonin (3 mg/kg) or vehicle was administered to the control and lead-exposed rats from the time of their weaning by gastric gavage each day for 60 days, depending on their groups. At the age of 81-90 days, all the animals were subjected to Morris water maze test and then used for extracellular recording of LTP in the dentate gyrus (DG) area of the hippocampus in vivo. Low dose of melatonin given from weaning for two months impaired LTP in the DG area of hippocampus and induced learning and memory deficit in the control rats. When melatonin was administered over a prolonged period to the lead-exposed rats, it exacerbated LTP impairment, learning and memory deficit induced by lead. Melatonin is not suitable for normal and lead-exposed children.

Long-term recording of LTP in cultured hippocampal slices.

Long-term potentiation (LTP) was elicited by high frequency stimulation in hippocampal slices cultured on multi-electrode arrays. LTP lasting more than 1 h was recorded in 75% of slices, and a significant number of slices exhibited a non-decaying LTP that lasted more than 48 h. LTP induction was completely and reversibly blocked by an antagonist of the NMDA receptor, APV. Our results suggest the possibility of using chronic recording in hippocampal slices cultured on multi-electrode arrays to study the mechanisms underlying LTP maintenance and stabilization.

Corticotropin-Releasing Factor Produces a Protein Synthesis–Dependent Long-Lasting Potentiation in Dentate Gyrus Neurons

Corticotropin-releasing factor (CRF) was shown to produce a long-lasting potentiation of synaptic efficacy in dentate gyrus neurons of the rat hippocampus in vivo. This potentiation was shown to share some similarities with tetanization-induced long-term potentiation (LTP). In the present study, we further examined the mechanism underlying CRF-induced long-lasting potentiation in rat hippocampus in vivo. Results indicated that the RNA synthesis inhibitor actinomycin-D, at a concentration that did not change basal synaptic transmission alone (5 microgram), significantly decreased CRF-induced potentiation. Similarly, the protein synthesis inhibitor emetine, at a concentration that did not affect hippocampal synaptic transmission alone (5 microgram), also markedly inhibited CRF-induced potentiation. These results suggest that like the late phase of LTP, CRF-induced long-lasting potentiation also critically depend on protein synthesis. Further, prior maximum excitation of dentate gyrus neurons with tetanization occluded further potentiation of these neurons produced by CRF and vise versa. Moreover, quantitative reverse transcription-polymerase chain reaction analysis revealed that CRF mRNA level in the dentate gyrus was significantly increased 1 h after LTP recording. Together with our previous findings that CRF antagonist dose-dependently diminishes tetanization-induced LTP, these results suggest that both CRF-induced long-lasting potentiation and tetanization-induced LTP require protein synthesis and that CRF neurons are possibly involved in the neural circuits underlying LTP.

Recording of long-term potentiation in single dorsal horn neurons in vivo in the rat

We have published several reports on long-term potentiation (LTP) in single spinal wide dynamic range (WDR) neurons (responding to both innocuous and noxious stimuli) in urethane-anaesthetised rats. The protocol presented here, with single unit recordings of dorsal horn neurons before and after a nociceptive conditioning stimulation, may be useful in many electrophysiological studies of plastic changes in the spinal cord, such as LTP. We invite others to use this protocol for the study of spinal plasticity. Findings using this technique may be relevant for the understanding of changes in nociceptive transmission, induction of central sensitisation and maybe even in mechanisms of pathological pain and chronic pain states. We describe modified and alternative protocols for the study of LTP mechanisms under different conditions in intact and in spinalised animals, and after natural noxious stimuli. We present a novel method minimising peripheral influence of afferent input induced by antidromic neurogenic inflammation or inflammatory changes following a natural noxious stimulation. This is made possible by dissection of the sciatic nerve at two separate locations and local anaesthetic block distal to the stimulation site. Themes: Sensory systems Topics: Spinal cord

The nitric oxide‐cyclic GMP pathway and synaptic plasticity in the rat superior cervical ganglion

1. We have investigated the possibility that nitric oxide (NO) and soluble guanylyl cyclase, an enzyme that synthesizes guanosine 3':5'-cyclic monophosphate (cyclic GMP) in response to NO, contributes to plasticity of synaptic transmission in the rat isolated superior cervical ganglion (SCG). 2. Exposure of ganglia to the NO donor, nitroprusside, caused a concentration-dependent accumulation of cyclic GMP which was augmented in the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine. The compound, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a selective inhibitor of soluble guanylyl cyclase, completely blocked this cyclic GMP response. 3. As assessed by extracellular recording, nitroprusside (100 microM) and another NO donor, S-nitrosoglutathione (30 microM) increased the efficacy of ganglionic synaptic transmission in response to electrical stimulation of the preganglionic nerve, an effect that was reversible and which could be replicated by the cyclic GMP analogue, 8-bromo-cyclic GMP. Ganglionic depolarizations resulting from stimulation of nicotinic receptors with carbachol were not increased by nitroprusside. The potentiating actions of the NO donors on synaptic transmission, but not that of 8-bromo-cyclic GMP, were inhibited by ODQ. 4. Brief tetanic stimulation of the preganglionic nerve resulted in a long-term potentiation (LTP) of synaptic transmission that was unaffected by ODQ, either in the absence or presence of the NO synthase inhibitor, NG-nitro-L-arginine (L-NOARG, 100 microM). A lack of influence of L-NOARG was confirmed in intracellular recordings of LTP of the excitatory postsynaptic potential. Furthermore, under conditions where tetanically-induced LTP was saturated, nitroprusside was still able to potentiate synaptic transmission, as judged from extracellular recording. 5. We conclude that NO is capable of potentiating ganglionic neurotransmission and this effect is mediated through the stimulation of soluble guanylyl cyclase and the accumulation of cyclic GMP. However, this potentiation is distinct from LTP of nicotinic synaptic transmission, in which neither NO nor soluble guanylyl cyclase appear to participate.