Hippocampal Receptors Research Articles

AMPA and NMDA Receptors in Hippocampus of Rats with Fluoride-Induced Cognitive Decline

This experimental study was performed to evaluate the alterations in the expression of a few subunits composing glutamate AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-D-aspartate) receptors in the hippocampal cells of Wistar rats in response to long-term fluoride (F-) exposure. The animals were given water with background 0.4 (control), 5, 20, and 50 ppm F- (as NaF) for 12 months. The cognitive capacities of rats were examined by novel object recognition (NOR), Y-maze test, and Morris water maze tests. RT-qPCR and Western blotting techniques were used to evaluate the expression of different AMPA and NMDA subunits at transcriptional and translational levels, respectively. Long-term F- poisoning disturbed the formation of hippocampus-dependent working spatial and long-term non-spatial memory. The expression of Gria1, Gria2, and Gria3 genes encoding different subunits of AMPA receptors were comparable in hippocampi of control and F--exposed animals, although the levels of both Grin2a and Grin2b mRNA increased. Long-term F- intake enhanced the ratio of phospho-GluA1/total-GluA1 proteins in subcellular fraction enriched with cytosolic proteins, while decreased content of GluA2 but elevated level of GluA3 were observed in subcellular fraction enriched with membrane proteins. Such changes were accompanied by increased phosphorylation of GluN2A and GluN2B subunits, higher ratios of GluN2A/GluN1 and GluN2B/GluN1 proteins in the cytosol, and GluN2A/GluN2B ratio in membranes. These changes indicate the predominance of Ca2+-permeable AMPARs in membranes and a shift between different NMDARs subunits in hippocampal cells of F--exposed rats, which is typical for neurodegeneration and can at least partially underly the observed disturbances in cognitive capacities of animals.

The Effect of Exercise and Sildenafil on Brain-derived Neurotrophic Factor and Tropomyosin Kinase B Receptor in the Hippocampal of Alzheimer's Rats

Objectives: Alzheimer disease is a progressive neurodegenerative disorder with the formation of amyloid β plaques in the brain. This study investigates the effects of a resistance training course with sildenafil supplementation on brain-derived neurotrophic factor and tropomyosin receptor kinase B in the hippocampal tissue of rats with Alzheimer disease. Methods: A total of 40 Wistar rats were randomly assigned to five groups. Alzheimer induction was performed with β-amyloid peptides 1-14. Rats performed resistance training 5 sessions per week for six weeks. Sildenafil was injected intraperitoneally. Then, 72 h after the last training session, the hippocampus of the rats was extracted. The results of the analysis of variance showed a significant difference between brain-derived neurotrophic factor mRNA and tropomyosin receptor kinase B mRNA (P≤0.001). Results: The results of the Bonferroni post hoc test showed a significant difference between the control group and the experimental groups. Discussion: Training and sildenafil supplementation groups performed better in the Morris water maze cognitive test compared to other groups. Resistance training and sildenafil supplementation, by synergizing their effects, can increase tropomyosin receptor kinase B, the expression of neurotrophin genes, and hippocampal receptors; in addition, they are effective in the development of cognitive activity and memory.

A Truncated Receptor TrkB Isoform (TrkB.T1) in Mechanisms of Genetically Determined Depressive-like Behavior of Mice.

Depression is a mental disorder that significantly reduces quality of life, and the discovery of new drug targets is an urgent problem for modern neuroscience. Brain-derived neurotrophic factor (BDNF) and its receptors have been found to participate in mechanisms of depression and antidepressant drugs' action. In this study, we focused on a less-studied truncated isoform of receptor TrkB: TrkB.T1. Initially, we noticed that the level of TrkB.T1 is low in the hippocampus of Antidepressant-Sensitive Cataleptics (ASC) mice, which are characterized by genetically determined depressive-like behavior in contrast to "normal" C57BL/6J mice. Next, overexpression of TrkB.T1 receptor in hippocampal neurons of ACS mice was induced to clarify the role of this receptor in mechanisms of depressive-like behavior. TrkB.T1 overexpression lowered BDNF protein concentration in the hippocampus. On the behavioral level, TrkB.T1 overexpression severely decreased aggression and enhanced social behavior. Additionally, this excess of receptor TrkB.T1 slightly promoted anxiety and depressive-like behavioral traits without affecting learning and memory. Our results show that this TrkB isoform participates in the control of aggression, anxiety, and depressive-like behavior and in the regulation of BDNF system functioning in ASC mice (genetically predisposed to depressive-like behavior). Considering our findings, we believe that hippocampal receptor TrkB.T1 can be a drug target for the correction of behavioral pathologies.

Glucagon-like peptide-1 receptors in nucleus accumbens, ventral hippocampus, and lateral septum reduce alcohol reinforcement in mice.

Glucagon-like peptide 1 (GLP-1) receptor agonists can decrease alcohol intake by central mechanisms that are still poorly understood. The lateral septum (LS) and the ventral/caudal part of the hippocampus are enriched in GLP-1 receptors, and activity in these regions was shown to modulate reward-related behaviors. Using microinfusions of the GLP-1 receptor agonist exendin-4 in mice trained to self-administer oral alcohol in an operant assay, we tested whether pharmacological stimulation of GLP-1 receptors in hippocampus and LS decrease alcohol self-administration. We report that infusion of exendin-4 in the ventral hippocampus or LS was sufficient to reduce alcohol self-administration with as large effect sizes as we previously reported with systemic exendin-4 administration. Infusion of exendin-4 into the nucleus accumbens also reduced alcohol self-administration, as anticipated based on earlier reports, while infusion of exendin-4 into the caudate-putamen (dorsal striatum) had little effect, consistent with lack of GLP-1 receptor expression in this region. The distribution of exendin-4 after infusion into the LS or caudate putamen was visualized using a fluorescently labeled ligand. These findings add to our understanding of the circuit-level mechanisms underlying the ability of GLP-1 receptor agonists to reduce alcohol self-administration. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Specific antagonist of receptor for advanced glycation end‑products attenuates delirium‑like behaviours induced by sevoflurane anaesthesia with surgery in aged mice partially by improving damage to the blood‑brain barrier.

Postoperative delirium (POD), which occurs in hospital up to 1-week post-procedure or until discharge, is a common complication, especially in older adult patients. However, the pathogenesis of POD remains unclear. Although damage to blood-brain barrier (BBB) integrity is involved in the neuropathogenesis of POD, the specific role of the BBB in POD requires further elucidation. Anaesthesia using 2% isoflurane for 4 h results in the upregulation of hippocampal receptor for advanced glycation end-products (RAGE) expression and β-amyloid accumulation in aged rats. The present study investigated the role of RAGE in BBB integrity and its mechanisms in POD-like behaviours. The buried food, open field and Y maze tests were used to evaluate neurobehavioural changes in aged mice following 2.5% sevoflurane anaesthesia administration with exploratory laparotomy. Levels of tight junction proteins were assessed by western blotting. Multiphoton in vivo microscopy was used to observe the ultrastructural changes in the BBB in the hippocampal CA1 region. Anaesthesia with surgery decreased the levels of tight junction proteins occludin and claudin 5, increased matrix metalloproteinases (MMPs) 2 and 9, damaged the ultrastructure of the BBB and induced POD-like behaviour. FPS-ZM1, a specific RAGE antagonist, ameliorated POD-like behaviour induced by anaesthesia and surgery in aged mice. Furthermore, FPS-ZM1 also restored decreased levels of occludin and claudin 5 as well as increased levels of MMP2 and MMP9. The present findings suggested that RAGE signalling was involved in BBB damage following anaesthesia with surgery. Thus, RAGE has potential as a novel therapeutic intervention for the prevention of POD.

Spinal cord injury leads to more neurodegeneration in the hippocampus of aged male rats compared to young rats

Although the disruptive effects of spinal cord injury (SCI) on the hippocampus have been confirmed in some animal studies, no study has investigated its retrograde manifestations in the hippocampus of aged subjects. Herein, we compared the aged rats with young ones 3 weeks after the induction of SCI (Groups: Sham.Young, SCI.Young, Sham.Aged, SCI.Aged). The locomotion, hippocampal apoptosis, hippocampal rhythms (Delta, Theta, Beta, Gamma) max frequency (Max.rf) and power, hippocampal neurogenesis, and hippocampal receptors (NMDA, GABA A, Muscarinic1/M1), which are important in the generation of rhythms and neurogenesis, were compared in aged rats in contrast to young rats. At the end of the third week, the number of apoptotic (Tunel+) cells in the hippocampus (CA1, DG) of SCI animals was significantly higher compared to the sham animals, and also, it was significantly higher in the SCI.Aged group compared to SCI.Young group. Moreover, the rate of neurogenesis (DCX+, BrdU+ cells) and expression of M1 and NMDA receptors were significantly lower in the SCI.Aged group compared to SCI.Young group. The power and Max.fr of all rhythms were significantly lower in SCI groups compared to sham groups. Despite the decrease in the power of rhythms in the SCI.Aged group compared to SCI.Young group, there was no significant difference between them, and in terms of Max.fr index, only the Max.fr of theta and beta rhythms were significantly lower in the SCI.Aged group compared to SCI.Young group. This study showed that SCI could cause more neurodegeneration in the hippocampus of aged animals compared to young animals.

Effect of risperidone on morphine-induced conditioned place preference and dopamine receptor D2 gene expression in male rat hippocampus.

Previous studies suggest the possible effect of risperidone on brain reward system and D1 and D2 dopamine receptors' involvement in morphine-induced conditioned place preference (CPP). The present study was designed to investigate the effect of risperidone as an atypical antipsychotic drug on morphine-induced CPP and D2-like dopamine receptor gene expression in rat. An unbiased CPP paradigm was used to study the effect of risperidone. Intraperitoneal (i.p.) injection of risperidone (1, 2, and 4mg/kg) was performed 30min before the morphine (10mg/kg, i.p.) injection and just after the rat was placed in the CPP box. The open field test was used to assay the locomotor activity of animal. The gene expression of D2 dopamine receptor in hippocampus was measured by real-time PCR technique. The hippocampi of rats were also used for histology evaluation. Morphine-produced (10mg/kg) CPP and morphine-induced CPP were reversed only by the administration of a low dose of risperidone (1mg/kg). Low dose of risperidone (1mg/kg) showed no effect on locomotor activity but a higher dose of risperidone (2 and 4mg/kg) decreased locomotor activity. Real-time PCR data analysis revealed that the gene expression of D2 dopamine receptor had significant difference between morphine and a 1mg/kg dose of risperidone. Moreover, in histological evaluation, apoptosis was observed in the morphine group, whereas there was no evidence of apoptosis in the risperidone-treated groups. Our results suggest that risperidone (1mg/kg) reverses the morphine-induced CPP and may reduce the rewarding properties of morphine. It is also demonstrated that risperidone decreases the expression of D2 receptor in rat hippocampus. Therefore, risperidone can be considered potential adjunct therapy in morphine dependence.

Extracellular vesicles from mesenchymal stem cells reduce neuroinflammation in hippocampus and restore cognitive function in hyperammonemic rats

Chronic hyperammonemia, a main contributor to hepatic encephalopathy (HE), leads to neuroinflammation which alters neurotransmission leading to cognitive impairment. There are no specific treatments for the neurological alterations in HE. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) reduce neuroinflammation in some pathological conditions. The aims were to assess if treatment of hyperammonemic rats with EVs from MSCs restores cognitive function and analyze the underlying mechanisms. EVs injected in vivo reach the hippocampus and restore performance of hyperammonemic rats in object location, object recognition, short-term memory in the Y-maze and reference memory in the radial maze. Hyperammonemic rats show reduced TGFβ levels and membrane expression of TGFβ receptors in hippocampus. This leads to microglia activation and reduced Smad7–IkB pathway, which induces NF-κB nuclear translocation in neurons, increasing IL-1β which alters AMPA and NMDA receptors membrane expression, leading to cognitive impairment. These effects are reversed by TGFβ in the EVs from MSCs, which activates TGFβ receptors, reducing microglia activation and NF-κB nuclear translocation in neurons by normalizing the Smad7–IkB pathway. This normalizes IL-1β, AMPA and NMDA receptors membrane expression and, therefore, cognitive function. EVs from MSCs may be useful to improve cognitive function in patients with hyperammonemia and minimal HE.

Air pollution nanoparticle exposure reduces neurotrophin signaling and causes hippocampal neural stem cell quiescence in mouse brain

AbstractBackgroundExposure to urban air pollution particles is strongly associated with higher risks of accelerated cognitive decline, cerebral atrophy, and dementia in multiple population studies. Among possible mechanisms is the decrease of neurotrophins, shown for BDNF in human exposures, which have critical roles in regulating adult neurogenesis and synaptic plasticity.MethodC57BL/6 mice were exposed to nano‐sized particulate matter (nPM, batch nPM2016a) from urban traffic air pollution for 8 weeks and the mRNAs of neurotrophins and receptors in mouse brain were measured by qPCR assay and neural stem cells measured by immunohistochemistry.ResultnPM exposure altered mRNA levels of neurotrophin genes (Ngf, Bdnf, Ntf‐3 and Ntf‐4/5) with brain region‐specificity. In cerebral cortex (CX), Ngf and Ntf‐3 were decreased (17% and 29% respectively), Ntf‐4/5 increased (78%), and Bdnf unchanged. In hippocampus (HP), Bdnf and Ntf‐4/5 were decreased (40% and 38% respectively) while Ngf and NTF‐3 unchanged. In olfactory bulb (OB), only Bdnf was decreased (10%). The mRNAs of neurotrophin receptors (Trka, Trkb, Trkc and p75Ntr) in CX, HP and OB were less responsive to nPM exposure, and only shown by OB with 22% decrease of p75Ntr and 14% decrease of Vgr (VGF nerve growth factor inducible). Exposure to nPM increased the quiescence of neural stem cells in hippocampal SGZ by IHC assay (Control 69.3% VS nPM 76.6%, P = 0.02), but did not alter the total number of neural stem cells. .ConclusionChronic air pollution exposure altered neurotrophin signaling with factor‐ and brain region‐specificity, and increased neural stem cell quiescence.

The Effect of Stilbene Glycosides on the Hippocampal Neurons and N-methyl D-aspartate Receptor Subtype 2B Receptors in Alzheimer’s Disease Rats

Our study investigated the effect of stilbene glycosides (TSG) on hippocampal neurons and NMDAR2B receptors in Alzheimer’s disease (AD). 40 SPF-grade male rats aged 8 weeks and weighted 0.3 kg were divided into control group (DG group), model group (WG group) (stereotactic injection of Aβ into hippocampus), low TSG group, and high TSG group followed by analysis of NR2B receptor level in hippocampus by immunohistochemical (IHC) staining and hippocampal neuronal apoptosis. The escape period of WG group and TSG treatment group was significantly longer than DG group (P < 0.05) with more significant improvement in TSG group than WG group (P < 0.05); NR2B positive number in WG group (140.31±2.81) was significantly lower than DG group (162.07±4.61) and TSG group (P < 0.05); WG and TSG group had a significantly higher apoptosis rate than DG group (P < 0.05). In addition, NR2B and NR1 expression in WG group was decreased slightly (P < 0.05) with a higher clu level (P < 0.05) which was decreased after TSG treatment (P < 0.05). However, NR2B and NR1 levels showed a significant increase trend after TSG treatment. In conclusion, TSG can effectively reduce the increase of Aβ in the hippocampus, promote NR2B expression, reduce apoptosis and improve the learning ability of rats.

Intersection of hippocampus and spinal cord: a focus on the hippocampal alpha-synuclein accumulation, dopaminergic receptors, neurogenesis, and cognitive function following spinal cord injury in male rats

BackgroundFollowing Spinal Cord Injury (SCI), innumerable inflammatory and degenerative fluctuations appear in the injured site, and even remotely in manifold areas of the brain. Howbeit, inflammatory, degenerative, and oscillatory changes of motor cortices have been demonstrated to be due to SCI, according to recent studies confirming the involvement of cognitive areas of the brain, such as hippocampus and prefrontal cortex. Therefore, addressing SCI induced cognitive complications via different sights can be contributory in the treatment approaches.ResultsHerein, we used 16 male Wistar rats (Sham = 8, SCI = 8). Immunohistochemical results revealed that spinal cord contusion significantly increases the accumulation of alpha-synuclein and decreases the expression of Doublecortin (DCX) in the hippocampal regions like Cornu Ammonis1 (CA1) and Dentate Gyrus (DG). Theses degenerative manifestations were parallel with a low expression of Achaete-Scute Family BHLH Transcription Factor 1 (ASCL1), SRY (sex determining region Y)-box 2 (SOX2), and dopaminergic receptors (D1 and D5). Additionally, based on the TUNEL assay analysis, SCI significantly increased the number of apoptotic cells in the CA1 and DG regions. Cognitive function of the animals was assessed, using the O-X maze and Novel Object Recognition (NORT); the obtained findings indicted that after SCI, hippocampal neurodegeneration significantly coincides with the impairment of learning, memory and recognition capability of the injured animals.ConclusionsBased on the obtained findings, herein SCI reduces neurogenesis, decreases the expression of D1 and D5, and increases apoptosis in the hippocampus, which are all associated with cognitive function deficits.Graphical

Increased Voluntary Alcohol Consumption in Mice Lacking GABAB(1) Is Associated With Functional Changes in Hippocampal GABAA Receptors.

Gamma-aminobutyric acid type B receptor (GABABR) has been extensively involved in alcohol use disorders; however, the mechanisms by which this receptor modulates alcohol drinking behavior remain murky. In this study, we investigate alcohol consumption and preference in mice lacking functional GABABR using the 2-bottle choice paradigm. We found that GABAB(1), knockout (KO), and heterozygous (HZ) mice drank higher amounts of an alcoholic solution, preferred alcohol to water, and reached higher blood alcohol concentrations (BACs) compared to wild-type (WT) littermates. The GABABR agonist GHB significantly reduced alcohol consumption in the GABAB(1) HZ and WT but not in the KO mice. Next, because of a functional crosstalk between GABABR and δ-containing GABAA receptor (δ-GABAAR), we profiled δ subunit mRNA expression levels in brain regions in which the crosstalk was characterized. We found a loss of the alcohol-sensitive GABAAR δ subunit in the hippocampus of the GABAB(1) KO alcohol-naïve mice that was associated with increased ɣ2 subunit abundance. Electrophysiological recordings revealed that these molecular changes were associated with increased phasic inhibition, suggesting a potential gain of synaptic GABAAR responsiveness to alcohol that has been previously described in an animal model of excessive alcohol drinking. Interestingly, voluntary alcohol consumption did not revert the dramatic loss of hippocampal δ-GABAAR occurring in the GABAB(1) KO mice but rather exacerbated this condition. Finally, we profiled hippocampal neuroactive steroids levels following acute alcohols administration in the GABAB(1) KO and WT mice because of previous involvement of GABABR in the regulation of cerebral levels of these compounds. We found that systemic administration of alcohol (1.5 g/kg) did not produce alcohol-induced neurosteroid response in the GABAB(1) KO mice but elicited an expected increase in the hippocampal level of progesterone and 3α,5α-THP in the WT controls. In conclusion, we show that genetic ablation of the GABAB(1) subunit results in increased alcohol consumption and preference that were associated with functional changes in hippocampal GABAAR, suggesting a potential mechanism by which preference for alcohol consumption is maintained in the GABAB(1) KO mice. In addition, we documented that GABAB(1) deficiency results in lack of alcohol-induced neurosteroids, and we discussed the potential implications of this finding in the context of alcohol drinking and dependence.

Behavioral Training Related Neurotransmitter Receptor Expression Dynamics in the Nidopallium Caudolaterale and the Hippocampal Formation of Pigeons.

Learning and memory are linked to dynamic changes at the level of synapses in brain areas that are involved in cognitive tasks. For example, changes in neurotransmitter receptors are prerequisite for tuning signals along local circuits and long-range networks. However, it is still unclear how a series of learning events promotes plasticity within the system of neurotransmitter receptors and their subunits to shape information processing at the neuronal level. Therefore, we investigated the expression of different glutamatergic NMDA (GRIN) and AMPA (GRIA) receptor subunits, the GABAergic GABARG2 subunit, dopaminergic DRD1, serotonergic 5HTR1A and noradrenergic ADRA1A receptors in the pigeon’s brain. We studied the nidopallium caudolaterale, the avian analogue of the prefrontal cortex, and the hippocampal formation, after training the birds in a rewarded stimulus-response association (SR) task and in a simultaneous-matching-to-sample (SMTS) task. The results show that receptor expression changed differentially after behavioral training compared to an untrained control group. In the nidopallium caudolaterale, GRIN2B, GRIA3, GRIA4, DRD1D, and ADRA1A receptor expression was altered after SR training and remained constantly decreased after the SMTS training protocol, while GRIA2 and DRD1A decreased only under the SR condition. In the hippocampal formation, GRIN2B decreased and GABARG2 receptor expression increased after SR training. After SMTS sessions, GRIN2B remained decreased, GABARG2 remained increased if compared to the control group. None of the investigated receptors differed directly between both conditions, although differentially altered. The changes in both regions mostly occur in favor of the stimulus response task. Thus, the present data provide evidence that neurotransmitter receptor expression dynamics play a role in the avian prefrontal cortex and the hippocampal formation for behavioral training and is uniquely, regionally and functionally associated to cognitive processes including learning and memory.

Influences of Housing Environment on Functional State of the Body after Action of Ulcerogenic Stressor

Here we studied influences of housing environment on functional state of the body after action of ulcerogenic stressor. The effects of ulcerogenic stressor on the gastric mucosa, the hypothalamic‐pituitary‐adrenocortical (HPA) axis reactivity and glucocorticoid receptors in hippocampus, behavior and somatic pain sensitivity were compared in rats kept in enriched environment, social isolation, and standard laboratory conditions (control group). The rats aged 30 days were divided into groups and placed in standard cages 6 rats per cage (control) or 1 rats per cage (isolation) or in enriched cages 6 rats per cage (enriched environment). One month later, all rats (after 24 h fasting) were stressed by cold restraint (10˚C) for 3 h. In 3 h one half of rats in each group were decapitated to examine the gastric mucosa. Another half of rats were subjected to behavior tests (open field and elevated plus maze) and somatic pain sensitivity test (hot plate) as well as the HPA axis reactivity testing by plasma corticosterone levels induced by mild procedural stressor. Glucocorticoid receptor expression was estimated in hippocampus by immunohistochemistry. Body weight gradually increased in all groups during 1 month before exposure of stressor, however, in the isolated rats, the weight gain was greater than that in enriched and control groups. In all groups cold restraint caused the gastric erosion, the mean areas of which were not significantly differed. In behavior tests, the animals of isolated group were approximately equally divided into vulnerable (showing depressive‐like reactions in the open field) and resistant (not differed from the non‐stressed control) to ulcerogenic stress (active subgroup). All isolated rats showed a reduced level of exploratory activity in the elevated plus maze. Rats from enriched environment showed greater motor and exploratory activity, as well as lower anxiety level compared to those in isolated group. Isolated rats were most sensitive to action of pain, whereas rats kept in enriched environment were less sensitive to pain exposure. In the isolated group, the weakest corticosterone release among all groups was observed in response to mild procedural stress. Low HPA stress‐reactivity of isolated rats was combined with enhanced expression of glucocorticoid receptors in the hippocampus indicating a sensitization of the mechanisms of negative glucocorticoid feedback following prolonged social isolation. Thus, social isolation is a stressor leading to weight gain, a decrease in stress reactivity accompanied by an increase of glucocorticoid receptor expression in the hippocampus, a decrease of exploratory activity and increased of somatic pain sensitivity whereas enriched environment exerts beneficial action on functional state of the body: increases motor and exploratory activity, decreases anxiety and somatic pain sensitivity.

Hyperammonemia Alters the Function of AMPA and NMDA Receptors in Hippocampus: Extracellular cGMP Reverses Some of These Alterations.

Chronic hyperammonemia alters membrane expression of AMPA and NMDA receptors subunits in hippocampus leading to impaired memory and learning. Increasing extracellular cGMP normalizes these alterations. However, it has not been studied whether hyperammonemia alters the function of AMPA and NMDA receptors. The aims of this work were: (1) assess if hyperammonemia alters AMPA and NMDA receptors function; (2) analyze if extracellular cGMP reverses these alterations. A multielectrode array device was used to stimulate Schäffer collaterals and record postsynaptic currents in the CA1 region in hippocampal slices from control and hyperammonemic rats and analyze different features of the excitatory postsynaptic potentials. Hyperammonemia reduces the amplitude and delays appearance of AMPA EPSPs, whereas increases amplitude, hyperpolarization, depolarization and desensitization area of the NMDA EPSPs. These alterations in AMPA and NMDA function are accentuated as the stimulation intensity increases. Adding extracellular cGMP reverses the alteration in amplitude in both, AMPA and NMDA EPSPs. In control slices extracellular cGMP decreases the AMPA and NMDA EPSPs amplitude and delays the response of neurons and the return to the resting potential at all stimulation intensities. In conclusion, hyperammonemia decreases the AMPA response, whereas increases the NMDA response and extracellular cGMP reverses these alterations.

Age-related changes in medial septal cholinergic and GABAergic projection neurons and hippocampal neurotransmitter receptors: relationship with memory impairment.

The hippocampus, which provides cognitive functions, has been shown to become highly vulnerable during aging. One important modulator of the hippocampal neural network is the medial septum (MS). The present study attempts to determine how age-related mnemonic dysfunction is associated with neurochemical changes in the septohippocampal (SH) system, using behavioral and immunochemical experiments performed on young-adult, middle-aged and aged rats. According to these behavioral results, the aged and around 52.8% of middle-aged rats (within the "middle-aged-impaired" sub-group) showed both impaired spatial reference memory in the Morris water maze and habituation in the open field. Immunohistochemical studies revealed a significant decrease in the number of MS choline acetyltransferase immunoreactive cells in the aged and all middle-aged rats, in comparison to the young; however the number of gamma-aminobutyric acid-ergic (GABAergic) parvalbumin immunoreactive cells was higher in middle-aged-impaired and older rats compared to young and middle-aged-unimpaired rats. Western Blot analysis moreover showed a decrease in the level of expression of cholinergic, GABAergic and glutamatergic receptors in the hippocampus of middle-aged-impaired and aged rats in contrast to middle-aged-unimpaired and young rats. The present results demonstrate for the first time that a decrease in the expression level of hippocampal receptors in naturally aged rats with impaired cognitive abilities occurs in parallel with an increase in the number of GABAergic neurons in the MS, and it highlights the particular importance of inhibitory signaling in the SH network for memory function.

Hyperammonemia Enhances GABAergic Neurotransmission in Hippocampus: Underlying Mechanisms and Modulation by Extracellular cGMP.

Rats with chronic hyperammonemia reproduce the cognitive and motor impairment present in patients with hepatic encephalopathy. It has been proposed that enhanced GABAergic neurotransmission in hippocampus may contribute to impaired learning and memory in hyperammonemic rats. However, there are no direct evidences of the effects of hyperammonemia on GABAergic neurotransmission in hippocampus or on the underlying mechanisms. The aims of this work were to assess if chronic hyperammonemia enhances the function of GABAA receptors in hippocampus and to identify the underlying mechanisms. Activation of GABAA receptors is enhanced in hippocampus of hyperammonemic rats, as analyzed in a multielectrode array system. Hyperammonemia reduces membrane expression of the GABA transporters GAT1 and GAT3, which is associated with increased extracellular GABA concentration. Hyperammonemia also increases gephyrin levels and phosphorylation of the β3 subunit of GABAA receptor, which are associated with increased membrane expression of the GABAA receptor subunits α1, α2, γ2, β3, and δ. Enhanced levels of extracellular GABA and increased membrane expression of GABAA receptors would be responsible for the enhanced GABAergic neurotransmission in hippocampus of hyperammonemic rats. Increasing extracellular cGMP reverses the increase in GABAA receptors activation by normalizing the membrane expression of GABA transporters and GABAA receptors. The increased GABAergic neurotransmission in hippocampus would contribute to cognitive impairment in hyperammonemic rats. The results reported suggest that reducing GABAergic tone in hippocampus by increasing extracellular cGMP or by other means may be useful to improve cognitive function in hyperammonemia and in cirrhotic patients with minimal or clinical hepatic encephalopathy.

Subcellular localization of hippocampal ryanodine receptor 2 and its role in neuronal excitability and memory

Ryanodine receptor 2 (RyR2) is abundantly expressed in the heart and brain. Mutations in RyR2 are associated with both cardiac arrhythmias and intellectual disability. While the mechanisms of RyR2-linked arrhythmias are well characterized, little is known about the mechanism underlying RyR2-associated intellectual disability. Here, we employed a mouse model expressing a green fluorescent protein (GFP)-tagged RyR2 and a specific GFP probe to determine the subcellular localization of RyR2 in hippocampus. GFP-RyR2 was predominantly detected in the soma and dendrites, but not the dendritic spines of CA1 pyramidal neurons or dentate gyrus granular neurons. GFP-RyR2 was also detected within the mossy fibers in the stratum lucidum of CA3, but not in the presynaptic terminals of CA1 neurons. An arrhythmogenic RyR2-R4496C+/− mutation downregulated the A-type K+ current and increased membrane excitability, but had little effect on the afterhyperpolarization current or presynaptic facilitation of CA1 neurons. The RyR2-R4496C+/− mutation also impaired hippocampal long-term potentiation, learning, and memory. These data reveal the precise subcellular distribution of hippocampal RyR2 and its important role in neuronal excitability, learning, and memory.

Caffeine Functions by Inhibiting Dorsal and Ventral Hippocampal Adenosine 2A Receptors to Modulate Memory and Anxiety, Respectively.

As a nonspecific antagonist of the adenosine A2A receptor (A2AR), caffeine enhances learning and improves memory impairment. Simultaneously, the consumption of caffeine correlates with a feeling of anxiety. The hippocampus is functionally differentiated along its dorsal/ventral axis and plays a crucial role both in memory and anxiety. Whether caffeine exerts its regulation by inhibiting A2ARs in different subregions of the hippocampus is still unknown. In the present study, we found that after chronic intake of drinking water containing caffeine (1 g/L, 3 weeks), mice exhibited aggravated anxiety-like behavior and enhanced memory function. Tissue-specific, functional disruption of dorsal hippocampal A2ARs by the CRE-LoxP system prevented the memory-enhancing effect of caffeine, while selective disruption of ventral hippocampal A2ARs blocked the impact of caffeine on anxiety. These results, together with the enhanced memory of dorsal hippocampus A2AR knockout mice and greater anxiety-like behavior of ventral hippocampus A2AR knockout mice without caffeine, indicates a dissociation between the roles of ventral and dorsal hippocampal A2A receptors in caffeine’s effects on anxiety-like and memory-related behavioral measures, respectively. Furthermore, optogenetic activation of dorsal or ventral hippocampal A2ARs reversed the behavioral alterations caused by drinking caffeine, leading to impaired memory or decreased anxiety-like behaviors, respectively. Taken together, our findings suggest that the memory- and anxiety-enhancing effects of caffeine are related to the differential effects of inhibiting A2ARs in the dorsal and ventral hippocampus, respectively.

Evaluation of the anticonvulsant effect of carvacrol in Pentylenetetrazole (PTZ)-induced seizures in male mice: N-Methyl-D-Aspartic Acid receptor role

Background. Epilepsy is one of the most common neurological disorders after stroke. Due to the side effects and poor response of conventional anticonvulsant drugs, researchers have turned their attention to find new drugs. Carvacrol is a phenolic compound with neuroprotective, anti-inflammatory, antioxidant and anticonvulsant effects. The aim of the study was to investigate the anticonvulsant effects of carvacrol in PTZ-induced seizures in male mice and to investigate the role of N-Methyl-D-Aspartic Acid (NMDA) receptor. Methods. In the present experimental study, 90 mice were randomly divided into 9 groups (n=10). Drugs were injected intraperitoneally 30 minutes before PTZ injection. Then, seizure onset time, serum and brain antioxidant capacity (TAC) and malondialdehyde (MDA) and NMDA receptor gene expression in the hippocampus were examined. Results. Seizure onset time in the group received carvacrol (20 and 40 mg/kg) was significantly longer than the PTZ group (P<0.05). Treatment with carvacrol (20 and 40 mg/kg) significantly increased serum and brain antioxidant capacity and reduced serum and brain MDA in compared to the PTZ group (at doses of 5, 10, 20 and 40 mg/kg). The expression of NR2A and NR2B subunits of hippocampal NMDA receptors in carvacrol-received mice was significantly lower than the PTZ group (P<0.05). Conclusion. Carvacrol has anticonvulsant effects, possibly by inhibiting oxidative stress and reducing the expression of subunits of NMDA receptors.