Field Excitatory Postsynaptic Potentials Research Articles

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

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

Adenosine A2A receptors control generalization of contextual fear in rats

Fear learning is essential to survival, but traumatic events may lead to abnormal fear consolidation and overgeneralization, triggering fear responses in safe environments, as occurs in post-traumatic stress disorder (PTSD). Adenosine A2A receptors (A2AR) control emotional memory and fear conditioning, but it is not known if they affect the consolidation and generalization of fear, which was now investigated. We now report that A2AR blockade through systemic administration of the A2AR antagonist SCH58261 immediately after contextual fear conditioning (within the consolidation window), accelerated fear generalization. Conversely, A2AR activation with CGS21680 decreased fear generalization. Ex vivo electrophysiological recordings of field excitatory post-synaptic potentials (fEPSPs) in CA3-CA1 synapses and of population spikes in the lateral amygdala (LA), showed that the effect of SCH58261 is associated with a reversion of fear conditioning-induced decrease of long-term potentiation (LTP) in the dorsal hippocampus (DH) and with increased amplitude of LA LTP in conditioned animals. These data suggest that A2AR are engaged during contextual fear consolidation, controlling long-term potentiation mechanisms in both DH and LA during fear consolidation, impacting on fear generalization; this supports targeting A2AR during fear consolidation to control aberrant fear processing in PTSD and other fear-related disorders.

Comparing the synaptic potentiation in schaffer collateral-CA1 synapses in dorsal and intermediate regions of the hippocampus in normal and kindled rats

There is growing evidence that the hippocampus comprises diverse neural circuits that exhibit longitudinal variation in their properties, however, the intermediate region of the hippocampus has received comparatively little attention. Therefore, this study was designed to compared short- and long-term synaptic plasticity between the dorsal and intermediate regions of the hippocampus in normal and PTZ-kindled rats. Short-term plasticity was assessed by measuring the ratio of field excitatory postsynaptic potentials’ (fEPSPs) slope in response to paired-pulse stimulation at three different inter-pulse intervals (20, 80, and 160 ms), while long-term plasticity was assessed using primed burst stimulation (PBS). The results showed that the basal synaptic strength differed between the dorsal and intermediate regions of the hippocampus in both control and kindled rats. In the control group, paired-pulse stimulation of Schaffer collaterals resulted in a significantly lower fEPSP slope in the intermediate part of the hippocampus compared to the dorsal region. Additionally, the magnitude of long-term potentiation (LTP) was significantly lower in the intermediate part of the hippocampus compared to the dorsal region. In PTZ-kindled rats, both short-term facilitation and long-term potentiation were impaired in both regions of the hippocampus. Interestingly, there was no significant difference in synaptic plasticity between the dorsal and intermediate regions in PTZ-kindled rats, despite impairments in both regions. This suggests that seizures eliminate the regional difference between the dorsal and intermediate parts of the hippocampus, resulting in similar electrophysiological activity in both regions in kindled animals. Future studies should consider this when investigating the responses of the dorsal and intermediate regions of the hippocampus following PTZ kindling.

Fabrication of a photo-crosslinkable fluoropolymer-passivated flexible neural probe and acute recording and stimulation performances in vivo

Herein, we fabricated fluorine-containing, polymer-based, flexible neural probes with fluorinated ethylene propylene (FEP) films as the substrates and photo-crosslinkable fluoropolymers as the passivation material. For fabrication, metal-free Au layer formation on the FEP film, the simultaneous photo-adhesion and photo-patterning technique, and the pulsed-laser scanning probe shaping technique were combined, followed by Au electrode surface modification. The resultant probes achieved a charge injection limit equal to 5.18 mC cm−2 by implementing iridium oxide-modified nanoporous Au (IrOx/NPG) structures. We performed simultaneous in vivo micro-stimulations of the Schaffer collateral fibres and recorded the evoked field excitatory postsynaptic potentials (fEPSPs) in the stratum radiatum layer of the hippocampal Cornu Ammonis 1 region using a single probe. Inducing the fEPSP at very low charge per pulse settings (3.2–3.6 nC/pulse) indicates the efficient charge injection capability of the IrOx/NPG electrode, thereby enabling safe, prolonged, and thrifty micro-stimulations. Furthermore, the single probe-induced and recorded long-term potentiation persisted for periods longer than 60 min following theta-burst stimulation. The materials used in this study are all biocompatible and chemically robust. The fabricated neural probes can be applied in chronic clinical trials in vivo.

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

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

Photoactivated Protein Degrader for Optical Control of Synaptic Function.

Hundreds of proteins determine the function of synapses, and synapses define the neuronal circuits that subserve myriad brain, cognitive, and behavioral functions. It is thus necessary to precisely manipulate specific proteins at specific sub-cellular locations and times to elucidate the roles of particular proteins and synapses in brain function. We developed PHOtochemically TArgeting Chimeras (PHOTACs) as a strategy to optically degrade specific proteins with high spatial and temporal precision. PHOTACs are small molecules that, upon wavelength-selective illumination, catalyze ubiquitylation and degradation of target proteins through endogenous proteasomes. Here, we describe the design and chemical properties of a PHOTAC that targets Ca2+/calmodulin-dependent protein kinase II alpha (CaMKIIα), which is abundant and crucial for the baseline synaptic function of excitatory neurons. We validate the PHOTAC strategy, showing that the CaMKIIα-PHOTAC is effective in mouse brain tissue. Light activation of CaMKIIα-PHOTAC removed CaMKIIα from regions of the mouse hippocampus only within 25 μm of the illuminated brain surface. The optically controlled degradation decreases synaptic function within minutes of light activation, measured by the light-initiated attenuation of evoked field excitatory postsynaptic potential (fEPSP) responses to physiological stimulation. The PHOTACs methodology should be broadly applicable to other key proteins implicated in synaptic function, especially for evaluating their precise roles in the maintenance of long-term potentiation and memory within subcellular dendritic domains.

Long-term high-fat diet's impact on synaptic plasticity in the visual cortex and hippocampus neurons: an experimental study

Objective: To investigate the effects and mechanisms of long-term high-fat diet on synaptic plasticity in the visual cortex and hippocampus neurons of juvenile mice. Methods: This was an experimental study. Twenty-four 4-week-old male C57BL/6J mice were randomly divided into two groups, using a randomized numerical table, with 12 mice in each group. The ND group was fed a normal diet, while the HFD group was fed a high-fat diet. After 12 weeks of feeding, mouse body weight, body fat percentage, glucose tolerance, and blood lipid levels were recorded. Six mice from each group were randomly selected using a randomized numerical table, and long-term potentiation (LTP) in the lateral geniculate nucleus (LGN)-primary visual cortex binocular zone (V1B area) and hippocampus CA3-CA1 were recorded in vitro. Field excitatory postsynaptic potentials (fEPSPs) were measured, and the normalized fEPSP slope was calculated to evaluate changes in cortical synaptic plasticity. Subsequently, brain tissue was collected for Golgi staining to observe the development of pyramidal neurons in layers Ⅱ-Ⅲ of the primary visual cortex and CA1 region of the hippocampus, and changes in dendritic spine morphology and quantity were compared. The remaining six mice from each group were euthanized, and brain tissue was collected for transmission electron microscopy to observe ultrastructural changes in the visual cortex V1B area and hippocampus CA1 region neurons. Independent samples t-test was used for statistical analysis. Results: After 12 weeks of feeding, the body weight of mice in the HFD group was (29.17±1.63) g, significantly lower than the ND group which was (37.99±6.87) g (t=4.33, P<0.001). The body fat percentage in the HFD group was 1.09%±0.22%, which was higher than the ND group with 0.85%±0.09% (t=2.50, P=0.032). HFD mice showed a significant increase in blood glucose level 30 minutes after glucose injection, reaching (17.80±3.94) mmol/L, compared to the ND group with (23.10±1.48) mmol/L (t=3.07, P=0.013). At 60 minutes after glucose injection, the difference in blood glucose levels between the ND group [(13.58±2.39) mmol/L] and the HFD group [(23.70±3.56) mmol/L] was statistically significant (t=5.40, P<0.001). Subsequently, both groups showed a decline in blood glucose levels, and at 120 minutes after glucose injection, the blood glucose level in the ND group decreased to (8.50±1.05) mmol/L, while the HFD group remained at a higher level of (16.03±4.17) mmol/L, showing a statistically significant difference (t=3.91, P=0.004). The serum total cholesterol levels in the ND and HFD groups were (4.08±0.35) mmol/L and (10.80±0.90) mmol/L, respectively, with the HFD group higher than the ND group (t=15.23, P<0.001). However, there was no significant difference in triglyceride levels (P>0.05). The high-density lipoprotein cholesterol level in the ND group was (2.12±0.57) mmol/L, while in the HFD group, it was (1.28±0.15) mmol/L, with the HFD group lower than the ND group (t=3.15, P=0.014). Non-high-density lipoprotein cholesterol level in the HFD group was (11.06±1.46) mmol/L, significantly higher than the ND group with (2.28±0.43) mmol/L (t=12.88, P<0.001). In the hippocampal CA3-CA1 pathway, the fEPSP slope increased by 239.1%±88.8% of baseline in the ND group, while in the HFD group, it was only 147.6%±31.6% of baseline, indicating lower LTP compared to the ND group (t=7.20, P<0.001). For the LGN-V1 pathway, the fEPSP slope increased by 204.8%±67.0% of baseline in the ND group, while in the HFD group, it was 121.1%±15.7% of baseline, showing reduced LTP compared to the ND group (t=9.11, P<0.001). Regarding the visual cortex, in the V1B area of the ND group, the number of dendritic spines per 10 μm was (1.31±1.14), while in the HFD group, it was (0.77±0.43), demonstrating a significant decrease in dendritic spine density (t=3.45, P<0.001). The proportion of mature dendritic spines in the ND group was 69.98%, while non-mature dendritic spines accounted for 30.02%. In contrast, the HFD group had 45.76% mature dendritic spines and 54.24% non-mature dendritic spines. Regarding changes in hippocampal CA1 pyramidal neurons, the cell bodies and axons were not damaged, but HFD group neurons exhibited simplified dendritic structures with reduced branching. The number of dendritic spines per 10 μm was (10.25±3.84) in the HFD group and (25.22±8.21) in the ND group, indicating significantly lower dendritic spine density in the HFD group (t=12.42, P<0.001). The proportion of mature dendritic spines in the ND group was 70.88%, while non-mature dendritic spines accounted for 29.12%. In contrast, the HFD group had 47.37% mature dendritic spines and 52.63% non-mature dendritic spines. Moreover, the ultrastructure of neurons in the visual cortex V1B area and hippocampus CA1 region of HFD mice showed evident damage, with disrupted cell structures, swollen and vacuolated mitochondria, reduced or even disappeared mitochondrial cristae, and decreased synaptic quantity with damaged structure. Conclusions: Long-term high-fat diet in juvenile mice leads to abnormal development and functional maturation of synapses in the visual cortex and hippocampal regions. Dendrites, as the foundation of synaptic structures, undergo abnormal development, which can cause alterations in synaptic plasticity of related neural circuits.

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

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

Comparative effects of the alcoholic extract of Terminalia chebula and crocin on stress‑induced anxiety‑like behavior and memory impairment in male rats.

Crocin and Terminalia chebula (T. chebula) were proven to have neuroprotective effects. In this study, we evaluated the preventive effects of crocin and alcoholic extract of the T. chebula alone and in combination to examine their efficacy against chronic restraint stress (CRS)‑induced cognitive impairment, anxiety‑like behaviors, hippocampal synaptic plasticity deficit as well as neuronal arborization damage in the hippocampal CA1 neurons. Over 14 consecutive days, animals received crocin, T. chebula, or their combination (5 min before CRS). The elevated plus‑maze results showed that crocin and T. chebula alone and in combination treatment significantly increased the time spent in open arms, percentage of open arm entries, and head dipping as compared with the CRS group. Barnes maze results showed that administration of crocin and T. chebula alone and their combination significantly improves spatial memory indicators such as distance traveled, latency time to achieving the target hole, and the number of errors when compared to the CRS group. These learning deficits in CRS animals correlated with a reduction of long-term potentiation (LTP) in hippocampal CA1 synapses, which both T. chebula and crocin treatment improved field excitatory postsynaptic potentials (fEPSP) amplitude and fEPSP slope reduction induced by CRS. Golgi‑Cox staining showed that T. chebula and crocin treatment increased the number of dendrites and soma arbors in the CA1 neurons compared with the CRS group. Our results suggest that both T. chebula and crocin attenuated CRS‑induced anxiety‑like behaviors, memory impairment, and synaptic plasticity loss in hippocampal CA1 neurons. We found no significant difference between single treatments of T. chebula or crocin and their combination in protecting CRS‑induced anxiety‑like behaviors, memory impairment, and synaptic plasticity loss in hippocampal CA1 neurons.

In vivo synaptic potency, short-term and long-term plasticity at the hippocampal Schaffer collateral-CA1 synapses: Role of different light–dark cycles in male rats

The changes in the light–dark(L/D) cycle could modify cellular mechanisms in some brain regions. The present study compared the effects of various L/D cycles on invivo synaptic potency, short-term and long-term plasticity in the hippocampal CA1 area, adrenal glands weight(AGWs), corticosterone (CORT) levels, and body weight differences(BWD) in male rats.Male rats were assigned into different L/D cycle groups: L4/D20, L8/D16, L12/D12(control), L16/D8, and L20/D4. The slope, amplitude, and the area under curve(AUC) related to the field excitatory postsynaptic potentials(fEPSPs) were assessed, using the input–output(I/O) functions, paired-pulse(PP) responses at different interpulse intervals, and after the induction of long-term potentiation(LTP) in the hippocampal CA1 area. Also, the CORT levels, AGWs, and BWDs were measured in all groups.The slope, amplitude, and AUC of fEPSP in the I/O functions, all three phases of PP, before and after the LTP induction, were significantly decreased in all experimental groups, especially in the L20/D4 and L4/D20 groups. As such, the CORT levels and AGWs were significantly increased in all experimental groups, especially in the L20/D4 group.Overall, the uncommon L/D cycles (minimum and particularly maximum durations of light) significantly reduced the cellular mechanism of learning and memory. Also, downtrends were observed in synaptic potency, as well as short-term and long-term plasticity. The changes in PP with high interpulse intervals, or activity of GABAB receptors, were more significant than the changes in other PP phases with different L/D durations. Additionally, the CORT levels, adrenal glands, and body weight gain occurred time-independently concerning different L/D lengths.

Chronic maternal morphine exposure and early-life adversity induce impairment in synaptic plasticity of adolescent male rats

Maternal morphine exposure has negative consequences for learning and memory in the offspring. Interaction between mothers and pups has a crucial effect on the mammal's development. Maternal Separation (MS) can cause behavioral and neuropsychiatric problems later in life. It seems that adolescents are more susceptible to the effects of early life stress; evidence for the combinatory effects of oral chronic maternal morphine exposure and MS in the CA1 area of the hippocampus in the male adolescent offspring is not found. Therefore, this study aimed to evaluate the effects of chronic maternal morphine consumption (21 days before and after mating, and gestation), and MS (180 min/day from postnatal day (PND) 1–21) on the synaptic plasticity of male offspring in mid-adolescence. Control, MS, Vehicle (V), Morphine, V + MS, and Morphine + MS groups were tested for in vivo field potential recording from the CA1 area of the hippocampus. The current results demonstrated that chronic maternal morphine exposure impaired the induction of early long-term potentiation (LTP). MS impaired average fEPSPs, induction of early-LTP and maintenance. Chronic maternal morphine exposure in combination with MS impaired the induction of early LTP but didn't deteriorate maintenance and the average field excitatory post-synaptic potentials (fEPSPs) measured in two hours. Prepulse facilitation ratios remained undisturbed and I/O curves showed decreased fEPSP slopes at high stimulus intensities in combinatory group. We concluded that chronic maternal morphine exposure in combination with MS negatively affects synaptic plasticity in the CA1 area in male adolescent offspring.

LTD‐inducing low frequency stimulation enhances p‐Tau181 and p‐Tau217 in an age‐dependent manner in live rats

AbstractBackgroundThe progressive cognitive decline in Alzheimer’s disease (AD) patients correlates with the extent of tau pathology, in particular tau hyperphosphorylation, which is strongly age‐associated. Although elevation of phosphorylated tau (p‐Tau) on residues Thr181 (p‐Tau181), Thr217 (p‐Tau217), and Thr231 (p‐Tau231) in cerebrospinal fluid or blood are recently proposed to be particularly sensitive markers of early Alzheimer’s disease (AD), the generation of p‐Tau during brain activity is poorly understood. A major form of synaptic plasticity, long‐term depression (LTD), has recently been linked to the enhancement of tau phosphorylation. It is still unknown whether the expression levels of p‐Tau181, p‐Tau217, and p‐Tau231 can be enhanced by physiological LTD induction.MethodYoung adult (2‐3‐months) and aged (17‐18‐months) male Sprague Dawley rats were used in all experiments. Prior to the surgery, animals were anesthetized with urethane (1.5‐1.6 g/kg, i.p.). Field excitatory postsynaptic potentials (EPSPs) were recorded from the stratum radiatum in the CA1 area of left or right hippocampus in response to stimulation of the Schaffer collateral‐commissural pathway. LTD was induced using 1 Hz low frequency stimulation (LFS) consisting of 900 pulses (0.2 ms duration). The rats were sacrificed 30 min post‐LFS. The expression levels of p‐Tau181, p‐Tau217, p‐Tau231, p‐Tau202/205, p‐Tau396, and total tau were analyzed using western blotting and immunofluorescent staining.ResultHere we show that LFS, used to induce LTD, enhances p‐Tau181 and p‐Tau217 in an age‐dependent manner in the hippocampus of live rats. In contrast, phosphorylation at residues Thr231, Ser202/Thr205, and Ser396 is less sensitive to LFS. Further, blocking either NMDARs or mGluR5 strongly inhibits the elevation of both p‐Tau181 and p‐Tau217. Finally, targeting ageing with a small molecule cognitive enhancer ISRIB (trans‐isomer) prevents the increase of both p‐Tau181 and p‐Tau217 by LFS in aged rats.ConclusionOur data provide an in vivo means to uncover brain plasticity‐related cellular and molecular processes of tau phosphorylation in health and ageing conditions.

Umbelliferone Ameliorates Memory Impairment and Enhances Hippocampal Synaptic Plasticity in Scopolamine-Induced Rat Model.

Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by memory loss and cognitive decline. Among the suggested pathogenic mechanisms of AD, the cholinergic hypothesis proposes that AD symptoms are a result of reduced synthesis of acetylcholine (ACh). A non-selective antagonist of the muscarinic ACh receptor, scopolamine (SCOP) induced cognitive impairment in rodents. Umbelliferone (UMB) is a Apiaceae-family-derived 7-hydeoxycoumarin known for its antioxidant, anti-tumor, anticancer, anti-inflammatory, antibacterial, antimicrobial, and antidiabetic properties. However, the effects of UMB on the electrophysiological and ultrastructure morphological aspects of learning and memory are still not well-established. Thus, we investigated the effect of UMB treatment on cognitive behaviors and used organotypic hippocampal slice cultures for long-term potentiation (LTP) and the hippocampal synaptic ultrastructure. A hippocampal tissue analysis revealed that UMB attenuated a SCOP-induced blockade of field excitatory post-synaptic potential (fEPSP) activity and ameliorated the impairment of LTP by the NMDA and AMPA receptor antagonists. UMB also enhanced the hippocampal synaptic vesicle density on the synaptic ultrastructure. Furthermore, behavioral tests on male SD rats (7-8 weeks old) using the Y-maze test, passive avoidance test (PA), and Morris water maze test (MWM) showed that UMB recovered learning and memory deficits by SCOP. These cognitive improvements were in association with the enhanced expression of BDNF, TrkB, and the pCREB/CREB ratio and the suppression of acetylcholinesterase activity. The current findings indicate that UMB may be an effective neuroprotective reagent applicable for improving learning and memory against AD.

Chronic Administration of Non-Constitutive Proteasome Inhibitor Modulates Long-Term Potentiation and Glutamate Signaling-Related Gene Expression in Murine Hippocampus.

Proteasomes degrade most intracellular proteins. Several different forms of proteasomes are known. Little is known about the role of specific proteasome forms in the central nervous system (CNS). Inhibitors targeting different proteasome forms are used in clinical practice and were shown to modulate long-term potentiation (LTP) in hippocampal slices of untreated animals. Here, to address the role of non-constitutive proteasomes in hippocampal synaptic plasticity and reveal the consequences of their continuous inhibition, we studied the effect of chronic administration of the non-constitutive proteasome inhibitor ONX-0914 on the LTP induced by two different protocols: tetanic stimulation and theta-burst stimulation (TBS). Both the tetanus- and TBS-evoked potentiation contribute to the different forms of hippocampal-dependent memory and learning. Field-excitatory postsynaptic potentials (fEPSPs) in hippocampal slices from control animals and animals treated with DMSO or ONX-0914 were compared. LTP induced by the TBS was not affected by ONX-0914 administration; however, chronic injections of ONX-0914 led to a decrease in fEPSP slopes after tetanic stimulation. The observed effects correlated with differential expression of genes involved in synaptic plasticity, glutaminergic synapse, and synaptic signaling. Obtained results indicate that non-constitutive proteasomes are likely involved in the tetanus-evoked LTP, but not the LTP occurring after TBS, supporting the relevance and complexity of the role of specific proteasomes in synaptic plasticity, memory, and learning.

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

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

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

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

Fingolimod Administration Following Hypoxia Induced Neonatal Seizure Can Restore Impaired Long-term Potentiation and Memory Performance in Adult Rats

Neonatal seizures commonly caused by hypoxia can lead to long-term neurological outcomes. Early inflammation plays an important role in the pathology of these outcomes. Therefore, in the current study, we explored the long-term effects of Fingolimod (FTY720), an analog of sphingosine and potent sphingosine 1-phosphate (S1P) receptors modulator, as an anti-inflammatory and neuroprotective agent in attenuating anxiety, memory impairment, and possible alterations in gene expression of hippocampal inhibitory and excitatory receptors following hypoxia-induced neonatal seizure (HINS). Seizure was induced in 24 male and female pups (6 in each experimental group) at postnatal day 10 (P10) by premixed gas (5% oxygen/ 95% nitrogen) in a hypoxic chamber for 15 minutes. Sixty minutes after the onset of hypoxia, FTY720 (0.3 mg/kg) or saline (100 µl) was administered for 12 days (from P10 up to P21). Anxiety-like behavior and hippocampal memory function were assessed at P90 by elevated plus maze (EPM) and novel object recognition (NOR), respectively. Long-term potentiation (LTP) was recorded from hippocampal dentate gyrus region (DG) following stimulation of perforant pathway (PP). In addition, the hippocampal concentration of superoxide dismutase activity (SOD), malondialdehyde (MDA), and thiol as indices of oxidative stress were evaluated. Finally, the gene expression of NR2A subunit of N-Methyl-D-aspartic acid (NMDA) receptor, GluR2 subunit of (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) AMPA receptor and γ2 subunit of γ-Aminobutyric acid (GABAA) receptor were assessed at P90 by the quantitative real-time PCR. FTY720 significantly reduced later-life anxiety-like behavior, ameliorated object recognition memory and increased the amplitude and slope of the field excitatory postsynaptic potential (fEPSP) in the rats following HINS. These effects were associated with restoration of the hippocampal thiol content to the normal values and the regulatory role of FTY720 in the expression of hippocampal GABA and glutamate receptors subunits. In conclusion, FTY720 could restore the dysregulated gene expression of excitatory and inhibitory receptors. It also increased the reduced hippocampal thiol content, which was accompanied with attenuation of HINS-induced anxiety, reduced the impaired hippocampal related memory, and prevented hippocampal LTP deficits in later life following HINS.

Coenzyme Q10 supplementation improves the motor function of middle-aged mice by restoring the neuronal activity of the motor cortex

Physiological aging causes motor function decline and anatomical and biochemical changes in the motor cortex. We confirmed that middle-aged mice at 15–18 months old show motor function decline, which can be restored to the young adult level by supplementing with mitochondrial electron transporter coenzyme Q10 (CoQ10) as a water-soluble nanoformula by drinking water for 1 week. CoQ10 supplementation concurrently improved brain mitochondrial respiration but not muscle strength. Notably, we identified an age-related decline in field excitatory postsynaptic potential (fEPSP) amplitude in the pathway from layers II/III to V of the primary motor area of middle-aged mice, which was restored to the young adult level by supplementing with CoQ10 for 1 week but not by administering CoQ10 acutely to brain slices. Interestingly, CoQ10 with high-frequency stimulation induced NMDA receptor-dependent long-term potentiation (LTP) in layer V of the primary motor cortex of middle-aged mice. Importantly, the fEPSP amplitude showed a larger input‒output relationship after CoQ10-dependent LTP expression. These data suggest that CoQ10 restores the motor function of middle-aged mice by improving brain mitochondrial function and the basal fEPSP level of the motor cortex, potentially by enhancing synaptic plasticity efficacy. Thus, CoQ10 supplementation may ameliorate the age-related decline in motor function in humans.

Deubiquitinase CYLD regulates excitatory synaptic transmission and short-term plasticity in the hippocampus

The fate of proteins is determined by the addition of various forms of polyubiquitin during ubiquitin-mediated proteasomal degradation. Cylindromatosis (CYLD), a K63-specific deubiquitinase, is enriched in postsynaptic density fractions of the rodent central nervous system (CNS), but the synaptic role of CYLD in the CNS is poorly understand. Here we show that CYLD deficiency (Cyld−/−) results in reduced intrinsic hippocampal neuronal firing, a decrease in the frequency of spontaneous excitatory postsynaptic currents and a decrease in the amplitude of field excitatory postsynaptic potentials. Moreover, Cyld−/− hippocampus shows downregulated levels of presynaptic vesicular glutamate transporter 1 (vGlut1) and upregulated levels of postsynaptic GluA1, a subunit of the AMPA receptor, together with an altered paired-pulse ratio (PPR). We also found increased activation of astrocytes and microglia in the hippocampus of Cyld−/− mice. The present study suggests a critical role for CYLD in mediating hippocampal neuronal and synaptic activity.

Effect of Sinapic Acid on Scopolamine-Induced Learning and Memory Impairment in SD Rats

The seriousness of the diseases caused by aging have recently gained attention. Alzheimer's disease (AD), a chronic neurodegenerative disease, accounts for 60-80% of senile dementia cases. Continuous research is being conducted on the cause of Alzheimer's disease, and it is believed to include complex factors, such as genetic factors, the accumulation of amyloid beta plaques, a tangle of tau protein, oxidative stress, cholinergic dysfunction, neuroinflammation, and cell death. Sinapic acid is a hydroxycinnamic acid found in plant families, such as oranges, grapefruit, cranberry, mustard seeds, and rapeseeds. It exhibits various biological activities, including anti-inflammatory, anti-oxidant, anti-cancer, and anti-depressant effects. Sinapic acid is an acetylcholine esterase inhibitor that can be applied to the treatment of dementia caused by Alzheimer's disease and Parkinson's disease. However, electrophysiological studies on the effects of sinapic acid on memory and learning must still be conducted. Therefore, it was confirmed that sinapic acid was effective in long-term potentiation (LTP) using organotypic hippocampal segment tissue. In addition, the effect on scopolamine-induced learning and memory impairment was measured by oral administration of sinapic acid 10 mg/kg/day for 14 days, and behavioral experiments related to short-term and long-term spatial memory and avoidance memory were conducted. Sinapic acid increased the activity of the field excitatory postsynaptic potential (fEPSP) in a dose-dependent manner after TBS, and restored fEPSP activity in the CA1 region suppressed by scopolamine. The scopolamine-induced learning and memory impairment group showed lower results than the control group in the Y-maze, Passive avoidance (PA), and Morris water maze (MWM) experiments. Sinapic acid improved avoidance memory, short and long-term spatial recognition learning, and memory. In addition, sinapic acid weakened the inhibition of the brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB) and the activation of prostaglandin-endoperoxide synthase 2 (COX-2) and interleukin 1 beta (IL-1β) induced by scopolamine in the hippocampus. These results show that sinapic acid is effective in restoring LTP and cognitive impairment induced by the cholinergic receptor blockade. Moreover, it showed the effect of alleviating the reduction in scopolamine-induced BDNF and TrkB, and alleviated neuroinflammatory effects by inhibiting the increase in COX-2 and IL-1β. Therefore, we showed that sinapic acid has potential as a treatment for neurodegenerative cognitive impairment.