β-Sitosterol treatment attenuates cognitive deficits and prevents amyloid plaque deposition in amyloid protein precursor/presenilin 1 mice

Alzheimer's disease (AD) is the most common neurodegenerative disorder causing dementia worldwide, and is mainly characterized by aggregated β-amyloid (Aβ). Increasing evidence has shown that plant extracts have the potential to delay AD development. The plant sterol β-Sitosterol has a potential role in inhibiting the production of platelet Aβ, suggesting that it may be useful for AD prevention. In the present study, we aimed to investigate the effect and mechanism of β-Sitosterol on deficits in learning and memory in amyloid protein precursor/presenilin 1 (APP/PS1) double transgenic mice. APP/PS1 mice were treated with β-Sitosterol for four weeks, from the age of seven months. Brain Aβ metabolism was evaluated using ELISA and Western blotting. We found that β-Sitosterol treatment can improve spatial learning and recognition memory ability, and reduce plaque load in APP/PS1 mice. β-Sitosterol treatment helped reverse dendritic spine loss in APP/PS1 mice and reversed the decreased hippocampal neuron miniature excitatory postsynaptic current frequency. Our research helps to explain and support the neuroprotective effect of β-Sitosterol, which may offer a novel pharmaceutical agent for the treatment of AD. Taken together, these findings suggest that β-Sitosterol ameliorates memory and learning impairment in APP/PS1 mice and possibly decreases Aβ deposition.

Effects of intra-dentate gyrus microinjection of myokine irisin on long-term potentiation in male rats / Efeitos da microinjeção da miocina irisina no giro denteado sobre a potenciação a longo prazo em ratos machos

ABSTRACT Induction of long-term potentiation (LTP) increases the storage capacity of synapses in the hippocampal dentate gyrus (DG). Irisin is a myokine generated from FNDC5 (a gene precursor) during exercise. Although intra-cornu ammonis 1 administration of irisin fortifies LTP in mice with Alzheimer's disease, the effects of intra-DG injection of irisin on the LTP in rats remains to be elucidated in vivo. In this study, male Wistar rats were randomly divided into a control group (saline), irisin (0.5, 1, and 1.5 μg/rat), and dimethyl sulfoxide (DMSO). After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the DG of rats in vivo. Moreover, following completion of the experiments, the stimulating and recording sites in the hippocampus were confirmed histologically from brain sections. Furthermore, biochemical assays like malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS) were evaluated (the antioxidant markers were analyzed in the plasma). Our results suggest that all doses of irisin (0.5, 1, 1.5 μg/rat) caused an increase in the EPSP slope and PS amplitude when compared with the control group. In addition, the results obtained showed that irisin decreased TOS and MDA levels while increasing TAC levels as a marker of lipid peroxidation in plasma. The present report provides direct evidence that irisin affects the activity-dependent synaptic plasticity in the dentate gyrus.

RESUMO A indução de potenciação de longo prazo (LTP) aumenta a capacidade de armazenamento das sinapses no giro denteado (DG) do hipocampo. A irisina é uma miocina gerada a partir do FNDC5 (um precursor genético) durante o exercício. Embora a administração intra-Cornu Ammonis1 de irisina fortaleça a LTP em camundongos com doença de Alzheimer, os efeitos da injeção intra-denteada de irisina sobre a LTP em ratos ainda precisam ser elucidados in vivo. Neste estudo, ratos Wistar machos foram divididos aleatoriamente em um grupo controle (solução salina), irisina (0,5, 1 e 1,5 μg / rato) e dimetilsulfóxido (DMSO). Após o tratamento, a amplitude do pico populacional (PS) e a variação dos potenciais pós-sinápticos excitatórios (EPSP) foram medidos no DG de ratos in vivo. Além disso, após a conclusão das experiências, os locais de estimulação e registro no hipocampo foram confirmados histologicamente a partir de secções do cérebro. Adicionalmente, ensaios bioquímicos como malondialdeído (MDA), capacidade antioxidante total (TAC) e status oxidante total (TOS) foram avaliados (os marcadores antioxidantes foram analisados no plasma). Nossos resultados sugerem que todas as doses de irisina (0,5, 1, 1,5 μg / rato) causaram um aumento na variação da EPSP e na amplitude da PS quando comparadas com o grupo controle. Além disso, os resultados obtidos mostraram que a irisina diminuiu os níveis de TOS e MDA, enquanto aumentou os níveis de TAC como um marcador da peroxidação lipídica no plasma. O presente estudo fornece evidências diretas de que a irisina afeta a plasticidade sináptica dependente de atividade no DG.

Impaired Hypothalamic Regulation of Sympathetic Outflow in Primary Hypertension / 神经科学通报·英文版

The hypothalamic paraventricular nucleus (PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN pre-sympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension. This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.

Characterization on Responsiveness of Excitatory Synaptic Transmissions to α1-Adrenoceptor Blockers in Substantia Gelatinosa Neurons Isolated From Lumbo-Sacral Level in Rat Spinal Cords / 대한배뇨장애요실금학회지

PURPOSE: The aim of this study was to characterize the responsiveness of miniature excitatory postsynaptic currents (mEPSCs) to α1-adrenoceptor blockers in substantia gelatinosa (SG) neurons from the spinal cord to develop an explanation for the efficacy of α1-adrenoceptor blockers in micturition dysfunction. METHODS: Male adult Sprague-Dawley rats were used. Blind whole-cell patch-clamp recordings were performed using SG neurons in spinal cord slices. Naftopidil (100μM), tamsulosin (100μM), or silodosin (30μM), α1-adrenoceptor blockers, was perfused. The frequency of mEPSCs was recorded in an SG neuron to which the 3 blockers were applied sequentially with wash-out periods. Individual frequencies in a pair before naftopidil and tamsulosin perfusion were plotted as baseline, and the correlation between them was confirmed by Spearman correlation coefficient; linear regression was then performed. The same procedure was performed before naftopidil and silodosin perfusion. Frequencies of pairs after naftopidil and tamsulosin perfusion and after naftopidil and silodosin perfusion were similarly analyzed. The ratios of the frequencies after treatment to before were then calculated. RESULTS: After the treatments, Spearman ρ and the slope were decreased to 0.682 from 0.899 at baseline and 0.469 from 1.004 at baseline, respectively, in the tamsulosin group relative to the naftopidil group. In the silodosin group, Spearman ρ and the slope were also decreased to 0.659 from 0.889 at baseline and 0.305 from 0.989 at baseline, respectively, relative to the naftopidil group. Naftopidil significantly increased the ratio of the frequency of mEPSCs compared to tamsulosin and silodosin (P=0.015 and P=0.004, respectively). CONCLUSIONS: There was a difference in responsiveness in the frequency of mEPSCs to α1-adrenoceptor blockers, with the response to naftopidil being the greatest among the α1-adrenoceptor blockers. These data are helpful to understand the action mechanisms of α1-adrenoceptor blockers for male lower urinary tract symptoms in clinical usage.

Pre- and Postsynaptic Actions of Reactive Oxygen Species and Nitrogen Species in Spinal Substantia Gelatinosa Neurons

Reactive oxygen species (ROS) and nitrogen species (RNS) are involved in cellular signaling processes as a cause of oxidative stress. According to recent studies, ROS and RNS are important signaling molecules involved in pain transmission through spinal mechanisms. In this study, a patch clamp recording was used in spinal slices of rats to investigate the action mechanisms of O₂˙⁻ and NO on the excitability of substantia gelatinosa (SG) neuron. The application of xanthine and xanthine oxidase (X/XO) compound, a ROS donor, induced inward currents and increased the frequency of spontaneous excitatory postsynaptic currents (sEPSC) in slice preparation. The application of S-nitroso-N-acetyl-DLpenicillamine (SNAP), a RNS donor, also induced inward currents and increased the frequency of sEPSC. In a single cell preparation, X/XO and SNAP had no effect on the inward currents, revealing the involvement of presynaptic action. X/XO and SNAP induced a membrane depolarization in current clamp conditions which was significantly decreased by the addition of thapsigargin to an external calcium free solution for blocking synaptic transmission. Furthermore, X/XO and SNAP increased the frequency of action potentials evoked by depolarizing current pulses, suggesting the involvement of postsynaptic action. According to these results, it was estblished that elevated ROS and RNS in the spinal cord can sensitize the dorsal horn neurons via pre- and postsynaptic mechanisms. Therefore, ROS and RNS play similar roles in the regulation of the membrane excitability of SG neurons.

Intravenous Anesthetic, Propofol Affects Synaptic Responses in Cerebellar Purkinje Cells

OBJECTIVE: Propofol is an intravenously administered anesthetic that enhances γ-aminobutyric acid-mediated inhibition in the central nerve system. Other mechanisms may also be involved in general anesthesia. Propofol has been implicated in movement disorders. The cerebellum is important for motor coordination and motor learning. The aim of the present study was to investigate the propofol effect on excitatory synaptic transmissions in cerebellar cortex. METHODS: Excitatory postsynaptic currents by parallel fiber stimulation and complex spikes by climbing fiber stimulation were monitored in Purkinje cells of Wister rat cerebellar slice using whole-cell patch-clamp techniques. RESULTS: Decay time, rise time and amplitude of excitatory postsynaptic currents at parallel fiber Purkinje cell synapses and area of complex spikes at climbing fiber Purkinje cell synapses were significantly increased by propofol administration. CONCLUSION: The detected changes of glutamatergic synaptic transmission in cerebellar Purkinje cell, which determine cerebellar motor output, could explain cerebellar mechanism of motor deficits induced by propofol.

Expression and Role of Voltage-Gated Sodium Channels in Human Dorsal Root Ganglion Neurons with Special Focus on Nav1.7, Species Differences, and Regulation by Paclitaxel / 神经科学通报·英文版

Voltage-gated sodium channels (Navs) play an important role in human pain sensation. However, the expression and role of Nav subtypes in native human sensory neurons are unclear. To address this issue, we obtained human dorsal root ganglion (hDRG) tissues from healthy donors. PCR analysis of seven DRG-expressed Nav subtypes revealed that the hDRG has higher expression of Nav1.7 (~50% of total Nav expression) and lower expression of Nav1.8 (~12%), whereas the mouse DRG has higher expression of Nav1.8 (~45%) and lower expression of Nav1.7 (~18%). To mimic Nav regulation in chronic pain, we treated hDRG neurons in primary cultures with paclitaxel (0.1-1 μmol/L) for 24 h. Paclitaxel increased the Nav1.7 but not Nav1.8 expression and also increased the transient Na currents and action potential firing frequency in small-diameter (<50 μm) hDRG neurons. Thus, the hDRG provides a translational model in which to study "human pain in a dish" and test new pain therapeutics.

Echinacoside, an active constituent of Herba Cistanche, suppresses epileptiform activity in hippocampal CA3 pyramidal neurons

Echinacoside, an active compound in the herb Herba Cistanche, has been reported to inhibit glutamate release. In this study, we investigated the effects of echinacoside on spontaneous excitatory synaptic transmission changes induced by 4-aminopyridine (4-AP), by using the in vitro rat hippocampal slice technique and whole-cell patch clamp recordings from CA3 pyramidal neurons. Perfusion with echinacoside significantly suppressed the 4-AP-induced epileptiform activity in a concentration-dependent manner. Echinacoside reduced 4-AP-induced increase in frequency of spontaneous excitatory postsynaptic currents (sEPSCs) but it did not affect the amplitude of sEPSCs or glutamate-activated currents, implicating a presynaptic mechanism of action. Echinacoside also potently blocked sustained repetitive firing, which is a basic mechanism of antiepileptic drugs. These results suggest that echinacoside exerts an antiepileptic effect on hippocampal CA3 pyramidal neurons by simultaneously decreasing glutamate release and blocking abnormal firing synchronization. Accordingly, our study provides experimental evidence that echinacoside may represent an effective pharmacological agent for treating epilepsy.

The effect of µ-opioid receptor activation on GABAergic neurons in the spinal dorsal horn

The superficial dorsal horn of the spinal cord plays an important role in pain transmission and opioid activity. Several studies have demonstrated that opioids modulate pain transmission, and the activation of µ-opioid receptors (MORs) by opioids contributes to analgesic effects in the spinal cord. However, the effect of the activation of MORs on GABAergic interneurons and the contribution to the analgesic effect are much less clear. In this study, using transgenic mice, which allow the identification of GABAergic interneurons, we investigated how the activation of MORs affects the excitability of GABAergic interneurons and synaptic transmission between primary nociceptive afferent and GABAergic interneurons. We found that a selective µ-opioid agonist, [D-Ala², NMe-Phe⁴, Gly-ol]-enkephanlin (DAMGO), induced an outward current mediated by K⁺ channels in GABAergic interneurons. In addition, DAMGO reduced the amplitude of evoked excitatory postsynaptic currents (EPSCs) of GABAergic interneurons which receive monosynaptic inputs from primary nociceptive C fibers. Taken together, we found that DAMGO reduced the excitability of GABAergic interneurons and synaptic transmission between primary nociceptive C fibers and GABAergic interneurons. These results suggest one possibility that suppression of GABAergic interneurons by DMAGO may reduce the inhibition on secondary GABAergic interneurons, which increase the inhibition of the secondary GABAergic interneurons to excitatory neurons in the spinal dorsal horn. In this circumstance, the sum of excitation of the entire spinal network will control the pain transmission.

Effects of High Concentrations of Naftopidil on Dorsal Root-Evoked Excitatory Synaptic Transmissions in Substantia Gelatinosa Neurons In Vitro / 대한배뇨장애요실금학회지

PURPOSE: Naftopidil ((±)-1-[4-(2-methoxyphenyl) piperazinyl]-3-(1-naphthyloxy) propan-2-ol) is prescribed in several Asian countries for lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Previous animal experiments showed that intrathecal injection of naftopidil abolished rhythmic bladder contraction in vivo. Naftopidil facilitated spontaneous inhibitory postsynaptic currents in substantia gelatinosa (SG) neurons in spinal cord slices. These results suggest that naftopidil may suppress the micturition reflex at the spinal cord level. However, the effect of naftopidil on evoked excitatory postsynaptic currents (EPSCs) in SG neurons remains to be elucidated. METHODS: Male Sprague-Dawley rats at 6 to 8 weeks old were used. Whole-cell patch-clamp recordings were made using SG neurons in spinal cord slices isolated from adult rats. Evoked EPSCs were analyzed in Aδ or C fibers. Naftopidil or prazosin, an α1-adrenoceptor blocker, was perfused at 100 μM or 10 μM, respectively. RESULTS: Bath-applied 100 μM naftopidil significantly decreased the peak amplitudes of Aδ and C fiber-evoked EPSCs to 72.0%±7.1% (n=15) and 70.0%±5.5% (n=20), respectively, in a reversible and reproducible manner. Bath application of 10μM prazosin did not inhibit Aδ or C fiber-evoked EPSCs. CONCLUSIONS: The present study suggests that a high concentration of naftopidil reduces the amplitude of evoked EPSCs via a mechanism that apparently does not involve α1-adrenoceptors. Inhibition of evoked EPSCs may also contribute to suppression of the micturition reflex, together with nociceptive stimulation.

Effects of low frequency stimulation on spontaneous inhibitory and excitatory post-synaptic currents in hippocampal CA1 pyramidal cells of kindled rats

Objective: Low-frequency stimulation [LFS] exerts suppressive effects in kindled animals. It is believed that overstimulated glutamatergic and decreased GABAergic transmission have long been associated with seizure activity. In this study, we investigated the effect of electrical LFS on different parameters of spontaneous excitatory and inhibitory post-synaptic currents [sEPSCs and sIPSCs] in hippocampal CA1 pyramidal cells in kindled animals

Materials and Methods: In this experimental study, rats were kindled by electrical stimulation of the hippocampal CA1 area in a semi-rapid manner [12 stimulations/day]. The animals were considered fully kindled when they showed stage 5 seizures on three consecutive days. One group of animals received LFS 4 times at 30 seconds, 6 hours, 18 and 24 hours following the last kindling stimulation. Each LFS consisted of 4 packages at 5 minutes intervals. Each package of LFS consisted of 200 pulses at 1 Hz and each monophasic square wave pulse duration was 0.1 millisecond. At 2-3 hours post-LFS, acute hippocampal slices were prepared and a whole cell patch clamp recording was performed in all animals to measure the different parameters of sEPSCs and sIPSCs

Results: In kindled animals, the inter-event interval [as an index of occurrence] of sEPSCs decreased, whereas sIPSC increased. In addition, the decay time constant of sIPSCs as an index of the duration of its activity decreased compared to the control group. There was no significant difference in other parameters between the kindled and control groups. Application of LFS in kindled animals prevented the observed changes. There was no significant difference between the measured parameters in kindled+LFS and control groups

Conclusion: LFS application may prevent seizure-induced increase in the occurrence of sEPSCs and seizure-induced decrease in occurrence and activity duration of sIPSCs

Protective effect of succinic acid on cerebellar Purkinje cells of neonatal rats with convulsion / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the protective effect of succinic acid (SA) on the cerebellar Purkinje cells (PCs) of neonatal rats with convulsion.</p><p><b>METHODS</b>A total of 120 healthy neonatal Sprague-Dawley rats aged 7 days were randomly divided into a neonatal period group and a developmental period group. Each of the two groups were further divided into 6 sub-groups: normal control, convulsion model, low-dose phenobarbital (PB) (30 mg/kg), high-dose PB (120 mg/kg), low-dose SA (30 mg/kg), and high-dose SA (120 mg/kg). Intraperitoneal injection of pentylenetetrazole was performed to establish the convulsion model. The normal control group was treated with normal saline instead. The rats in the neonatal group were sacrificed at 30 minutes after the injection of PB, SA, or normal saline, and the cerebellum was obtained. Those in the developmental group were sacrificed 30 days after the injection of PB, SA, or normal saline, and the cerebellum was obtained. Whole cell patch clamp technique was used to record the action potential (AP) of PCs in the cerebellar slices of neonatal rats; the parallel fibers (PF) were stimulated at a low frequency to induce excitatory postsynaptic current (EPSC). The effect of SA on long-term depression (LTD) of PCs was observed.</p><p><b>RESULTS</b>Compared with the normal control groups, the neonatal and developmental rats with convulsion had a significantly higher AP frequency of PCs (P<0.05), and the developmental rats with convulsion had a significantly decreased threshold stimulus (P<0.01) and a significantly greater inhibition of the amplitude of EPSC in PCs (P<0.05). Compared with the normal control groups, the neonatal and developmental rats with convulsion in the high-dose PB groups had a significantly decreased threshold stimulus (P<0.01), a significantly higher AP frequency of PCs (P<0.05), and a significantly greater inhibition of EPSC in PCs (P<0.05). Compared with the neonatal and developmental rats in the convulsion model groups, those in the high-dose SA groups had a significantly decreased AP frequency of PCs (P<0.05). The developmental rats in the low- and high-dose SA groups had a significantly higher AP threshold than those in the convulsion model group (P<0.05).</p><p><b>CONCLUSIONS</b>The high excitability of PCs and the abnormal PF-PC synaptic plasticity caused by convulsion in neonatal rats may last to the developmental period, which can be aggravated by PB, while SA can reduce the excitability of PCs in neonatal rats with convulsion and repair the short- and long-term abnormalities of LTD of PCs caused by convulsion.</p>

Changes in Synaptic Transmission and Long-term Potentiation Induction as a Possible Mechanism for Learning Disability in an Animal Model of Multiple Sclerosis / 대한배뇨장애요실금학회지

PURPOSE: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. It has been shown that memory deficits is common in patients with MS. Recent studies using experimental autoimmune encephalomyelitis (EAE) as an animal model of MS have shown that indicated that EAE causes hippocampal-dependent impairment in learning and memory. Thus far, there have been no in vivo electrophysiological reports describing synaptic transmission in EAE animals. The aim of the present work is to evaluate the synaptic changes in the CA1 region of the hippocampus of EAE rats. METHODS: To evaluate changes in synaptic transmission in the CA1 region of the hippocampus of EAE rats, field excitatory postsynaptic potentials (fEPSPs) from the stratum radiatum of CA1 neurons, were recorded following Schaffer collateral stimulation. RESULTS: The results showed that EAE causes deficits in synaptic transmission and long-term potentiation (LTP) in the hippocampus. In addition, paired-pulse index with a 120 msec interstimulus interval was decreased in the EAE group. These findings indicate that EAE might induce suppression in synaptic transmission and LTP by increasing the inhibitory effect of GABAB receptors on the glutamate-mediated EPSP. CONCLUSIONS: In conclusion, influence of inflammation-triggered mechanisms on synaptic transmission may explain the negative effect of EAE on learning abilities in rats.

Salvia miltiorrhiza Bunge Blocks Ethanol-Induced Synaptic Dysfunction through Regulation of NMDA Receptor-Dependent Synaptic Transmission

Consumption of high doses of ethanol can lead to amnesia, which often manifests as a blackout. These blackouts experienced by ethanol consumers may be a major cause of the social problems associated with excess ethanol consumption. However, there is currently no established treatment for preventing these ethanol-induced blackouts. In this study, we tested the ethanol extract of the roots of Salvia miltiorrhiza (SM) for its ability to mitigate ethanol-induced behavioral and synaptic deficits. To test behavioral deficits, an object recognition test was conducted in mouse. In this test, ethanol (1 g/kg, i.p.) impaired object recognition memory, but SM (200 mg/kg) prevented this impairment. To evaluate synaptic deficits, NMDA receptor-mediated excitatory postsynaptic potential (EPSP) and long-term potentiation (LTP) in the mouse hippocampal slices were tested, as they are known to be vulnerable to ethanol and are associated with ethanol-induced amnesia. SM (10 and 100 μg/ml) significantly ameliorated ethanol-induced long-term potentiation and NMDA receptor-mediated EPSP deficits in the hippocampal slices. Therefore, these results suggest that SM prevents ethanol-induced amnesia by protecting the hippocampus from NMDA receptor-mediated synaptic transmission and synaptic plasticity deficits induced by ethanol.

Influence of cefuroxime sodium on synaptic plasticity of parallel fiber-Purkinje cells in young rats / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To investigate the influence of cefuroxime sodium (CS) on the electrophysiological function of cerebellar Purkinje cells (PCs) in Sprague-Dawley rats.</p><p><b>METHODS</b>Postnatal day 7 (P7) Sprague-Dawley rats were divided into early administration I and II groups (administered from P7 to P14) and late administration group (administered from P14 to P21), and all the groups received intraperitoneally injected CS. The control groups for early and late administration groups were also established and treated with intraperitoneally injected normal saline of the same volume. There were 10 rats in each group. The rats in the early administration I group and early administration control group were sacrificed on P15, and those in the early administration II group, late administration group, and late administration control group were sacrificed on P22. The whole-cell patch-clamp technique was used to record inward current and action potential of PCs on cerebellar slices, as well as the long-term depression (LTD) of excitatory postsynaptic current (EPSC) in PCs induced by low-frequency stimulation of parallel fiber (PF).</p><p><b>RESULTS</b>Compared with the control groups, the early and late administration groups had a slightly higher magnitude of inward current and a slightly higher amplitude of action potential of PCs (P>0.05). All administration groups had a significantly higher degree of EPSC inhibition than the control groups (P<0.01), and the early administration II group had a significantly greater degree of EPSC inhibition than the late administration group (P<0.01).</p><p><b>CONCLUSIONS</b>Early CS exposure after birth affects the synaptic plasticity of PF-PCs in the cerebellum of young rats, which persists after drug withdrawal.</p>

Effects of Modafinil on Behavioral Learning and Hippocampal Synaptic Transmission in Rats / 대한배뇨장애요실금학회지

PURPOSE: Modafinil is a wake-promoting agent that has been proposed to improve cognitive performance at the preclinical and clinical levels. Since there is insufficient evidence for modafinil to be regarded as a cognitive enhancer, the aim of this study was to investigate the effects of chronic modafinil administration on behavioral learning in healthy adult rats. METHODS: Y-maze training was used to assess learning performance, and the whole-cell patch clamp technique was used to assess synaptic transmission in pyramidal neurons of the hippocampal CA1 region of rats. RESULTS: Intraperitoneal administration of modafinil at 200 mg/kg or 300 mg/kg significantly improved learning performance. Furthermore, perfusion with 1mM modafinil enhanced the frequency and amplitude of spontaneous postsynaptic currents and spontaneous excitatory postsynaptic currents in CA1 pyramidal neurons in hippocampal slices. However, the frequency and amplitude of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons were inhibited by treatment with 1mM modafinil. CONCLUSIONS: These results indicate that modafinil improves learning and memory in rats possibly by enhancing glutamatergic excitatory synaptic transmission and inhibiting GABAergic (gamma-aminobutyric acid-ergic) inhibitory synaptic transmission.

Inhibitory effects of propofol on excitatory synaptic transmission in supraoptic nucleus neurons in vitro / 生理学报

The present study was designed to investigate the inhibitory effects of intravenous general anesthetic propofol (0.1-3.0 mmol/L) on excitatory synaptic transmission in supraoptic nucleus (SON) neurons of rats, and to explore the underlying mechanisms by using intracellular recording technique and hypothalamic slice preparation. It was observed that stimulation of the dorsolateral region of SON could elicit the postsynaptic potentials (PSPs) in SON neurons. Of the 8 tested SON neurons, the PSPs of 7 (88%, 7/8) neurons were decreased by propofol in a concentration-dependent manner, in terms of the PSPs' amplitude (P < 0.01), area under curve, duration, half-width and 10%-90% decay time (P < 0.05). The PSPs were completely and reversibly abolished by 1.0 mmol/L propofol at 2 out of 7 tested cells. The depolarization responses induced by pressure ejection of exogenous glutamate were reversibly and concentration-dependently decreased by bath application of propofol. The PSPs and glutamate-induced responses recorded simultaneously were reversibly and concentration-dependently decreased by propofol, but 0.3 mmol/L propofol only abolished PSPs. The excitatory postsynaptic potentials (EPSPs) of 7 cells increased in the condition of picrotoxin (30 µmol/L, a GABA(A) receptor antagonist) pretreatment. On this basis, the inhibitory effects of propofol on EPSPs were decreased. These data indicate that the presynaptic and postsynaptic mechanisms may be both involved in the inhibitory effects of propofol on excitatory synaptic transmission in SON neurons. The inhibitory effects of propofol on excitatory synaptic transmission of SON neurons may be related to the activation of GABA(A) receptors, but at a high concentration, propofol may also act directly on glutamate receptors.

Propofol enhances the field excitatory postsynaptic potentials in CA1 hippocampal slices of young and aged mice / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Increasing age was shown to decrease the requirements for propfol. However, the mechanisms of ageing-induced potentiation of anesthetic actions have not been clearly explored. The aim of this study is to compare the effects of propofol on the field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices of young and aging mice.</p><p><b>METHODS</b>Brain slices were prepared from C57BL6 male young (2 months) and aging (>12 months) mice. The dendritic field excitatory postsynaptic potential was recorded from the CA1 stratum radiatum using patch clamp electrophysiological methods. A bipolar concentric stimulating electrode was placed along the Schaffer collateral for othodromic stimulation. The effects of clinically-relevant concentrations of propofol were studied in the young and ageing mouse tissues.</p><p><b>RESULTS</b>Propofol application increased the orthodromically evoked fEPSP produced in slices taken from young and older animals. A striking feature in the I/O relationship was the decreased enhancement of the fEPSPs by propofol in slices from older mice. A clinically relevant concentration of propofol, 10 µmol/L, showed more significant enhancement in amplitude and area under the curve (AUC) of fEPSP in young compared to tissues from older mice (amplitude: young (24.9 ± 3.4)%, old (4.6 ± 1.6)%; AUC young (30.6 ± 5.4)%, old (2.1 ± 1.7)%). There was no statistically significant difference between the paired-pulse facilitation (PPF) ratios calculated for the responses obtained in tissues from young mice. In slices from older mice, in the presence of 10 µmol/L propofol, PPF was decreased and returned to baseline after washout (baseline 1.21 ± 0.01, propofol: 1.16 ± 0.01). Bicuculline (15 µmol/L) blocked the enhancement of propofol on fEPSP in tissues from young and old mice.</p><p><b>CONCLUSION</b>The fEPSP of slices from aging mice demonstrates diminished sensitivity to the enhancing actions of propofol.</p>

Functional refinement of bushy cells in the anterior ventral cochlear nucleus precedes hearing onset in neonatal rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the development of the electrophysiological property of bushy cells in the anterior ventral cochlear nucleus (AVCN) of neonatal Sprague Dawley (SD) rats.</p><p><b>METHODS</b>The development of action potential and spontaneous miniature excitatory postsynaptic currents (mEPSCs) in AVCN bushy cells were investigated by whole-cell patch-clamp technique in SD rats during the postnatal days 5-21 (P5-21). The half band width of the action potential (AP), 10%-90% risetime and decay tau of the mEPSCs were analyzed.</p><p><b>RESULTS</b>The AP of the bushy cells became faster with age from P5 to P21 and stopped changing around the period of hearing onset, as evidenced by the alteration of half band width of the AP. The time accuracy of mEPSCs of the bushy cells also increased with age and stabilized around hearing onset as shown by briefer 10%-90% rise time and decay tau of mEPSCs in P14/P21 than in P7.</p><p><b>CONCLUSION</b>The functional refinement of the bushy cells in the AVCN precedes hearing onset in neonatal rats.</p>

Receptor kinetics analyses of long-term potentiation of synaptic transmission in spinal cord motoneurons in vitro / 生理学报

The aim of the present study is to observe the receptor kinetics property of long-term potentiation (LTP) of excitatory postsynaptic potential (EPSP) in spinal cord motoneurons (MNs) by descending activation. The intracellular recording techniques were conducted in spinal cord MNs of neonatal rats aged 8-14 days. The changes of EPSP induced by ipsilateral ventrolateral funiculus (iVLF) stimulation (iVLF-EPSPs) were observed, and receptor kinetics of iVLF-EPSPs were analyzed. The results showed that, the amplitude, area under curve and maximum left slope of EPSP were positively correlated with stimulus intensity (P < 0.05 or P < 0.01), while the apparent receptor kinetic parameters apparent dissociation rate constant (K(2)), apparent equilibrium dissociation constant (K(T)) of EPSP were negatively correlated with stimulus intensity (P < 0.01 or P < 0.05). The iVLF-EPSPs were persistently increased after tetanic stimulation (100 Hz, 50 pulses/train, duration 0.4-1.0 ms, 6 trains, main interval 10 s, 10-100 V) in 5 of 11 tested MNs. The amplitude of iVLF-EPSPs was potentiated to more than 120% of baseline and lasted at least 30 min, which could be referred to as iVLF-LTP. Meanwhile, the area under curve and maximum left slope of EPSPs were also increased to more than 120% of baseline. During iVLF-LTP, apparent receptor kinetics analyses of iVLF-EPSPs indicated that K(2) and KT were decreased significantly to less than 80% of the baseline within 10 min and gradually and partially recovered in 3 MNs. These results of receptor kinetics analyses of iVLF-EPSPs suggest a possible enhancement in affinity of postsynaptic receptors in the early stage of iVLF-LTP in some MNs.