Aberrant activation of hippocampal astrocytes causes neuroinflammation and cognitive decline in mice.

Reactive astrocytes are associated with neuroinflammation and cognitive decline in diverse neuropathologies; however, the underlying mechanisms are unclear. We used optogenetic and chemogenetic tools to identify the crucial roles of the hippocampal CA1 astrocytes in cognitive decline. Our results showed that repeated optogenetic stimulation of the hippocampal CA1 astrocytes induced cognitive impairment in mice and decreased synaptic long-term potentiation (LTP), which was accompanied by the appearance of inflammatory astrocytes. Mechanistic studies conducted using knockout animal models and hippocampal neuronal cultures showed that lipocalin-2 (LCN2), derived from reactive astrocytes, mediated neuroinflammation and induced cognitive impairment by decreasing the LTP through the reduction of neuronal NMDA receptors. Sustained chemogenetic stimulation of hippocampal astrocytes provided similar results. Conversely, these phenomena were attenuated by a metabolic inhibitor of astrocytes. Fiber photometry using GCaMP revealed a high level of hippocampal astrocyte activation in the neuroinflammation model. Our findings suggest that reactive astrocytes in the hippocampus are sufficient and required to induce cognitive decline through LCN2 release and synaptic modulation. This abnormal glial-neuron interaction may contribute to the pathogenesis of cognitive disturbances in neuroinflammation-associated brain conditions.

Astrocyte-derived adenosine excites sleep-promoting neurons in the ventrolateral preoptic nucleus: Astrocyte-neuron interactions in the regulation of sleep.

Although ATP and/or adenosine derived from astrocytes are known to regulate sleep, the precise mechanisms underlying the somnogenic effects of ATP and adenosine remain unclear. We selectively expressed channelrhodopsin-2 (ChR2), a light-sensitive ion channel, in astrocytes within the ventrolateral preoptic nucleus (VLPO), which is an essential brain nucleus involved in sleep promotion. We then examined the effects of photostimulation of astrocytic ChR2 on neuronal excitability using whole-cell patch-clamp recordings in two functionally distinct types of VLPO neurons: sleep-promoting GABAergic projection neurons and non-sleep-promoting local GABAergic neurons. Optogenetic stimulation of VLPO astrocytes demonstrated opposite outcomes in the two types of VLPO neurons. It led to the inhibition of non-sleep-promoting neurons and excitation of sleep-promoting neurons. These responses were attenuated by blocking of either adenosine A1 receptors or tissue-nonspecific alkaline phosphatase (TNAP). In contrast, exogenous adenosine decreased the excitability of both VLPO neuron populations. Moreover, TNAP was expressed in galanin-negative VLPO neurons, but not in galanin-positive sleep-promoting projection neurons. Taken together, these results suggest that astrocyte-derived ATP is converted into adenosine by TNAP in non-sleep-promoting neurons. In turn, adenosine decreases the excitability of local GABAergic neurons, thereby increasing the excitability of sleep-promoting GABAergic projection neurons. We propose a novel mechanism involving astrocyte-neuron interactions in sleep regulation, wherein endogenous adenosine derived from astrocytes excites sleep-promoting VLPO neurons, and thus decreases neuronal excitability in arousal-related areas of the brain.

Economic Impact of Donating a Kidney on Living Donors: A Korean Cohort Study.

RATIONALE & OBJECTIVE: Although existing studies have reported adverse health outcomes after kidney donation, its socioeconomic impact on living donors requires further study. STUDY DESIGN: A retrospective observational cohort study including a matched comparison group. SETTING & PARTICIPANTS: 1,285 living kidney donors from 7 tertiary hospitals between 2003 and 2016, and a matched comparison group consisting of the same number of health screening examinees with similar baseline clinical characteristics and socioeconomic status. All participants were receiving Korean national health insurance. EXPOSURE: Kidney donation as reflected in the Korean National Health Insurance System (NHIS) database. OUTCOME: Changes in household economic status estimated by Korean national health insurance fees and changes in employment status reflected in the NHIS database. ANALYTICAL APPROACH: The outcomes of the donor group and matched control group were compared annually using multivariable logistic regression analyses adjusted for clinical and demographic characteristics. RESULTS: The median ages of the donors and matched controls were 45 and 46 years, respectively; 44.6% of both groups were male. Compared to the comparison group, living donors were at higher risk of being unemployed or losing employment during the first 2 years after donation (eg, first-year loss of employment: odds ratio (OR), 2.27 [95% CI, 1.55-3.33]); however, this association did not persist. Donors also had a significantly lower odds of improvement in economic status (OR, 0.57 [95% CI, 0.47-0.71]) and a higher odds of deterioration in financial status (OR, 1.54 [95% CI, 1.23-1.93]) in the first year after transplantation and subsequently. LIMITATIONS: Unmeasured differences between donors and matched controls creating residual selection bias and confounding. CONCLUSIONS: Living kidney donors may suffer loss of employment and poor economic status after their voluntary donation. The socioeconomic impact on these donors should be considered in conjunction with the potential long-term adverse health outcomes after donation.

Periodontal ligament preloading and rapid prototyping of the donor tooth in the autotransplantation of premolars with complete root formation.

This case report describes the successful orthodontic treatment of an 11-year-old girl with skeletal Class II malocclusion and congenitally missing mandibular second premolars. To resolve her upper lip protrusion and restore the missing mandibular premolars, extraction of the maxillary first premolars and subsequent autotransplantation of the extracted premolars onto the site of the missing mandibular second premolars were performed. To ensure the success of the autotransplantation and subsequent orthodontic treatment, an orthodontic force was preapplied on the donor teeth, and the recipient sockets were prepared with the aid of replica teeth. Thereafter, comprehensive orthodontic treatment was performed to close the extraction space in the maxilla and align the mandibular dentition, including the transplants. The patient achieved a functional occlusion with an improved facial profile. Results of the orthodontic treatment and autotransplantation were stable during the 5-year follow-up. On the basis of this report, a management protocol for a biomechanically enhanced autotransplantation procedure was suggested. This approach would enable an effective treatment procedure, thereby increasing the usefulness of autotransplantation.

Astrocytes in the Ventrolateral Preoptic Area Promote Sleep.

Although ventrolateral preoptic (VLPO) nucleus is regarded as a center for sleep promotion, the exact mechanisms underlying the sleep regulation are unknown. Here, we used optogenetic tools to identify the key roles of VLPO astrocytes in sleep promotion. Optogenetic stimulation of VLPO astrocytes increased sleep duration in the active phase in naturally sleep-waking adult male rats (n = 6); it also increased the extracellular ATP concentration (n = 3) and c-Fos expression (n = 3-4) in neurons within the VLPO. In vivo microdialysis analyses revealed an increase in the activity of VLPO astrocytes and ATP levels during sleep states (n = 4). Moreover, metabolic inhibition of VLPO astrocytes reduced ATP levels (n = 4) and diminished sleep duration (n = 4). We further show that tissue-nonspecific alkaline phosphatase (TNAP), an ATP-degrading enzyme, plays a key role in mediating the somnogenic effects of ATP released from astrocytes (n = 5). An appropriate sample size for all experiments was based on statistical power calculations. Our results, taken together, indicate that astrocyte-derived ATP may be hydrolyzed into adenosine by TNAP, which may in turn act on VLPO neurons to promote sleep.SIGNIFICANCE STATEMENT Glia have recently been at the forefront of neuroscience research. Emerging evidence illustrates that astrocytes, the most abundant glial cell type, are the functional determinants for fates of neurons and other glial cells in the central nervous system. In this study, we newly identified the pivotal role of hypothalamic ventrolateral preoptic (VLPO) astrocytes in the sleep regulation, and provide novel insights into the mechanisms underlying the astrocyte-mediated sleep regulation.

Is Primary Androgen Deprivation Therapy a Suitable Option for Asian Patients With Prostate Cancer Compared With Radical Prostatectomy?

BACKGROUND: We conducted a comparative survival analysis between primary androgen deprivation therapy (PADT) and radical prostatectomy (RP) based on nationwide Korean population data that included all patients with prostate cancer. MATERIALS AND METHODS: This study enrolled 4,538 patients with prostate cancer from the National Health Insurance Service (NHIS) database linked with Korean Central Cancer Registry data who were treated with PADT or RP between January 1, 2007, and December 31, 2014. Kaplan-Meier and multivariate survival analyses stratified by stage (localized and locally advanced) and age (<75 and ≥75 years) were performed using a Cox proportional hazards model to evaluate treatment effects. RESULTS: Among 18,403 patients from the NHIS database diagnosed with prostate cancer during the study period, 4,538 satisfied inclusion criteria and were included in the analyses. Of these, 3,136 and 1,402 patients underwent RP or received PADT, respectively. Risk of death was significantly increased for patients who received PADT compared with those who underwent RP in the propensity score-matched cohort. In subgroup analyses stratified by stage and age, in every subgroup, patients who received PADT had a significantly increased risk of death compared with those who underwent RP. In particular, a much greater risk was observed for patients with locally advanced prostate cancer. CONCLUSIONS: Based on a nationwide survival analysis of nonmetastatic prostate cancer, this study provides valuable clinical implications that favor RP over PDAT for treatment of Asian populations. However, the possibility that survival differences have been overestimated due to not accounting for potential confounding characteristics must be considered.

Effects of acidic pH on voltage-gated ion channels in rat trigeminal mesencephalic nucleus neurons.

The effects of acidic pH on several voltage-dependent ion channels, such as voltage-dependent K+ and Ca2+ channels, and hyperpolarization-gated and cyclic nucleotide-activated cation (HCN) channels, were examined using a whole-cell patch clamp technique on mechanically isolated rat mesencephalic trigeminal nucleus neurons. The application of a pH 6.5 solution had no effect on the peak amplitude of voltage-dependent K+ currents. A pH 6.0 solution slightly, but significantly inhibited the peak amplitude of voltage-dependent K+ currents. The pH 6.0 also shifted both the current-voltage and conductance-voltage relationships to the depolarization range. The application of a pH 6.5 solution scarcely affected the peak amplitude of membrane currents mediated by HCN channels, which were profoundly inhibited by the general HCN channel blocker Cs+ (1 mM). However, the pH 6.0 solution slightly, but significantly inhibited the peak amplitude of HCN-mediated currents. Although the pH 6.0 solution showed complex modulation of the current-voltage and conductance-voltage relationships, the midpoint voltages for the activation of HCN channels were not changed by acidic pH. On the other hand, voltage-dependent Ca2+ channels were significantly inhibited by an acidic pH. The application of an acidic pH solution significantly shifted the current-voltage and conductance-voltage relationships to the depolarization range. The modulation of several voltage-dependent ion channels by an acidic pH might affect the excitability of mesencephalic trigeminal nucleus neurons, and thus physiological functions mediated by the mesencephalic trigeminal nucleus could be affected in acidic pH conditions.

TRPA1-like channels enhance glycinergic transmission in medullary dorsal horn neurons.

The effect of icilin, a potent agonist of transient receptor potential ankyrin 1 (TRPA1) and TRPM8, on glycinergic transmission was examined in mechanically isolated rat medullary dorsal horn neurons by use of the conventional whole-cell patch-clamp technique. Icilin increased the frequency of glycinergic spontaneous miniature inhibitory post-synaptic currents (mIPSCs) in a dose-dependent manner. Either allyl isothiocyanate(AITC) or cinnamaldehyde, other TRPA1 agonists, also increased mIPSC frequency, but the extent of facilitation induced by AITC or cinnamaldehyde was less than that induced by icilin. However, menthol, a TRPM8 agonist, had no facilitatory effect on glycinergic mIPSCs. The icilin-induced increase in mIPSC frequency was significantly inhibited by either HC030031, a selective TRPA1 antagonist, or ruthenium red, a non-selective transient receptor potential channel blocker. Icilin failed to increase glycinergic mIPSC frequency in the absence of extracellular Ca(2+), suggesting that the icilin-induced increase in mIPSC frequency is mediated by the Ca(2+) influx from the extracellular space. In contrast, icilin still increased mIPSC frequency either in the Na(+) -free external solution or in the presence of Cd(2+), a general voltage-dependent Ca(2+) channel blocker. The present results suggest that icilin acts on pre-synaptic TRPA1-like ion channels, which are permeable to Ca(2+), to enhance glycinergic transmission onto medullary dorsal horn neurons. The TRPA1-like channel-mediated enhancement of glycinergic transmission in medullary dorsal horn neurons would contribute to the regulation of pain information from the peripheral tissues.

Perception regarding live kidney donation in the general population of South Korea.

This study aimed to know how the general population recognizes live kidney donation in Korea. Participants were randomly selected from the general population after proportional allocation by region, sex, and age. Selected participants received a questionnaire that included demographic information, socioeconomic and marital statuses, prior recognition of live donor kidney transplantation, expected changes after donation, and the need for support after donor nephrectomy. Among the 1,000 participants from the web-based survey, 83.8% answered they fully understood living donor kidney transplantation, 81.1% knew about them, and 51.1% were willing to donate. Various complications after nephrectomy and deterioration in health after donation were the most significant reasons for those reluctant to donate. Most agreed that the government should provide social and economic support to living kidney donors, especially after exposure to the description of donor nephrectomy. Financial support, including surgery and regular medical check-up costs, was the most preferred government support. The Korean general population seemed aware of the value and safety of kidney donation, although only half of them were willing to donate due to concerns about possible complications. Most participants agreed on social and economic support for living kidney donors, especially surgery-related costs.

Long-term risk of all-cause mortality in live kidney donors: a matched cohort study.

BACKGROUND: Long-term outcomes of live kidney donors remain controversial, although this information is crucial for selecting potential donors. Thus, this study compared the long-term risk of all-cause mortality between live kidney donors and healthy control. METHODS: We performed a retrospective cohort study including donors from seven tertiary hospitals in South Korea. Persons who underwent voluntary health screening were included as controls. We created a matched control group considering age, sex, era, body mass index, baseline hypertension, diabetes, estimated glomerular filtration rate, and dipstick albuminuria. The study outcome was progression to end-stage kidney disease (ESKD), and all-cause mortality as identified in the linked claims database. RESULTS: We screened 1,878 kidney donors and 78,115 health screening examinees from 2003 to 2016. After matching, 1,701 persons remained in each group. The median age of the matched study subjects was 44 years, and 46.6% were male. Among the study subjects, 2.7% and 16.6% had underlying diabetes and hypertension, respectively. There were no ESKD events in the matched donor and control groups. There were 24 (1.4%) and 12 mortality cases (0.7%) in the matched donor and control groups, respectively. In the age-sex adjusted model, the risk for all-cause mortality was significantly higher in the donor group than in the control group. However, the significance was not retained after socioeconomic status was included as a covariate (adjusted hazard ratio, 1.82; 95% confidence interval, 0.87-3.80). CONCLUSION: All-cause mortality was similar in live kidney donors and matched non-donor healthy controls with similar health status and socioeconomic status in the Korean population.

Menthol facilitates excitatory and inhibitory synaptic transmission in rat medullary dorsal horn neurons.

Menthol, which acts as an agonist for transient receptor potential melastatin 8 (TRPM8), has complex effects on nociceptive transmission, including pain relief and hyperalgesia. Here, we addressed the effects of menthol on spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs, respectively) in medullary dorsal horn neurons, using a whole-cell patch-clamp technique. Menthol significantly increased sEPSC frequency, in a concentration-dependent manner, without affecting current amplitudes. The menthol-induced increase in sEPSC frequency could be completely blocked by AMTB, a TRPM8 antagonist, but was not blocked by HC-030031, a transient receptor potential ankyrin 1 (TRPA1) antagonist. Menthol still increased sEPSC frequency in the presence of Cd2+, a general voltage-gated Ca2+ channel blocker, suggesting that voltage-gated Ca2+ channels are not involved in the menthol-induced increase in sEPSC frequency. However, menthol failed to increase sEPSC frequency in the absence of extracellular Ca2+, suggesting that TRPM8 on primary afferent terminals is Ca2+ permeable. On the other hand, menthol also increased sIPSC frequency, without affecting current amplitudes. The menthol-induced increase in sIPSC frequency could be completely blocked by either AMTB or CNQX, an AMPA/KA receptor antagonist, suggesting that the indirect increase in excitability of inhibitory interneurons may lead to the facilitation of spontaneous GABA and/or glycine release. The present results suggested that menthol exerts analgesic effects, via the enhancement of inhibitory synaptic transmission, through central feed-forward neural circuits within the medullary dorsal horn region.

Do Cardiac Rehabilitation Affect Clinical Prognoses Such as Recurrence, Readmission, Revascularization, and Mortality After AMI?: Systematic Review and Meta-Analysis.

OBJECTIVE: We conducted a systematic review and meta-analysis to analyze the effects of cardiac rehabilitation (CR) on post-discharge prognoses of patients with acute myocardial infarction (AMI). METHODS: A literature search was conducted through four international medical and two Korean databases. Primary outcomes for the effectiveness of CR included all-cause mortality, cardiovascular mortality, recurrence, revascularization, major adverse cardiovascular event, major adverse cardiocerebrovascular event, and readmission. We summarized and analyzed results of studies about CR for AMI, including not only randomized controlled trials (RCTs) but also non-RCTs. We calculated the effect size separately by the study type. RESULTS: Fourteen articles were finally selected. Of these, two articles were RCTs, while 12 were non-RCTs. In RCTs, the overall mortality rate was lower in the group that participated in CR than that in the conventional care group by 28% (relative risk=0.72; 95% confidence interval, 0.34-1.57). Among non-RCTs, CR participation significantly decreased the overall risk of mortality. Moreover, the rates of recurrence and major adverse cardiovascular events were lower in the group that participated in CR compared to those in the non-CR group. CONCLUSION: The meta-analysis shows that CR reduces the risk of re-hospitalization and all-cause mortality after AMI, compared to no participation in CR. This outcome was seen in RCTs as well as in non-RCTs. More studies are necessary for concrete conclusions about the beneficial effects of CR after AMI in various settings.

Metabolic risks in living kidney donors in South Korea.

BACKGROUND: Considering the growing prevalence of Western lifestyles and related chronic diseases occurring in South Korea, this study aimed to explore the progression of metabolic risk factors in living kidney donors. METHODS: This study enrolled living kidney donors from seven hospitals from 1982 to 2016. The controls were individuals that voluntarily received health check-ups from 1995 to 2016 that were matched with donors according to age, sex, diabetes status, baseline estimated glomerular filtration rate, and date of the medical record. Data on hyperuricemia, hypertension, hypercholesterolemia, and overweight/obesity were collected to determine metabolic risks. Logistic regressions with interaction terms between the medical record date and donor status were used to compare the trends in metabolic risks over time in the two groups. RESULTS: A total of 2,018 living kidney donors and matched non-donors were included. The median age was 44.0 years and 54.0% were women. The living kidney donors showed a lower absolute prevalence for all metabolic risk factors, except for those that were overweight/obese, than the non-donors. The proportion of subjects that were overweight/obese was consistently higher over time in the donor group. The changes over time in the prevalence of each metabolic risk were not significantly different between groups, except for a lower prevalence of metabolic risk factors ≥ 3 in donors. CONCLUSION: Over time, metabolic risks in living kidney donors are generally the same as in non-donors, except for a lower prevalence of metabolic risk factors ≥3 in donors.

Dopamine inhibition of glycine release in the rat trigeminal nucleus pars caudalis: possible involvement of trace amine receptors.

Dopamine (DA)-induced pre-synaptic inhibition of glycinergic transmission was studied from substantia gelatinosa (SG) neurons of the trigeminal nucleus pars caudalis using a conventional whole-cell patch clamp technique. The action potential-dependent glycinergic inhibitory post-synaptic currents (IPSCs) were recorded from SG neurons in the presence of 3 mM kynurenic acid and 10 µM 6-imino-3-(4-methoxyphenyl)-1(6H)-pyridazinebutanoic acid HBr (SR95531). In these conditions, bath applied DA (100 µM) reduced the amplitude of glycinergic IPSCs and increased the paired-pulse ratio, suggesting that DA acts pre-synaptically to reduce the probability of glycine release. However, the inhibitory action of DA on glycinergic IPSCs was not blocked by SCH23390 (10 µM) and spiperone (1 µM), selective D(1) - and D(2) -like receptor antagonists, respectively. In addition, either SKF38393 (100 µM), a selective D(1) -like receptor agonist, or quinpirole (100 µM), a selective D(2) -like receptor agonist, had no pre-synaptic effect on glycinergic IPSCs. The results suggest that both D(1) - and D(2) -like receptors are not involved in the DA-induced decrease in glycinergic IPSCs. On the other hand, tyramine (100 µM), one of representative trace amines, reduced the amplitude of glycinergic IPSCs and increased the paired-pulse ratio, suggesting that tyramine acts pre-synaptically to reduce the probability of glycine release. Considering that DA can activate trace amine (TA) receptors and that TA receptors are exclusively expressed on the trigeminal nucleus pars caudalis, DA might act on putative pre-synaptic TA receptors, rather than classical DA receptors, to inhibit glycinergic transmission onto SG neurons of the trigeminal nucleus pars caudalis.

Compound K, a metabolite of ginsenosides, facilitates spontaneous GABA release onto CA3 pyramidal neurons.

Ginsenoside Rb1, a major ingredient of ginseng saponins, can affect various brain functions, including learning and memory. When ingested orally, ginsenoside Rb1 is not found in plasma as well as urine, but its metabolite compound K (ComK) reaches the systemic circulation in animals and human. Nevertheless, the pharmacological actions of ComK are still poorly known. In the present study, we investigated the effect of ComK on GABAergic spontaneous miniature inhibitory post-synaptic currents (mIPSCs) in acutely isolated rat hippocampal CA3 pyramidal neurons using a conventional whole-cell patch-clamp technique. While ComK significantly increased mIPSC frequency in a concentration-dependent manner, it had no effect on the current amplitude, suggesting that ComK acts pre-synaptically to increase the probability of spontaneous GABA release. ComK still increased mIPSC frequency even in a Ca(2+) -free external solution, suggesting that the ComK-induced increase spontaneous GABA release is not related to Ca(2+) influx from the extracellular space. However, the ComK-induced increase mIPSC frequency was significantly decreased after the blockade of either sarcoplasmic/endoplasmic reticulum Ca(2+) -ATPase or Ca(2+) release channels. These results strongly suggest that ComK enhances spontaneous GABA release by increasing intraterminal Ca(2+) concentration via Ca(2+) release from pre-synaptic Ca(2+) stores. The ComK-induced modulation of inhibitory transmission onto CA3 pyramidal neurons could have a broad impact on the excitability of CA3 pyramidal neurons and affect the physiological functions mediated by the hippocampus.

Cardiac rehabilitation and 5-year mortality after acute myocardial infarction. Report from 11 tertiary hospitals in Korea (ETHIK Study).

BACKGROUND: The participation rate for cardiac rehabilitation (CR) remains low in some Europe and Asia including Korea. AIM: To investigate effects of CR on prognosis improvements in terms of recurrence, readmission, revascularization, and mortality rates in patients with acute myocardial infarction (AMI) in Korea. DESIGN: A retrospective cohort study. SETTING: Eleven Tertiary Hospitals In Korea (ETHIK Study). POPULATION: Data from a total of 7299 patients between January 2012 and December 2015 were collected, of which data from 7136 patients were linked to insurance claims data. In the final analysis, 6743 patients were included. METHODS: Patients who participated in the CR program while receiving outpatient treatment were classified into CR group. Those who did not participate in CR programs were classified into the non-CR group. RESULTS: Kaplan-Meier survival analyses showed five-year survival rate of 96.9% in the CR group and 93.3% in the non-CR group. The hazard ratio (HR) for total 5-year mortality in the CR group was approximately 0.41 (95% CI: 0.27-0.63) times that of the non-CR group, indicating a reduction in the risk of mortality by approximately 59% in propensity score weighted cohort of 1878 patients. The HR for major adverse cardiac events (MACE) with respect to 5-year mortality, MI recurrence, revascularization, and readmission due to cardiovascular disease in CR group was 0.96 times that of non-CR group (95% CI: 0.83-1.12), without significant difference between the two groups. CONCLUSIONS: In this study, 5-year mortality decreased by 59% in patients with AMI who had participated in CR compared to those who did not. CLINICAL REHABILITATION IMPACT: This finding should be very helpful in emphasizing the need for CR in a country like Korea where CR has not yet been actively implemented.

Presynaptic glycine receptors facilitate spontaneous glutamate release onto hilar neurons in the rat hippocampus.

Although glycine receptors are found in most areas of the brain, including the hippocampus, their functional significance remains largely unknown. In the present study, we have investigated the role of presynaptic glycine receptors on excitatory nerve terminals in spontaneous glutamatergic transmission. Spontaneous EPSCs (sEPSCs) were recorded in mechanically dissociated rat dentate hilar neurons attached with native presynaptic nerve terminals using a conventional whole-cell patch recording technique under voltage-clamp conditions. Exogenously applied glycine or taurine significantly increased the frequency of sEPSCs in a concentration-dependent manner. This facilitatory effect of glycine was blocked by 1 microM strychnine, a specific glycine receptor antagonist, but was not affected by 30 microM picrotoxin. In addition, Zn(2+) (10 microM) potentiated the glycine action on sEPSC frequency. Pharmacological data suggested that the activation of presynaptic glycine receptors directly depolarizes glutamatergic terminals resulting in the facilitation of spontaneous glutamate release. Bumetanide (10 microM), a specific Na-K-2C co-transporter blocker, gradually attenuated the glycine-induced sEPSC facilitation, suggesting that the depolarizing action of presynaptic glycine receptors was due to a higher intraterminal Cl(-) concentration. The present results suggest that presynaptic glycine receptors on excitatory nerve terminals might play an important role in the excitability of the dentate gyrus-hilus-CA3 network in physiological and/or pathological conditions.

Cyclic AMP-mediated long-term facilitation of glycinergic transmission in developing spinal dorsal horn neurons.

cAMP is known to regulate neurotransmitter release via protein kinase A (PKA)-dependent and/or PKA-independent signal transduction pathways at a variety of central synapses. Here we report the cAMP-mediated long-lasting enhancement of glycinergic transmission in developing rat spinal substantia gelatinosa neurons. Forskolin, an adenylyl cyclase activator, elicited a long-lasting increase in the amplitude of nerve-evoked glycinergic inhibitory postsynaptic currents (IPSCs), accompanied by a long-lasting decrease in the paired-pulse ratio in immature substantia gelatinosa neurons, and this forskolin-induced increase in glycinergic IPSCs decreased with postnatal development. Forskolin also decreased the failure rate of glycinergic IPSCs evoked by minimal stimulation, and increased the frequency of glycinergic miniature IPSCs. All of these data suggest that forskolin induces the long-lasting enhancement of glycinergic transmission by increasing in the presynaptic release probability. This pre-synaptic action of forskolin was mediated by hyperpolarization and cyclic nucleotide-activated cation channels and an increase in intraterminal Ca(2+) concentration but independent of PKA. The present results suggest that cAMP-dependent signal transduction pathways represent a dynamic mechanism by which glycinergic IPSCs could potentially be modulated during postnatal development.

Differential pharmacological properties of GABAA receptors in axon terminals and soma of dentate gyrus granule cells.

Although it has been well established that GABA(A) receptors are molecular targets of a variety of allosteric modulators, such as benzodiazepines, the pharmacological properties of presynaptic GABA(A) receptors are poorly understood. In this study, the effects of diazepam and Zn(2+) on presynaptic GABA(A) receptors have been investigated by measuring the GABA(A) receptor-mediated facilitation of spontaneous glutamate release in mechanically dissociated rat CA3 pyramidal neurons. Diazepam significantly enhanced the muscimol-induced facilitation (particularly at submicromolar concentrations) of spontaneous glutamate release and shifted the concentration-response relationship for muscimol toward the left, whereas Zn(2+) (