Controlling nutritional status (CONUT) score-based nomogram to predict overall survival of patients with HBV-associated hepatocellular carcinoma after curative hepatectomy.

PURPOSE: As a novel immune-nutritional biomarker, the controlling nutritional status (CONUT) score has been reported to predict outcomes in cancer patients. We aimed to elucidate the prognostic value of preoperative CONUT score and construct a CONUT score-based nomogram to predict individual survival of patients with hepatitis B viral (HBV)-associated hepatocellular carcinoma (HCC) after curative hepatectomy. METHODS: Preoperative CONUT score was retrospectively calculated in 380 HBV-associated HCC patients undergoing radical resection between 2006 and 2012. Patients were assigned to two groups: CONUT-low ( < 2) and CONUT-high ( ≥ 2), according to the optimal cut-off value determined using receiver operating characteristic analysis. Associations of CONUT score with oncological outcomes were evaluated. The Cox proportional hazard model was used to identify predictors of survival and a new nomogram was developed based on the independent prognostic factors for overall survival (OS). RESULTS: The CONUT score exhibited a higher area under the curve value than the other immune-nutritional parameters. The CONUT-high group had significant poorer OS and recurrence-free survival compared with CONUT-low group (P < 0.001 and P = 0.016, respectively). Multivariate analyses identified CONUT score, liver cirrhosis, tumor size and differentiation as independent prognostic factors for OS. And the nomogram based on these four variables had superior discriminative ability to predict survival compared with other conventional staging systems. CONCLUSIONS: Preoperative CONUT score is an effective independent predictor of OS in patients with resected HBV-related HCC. This novel nomogram based on CONUT may provide accurate and individualized survival prediction for HCC patients undergoing surgical resection.

Prognostic significance of preoperative albumin-to-globulin ratio in patients with cholangiocarcinoma.

BACKGROUND: This study aimed to assess the prognostic value of the serum albumin to globulin ratio (AGR) in cholangiocarcinoma patients after surgery. METHODS: We retrospectively enrolled 123 cholangiocarcinoma patients who underwent surgical treatment between June 2003 and September2014 at the Third Affiliated Hospital of Sun Yat-sen University. Univariate and multivariate analyses using the Cox regression model were performed to determine the prognostic value of AGR. RESULTS: Univariate analysis suggested that AGR was a predictive factor for (overall survival) OS but not for recurrence free survival (RFS). After adjustment for other risk factors, multivariate analysis showed that AGR remained independently associated with OS. The optimal cut-off point for AGR was determined to be 1.44. Kaplan-Meier curves showed that there was a significantly lower mean survival time in the low AGR group compared to the high AGR group. A low AGR was found to be significantly associated with high alkaline phosphatase, gamma-glutamyl transpeptidase, total bilirubin levels and an advanced American Joint Committee on Cancer TNM stage, but a low hemoglobin level. CONCLUSION: In summary, patients with higher AGRs have better outcomes than those with lower AGRs. Preoperative AGR can be a reliable marker for evaluating the prognosis of cholangiocarcinoma patients.

Developmental exposure to lead causes inherent changes on voltage-gated sodium channels in rat hippocampal CA1 neurons.

In this study, the effects of chronic lead (Pb(2+)) exposure, during day 0 of gestation (E0) to postnatal day 15 (P15), on voltage-gated sodium channel currents (I(Na)) were investigated in CA1 field of the hippocampus (CA1) neurons using the conventional whole-cell patch-clamp technique on rat hippocampal slices. We found that developmental lead exposure increased the activation threshold and the voltage at which the maximum I(Na) current was evoked, caused positive shifts of I(Na) steady-state activation curve, and enlarged I(Na) tail-currents; Pb(2+) delayed the activation of I(Na) in a voltage-dependent manner, prolonged the time course of the fast inactivation of sodium channels; Pb(2+) induced a right shift of the steady-state inactivation curve, accelerated the activity-dependent attenuation of I(Na), but made no significant effects on the time course of the recovery of I(Na) from inactivation and the fraction of inactivated channels. In addition, the co-treatment with alpha-tocopherol (VE), an effective antioxidant and free radical scavenger, completely prevented the aforementioned changes on I(Na). The alterations on I(Na) properties induced by developmental lead exposure were partly different from that in previous acute experiments under the conditions closer to physiological situation, and the process was considered related to the participating of lead in lipid peroxidation reaction, which has been reported to change the conformation and biophysical functions of membrane proteins.

Clioquinol and vitamin B12 (cobalamin) synergistically rescue the lead-induced impairments of synaptic plasticity in hippocampal dentate gyrus area of the anesthetized rats in vivo.

Lead (Pb(2+)) exposure in development induces impairments of synaptic plasticity in the hippocampal dentate gyrus (DG) area of the anesthetized rats in vivo. The common chelating agents have many adverse effects and are incapable of alleviating lead-induced neurotoxicity. Recently, CQ, clioquinol (5-chloro-7-iodo-8-hydroxy-quinoline), which is a transition metal ion chelator and/or ionophore with low affinity for metal ions, has yielded some promising results in animal models and clinical trials related to dysfunctions of metal ions. In addition, CQ-associated side effects are believed to be overcome with vitamin B12 (VB12) supplementation. To determine whether CQ treatment could rescue impairments of synaptic plasticity induced by chronic Pb(2+) exposure, we investigated the input/output functions (I/Os), paired-pulse reactions (PPRs) and long-term potentiation (LTP) of different treatment groups in hippocampal DG area of the anesthetized rat in vivo by recording field potentials and measured hippocampal Pb(2+) concentrations of different treatment groups by PlasmaQuad 3 inductive coupled plasma mass spectroscopy. The results show: CQ alone does not rescue the lead-induced impairments of synaptic plasticity in hippocampal DG area of the anesthetized rats in vivo; VB12 alone partly rescues the lead-induced impairments of LTP; however the co-administration of CQ and VB12 totally rescues these impairments of synaptic plasticity and moreover, the effects of CQ and VB12 co-administration are specific to the lead-exposed animals.

Lead inhibited N-methyl-D-aspartate receptor-independent long-term potentiation involved ryanodine-sensitive calcium stores in rat hippocampal area CA1.

Lead exposure is known to be associated with cognitive dysfunction in children. Impairment of the induction of long-term potentiation (LTP) has been reported in area CA1 of rat hippocampus following lead exposure in vivo and in vitro. The present study was carried out to investigate whether the alterations of N-methyl-d-aspartate (NMDA) receptor-independent LTP following lead exposure involve internal calcium stores in hippocampus CA1 synapses. Monosynaptic field excitatory postsynaptic potentials in hippocampal slice area CA1 were recorded using the whole-cell patch-clamp upon acute lead treatment, and these studies were coupled with calcium imaging experiments to observe internal calcium changes in cultured hippocampal neurons. Inhibiting calcium release by ryanodine significantly reduced NMDA receptor-independent LTP, and depletion of internal calcium stores with thapsigargin blocked this form of LTP. Caffeine, an agonist of ryanodine receptors, enhanced this form of LTP. However, caffeine-enhanced NMDA receptor-independent LTP was depressed after bath application of lead. Moreover, lead further decreased ryanodine- and thapsigargin-reduced NMDA receptor-independent LTP. Calcium imaging also confirmed that lead had an effect on internal calcium release and uptake. Taken together, these results demonstrated that lead inhibited NMDA receptor-independent LTP by action on calcium release and uptake by ryanodine-sensitive stores in rat hippocampal area CA1.

Protection by a taurine supplemented diet from lead-induced deficits of long-term potentiation/depotentiation in dentate gyrus of rats in vivo.

Previous studies have demonstrated that synaptic plasticity, which includes long-term potentiation (LTP) and depotentiation (DP) in hippocampus, is important for learning and memory. The purpose of this study is to evaluate the effect of taurine via drinking water on the lead-induced impairments of LTP and DP in rat dentate gyrus (DG) in vivo. The experiments were carried out in four groups of rats (control, lead-exposed, control and lead-exposed with a taurine-supplement diet, respectively). The input-output (I/O) function, excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude were measured in the DG area of adult rats (60-90 days) in response to stimulation applied to the lateral perforant path. The results show that: 1. chronic lead exposure impaired LTP/DP measured on both EPSP slope and PS amplitude in DG area of the hippocampus; 2. in control rats, taurine had no effect on LTP/DP; 3. the amplitudes of LTP/DP of lead-exposed group were significantly increased by applying taurine. These results suggest that dietary taurine supplement could protect rats from the lead-induced impairments of synaptic plasticity and might be a preventive medicine to cure the cognitive deficits induced by lead.

Effects of lead on voltage-gated sodium channels in rat hippocampal CA1 neurons.

In this study, the effects of lead (Pb2+) on voltage-gated sodium channel currents (INa) were investigated in acutely dissociated rat hippocampal CA1 neurons using the conventional whole-cell patch-clamp technique. We found that Pb2+ reduced the amplitudes of INa in a concentration-dependent manner, and the effect could be washed out by extracellular application of 3 mM EGTA. The results also showed that at the concentration of 100 microM, Pb2+ decreased the activation threshold and the voltage at which the maximum INa current was evoked and caused negative shifts of INa steady-state activation curve, and enlarged INa tail-currents; Pb2+ induces a left shift of the steady-state inactivation curve, and delayed the recovery of INa from inactivation, and reduced the fraction of available sodium channels; Pb2+ delayed the activation of INa in a concentration- and voltage-dependent manner, and prolonged the time course of the fast inactivation of sodium channels; activity-dependent attenuation of INa was not altered by Pb2+. It was suggested that Pb2+ might exert its effects on sodium channels by binding a specific site on the extracellular side of sodium channels and dragging the IIS4 voltage sensor outwardly. The interaction of Pb2+ with voltage-dependent sodium channels may lead to change in electrical activity and contribute to worsen the neurotoxicological damage.

Effects of chronic lead exposure on 1H MRS of hippocampus and frontal lobes in children.

The authors performed IQ testing and magnetic resonance spectroscopy on six lead-exposed and six control children. Levels of N-acetyl aspartate (neuronal density and mitochondrial metabolism), creatine + phosphocreatine (phosphate metabolism), and choline (membrane turnover) were decreased in four brain regions (left and right frontal, left and right hippocampus) in lead-exposed children vs controls. The reductions were right frontal > left frontal > hippocampus but were the same bilaterally in the hippocampus.

The influence of developmental period of aluminum exposure on synaptic plasticity in the adult rat dentate gyrus in vivo.

Previous studies from our group have demonstrated that chronic aluminum exposure from parturition throughout life impairs both long-term potentiation (LTP) and long-term depression (LTD) of the excitatory postsynaptic potential (EPSP) slope and reduces the population spike (PS) amplitude in the rat dentate gyrus in vivo. The present study sought to extend these findings by evaluating the developmental periods critical for aluminum-induced impairment of synaptic plasticity. Rats were exposed to aluminum (gestational, lactational and postlactational) through drinking 0.3% aluminum chloride in water over different developmental intervals: (1) prenatal exposure; (2) beginning from birth and terminating at weaning; (3) beginning at weaning throughout life; (4) beginning at birth and continuing throughout life. As adults (postnatal day 80-100), field potentials were measured in the dentate gyrus of hippocampus in response to stimulation applied to the lateral perforant path. The results showed: (1) Prenatal aluminum exposure had no effect on the magnitude of LTP as measured by the EPSP slope and LTD as measured for the PS amplitude, while it had a small effect on the magnitude of LTP as measured for the PS amplitude and LTD as measured by the EPSP slope. (2) Lactational, postlactational and throughout life exposure to aluminum impaired both LTP and LTD of the EPSP slope and PS amplitude, except that LTD of PS amplitude was not significantly changed in animals postlactationally exposed. (3) Aluminum exposure from parturition throughout life caused the greatest impairment of the range of synaptic plasticity, while prenatal aluminum exposure caused the least. From these results we conclude that the lactational period was the most susceptible to aluminum-induced impairment of synaptic plasticity and that chronic aluminum exposure from parturition throughout life is extremely disruptive to synaptic plasticity and should be avoided.

Three electrophysiological phenotypes of cultured human umbilical vein endothelial cells.

The conventional whole cell patch-clamp technique was used to measure the resting membrane conductance and membrane currents of nonstimulated cultured human umbilical vein endothelial cells (HUVECs) in different ionic conditions. Three electrophysiological phenotypes of cultured HUVECs (n = 122) were determined: first, 20% of cells as type I mainly displaying the inwardly rectifying potassium current (IKi); second, 38% of cells as type II in which IKi was super-posed on a TEA-sensitive, delayed rectifying current; third, 27% of cells as type III predominantly displaying the outwardly rectifying current which was sensitive to TEA and slightly inhibited by a chloride channel blocker niflumic acid (N.A.). In cells of type I, the mean zero-current potential (V0) was dependent on extracellular K+ ([K+]o) but not on Cl-, indicating major permeability to K+. Whereas V0 of type II was also affected by extracellular Cl- ([Cl-]o), indicating the contribution of an outward Cl- current in setting V0. The cells of type III were not sensitive to decrease of [Cl-]o and the outward current was activated in a relative stable voltage range. This varying phenotypic expression and multipotential behavior of HUVECs suggests that the electrical features of HUVEC may be primarily determined by embryonic origin and local effect of the microenvironment. This research provided the detailed electrophysiological knowledge of the endothelial cells.

Effects of Fe(2+) on ion channels: Na(+) channel, delayed rectified and transient outward K(+) channels.

The effects of Fe(2+) on the properties of three types of ion channels were studied in acutely dissociated rat hippocampal pyramidal neurons from area CA1 at postnatal ages of 7-14 days using the whole cell patch clamp technique. The results indicated that: (1) in the existence of Fe(2+), the activation voltage threshold of transient outward K(+) currents (I(A)) was decreased. The normalized current-voltage curves of activation were well fitted with a single Boltzmann function, and the V(1/2) was 2.44+/-1.14 mV (n=15) in control, whereas 1.79+/-1.53 (n=15), -2.96+/-0.92 (n=14), -5.11+/-1.31 (n=13), -9.05+/-1.64 mV (n=12) in 1, 10, 100 and 1000 microM Fe(2+), respectively. Differences between two groups were significant (P<0.05, n=12-15), except for that between the control and 1 microM (P>0.05, n=15). (2) Fe(2+) caused a left shift of the current-voltage curves of steady-state inactivation of I(A) in a concentration-dependent manner. The curves were well fitted with a single Boltzmann function with similar slope (P>0.05, n=10-13). The V(1/2) were -70.71+/-1.23 (n=13), -71.14+/-1.37 (n=13), -78.21+/-1.17 (n=11), -84.61+/-1.34 (n=12), and -89.68+/-2.59 mV (n=10) in control, 1, 10, 100 and 1000 microM Fe(2+), respectively. Fe(2+) also shifted the current-voltage curves of Na(+) channel steady-state inactivation to more negative depolarization potentials in parallel, with V(1/2), -67.37+/-1.33 mV (n=12) in control, and -67.52+/-1.28 mV (n=12), -68.24+/-1.61 mV (n=10), -71.58+/-1.45 mV (n=10), -76.65+/-1.76 mV (n=9) in 1, 10, 100 and 1000 microM Fe(2+) solutions, respectively. (3) In Fe(2+) solutions, the recovery from inactivation of I(A) was slowed. (4) With application of different concentrations of Fe(2+), the voltage threshold of activation of delayed rectified outward K(+) currents (I(K)) was decreased, while Fe(2+) showed a little inhibition at more positive depolarization. Briefly, the results demonstrated that Fe(2+) is a dose- and voltage-dependent, reversible modulator of I(A), I(K) and Na(+) channels. The results will be helpful to explain the mechanism of Fe(2+) physiological function and Fe(2+) intoxication in the central nervous system.

Effects of lead exposure on long-term potentiation induced by 2-deoxy-D-glucose in area CA1 of rat hippocampus in vitro.

Chronic developmental lead exposure is known to be associated with cognitive dysfunction in children. Previous studies have demonstrated that chronic lead exposure could impair the induction and maintenance of long-term potentiation induced by high-frequency stimulation (HFS-LTP). In area CA1 of rat hippocampus, long-term potentiation could also be induced following temporary replacement of 10 mM 2-deoxy-D-glucose (2-DG) for 10 mM glucose in the normal perfusate (artificial cerebrospinal fluid). The present study was carried out to investigate whether chronic lead exposure affected long-term potentiation induced by 2-DG (2-DG-LTP). Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams whose drinking water contained 0.2% lead acetate. Field excitatory postsynaptic potentials (EPSPs) in area CA1 of hippocampus were recorded on postnatal days 25-30. 2-DG application was followed by an increase in EPSP slopes in a time-course-dependent manner in both control and lead-exposed rats, while the amplitude of 2-DG-LTP in the lead-exposed rats (225.9+/-19.0%, n=12) was significantly greater than that in controls (155.2+/-9.8%, n=12). In contrast to the effects of lead exposure on 2-DG-LTP, the amplitude of HFS-LTP in the lead-exposed rats (121.5+/-13.7%, n=12) was significantly less than that in controls (183.9+/-18.6%, n=12). These results indicate that chronic lead exposure had opposite effects on the two types of LTP induced by HFS and 2-DG. This would suggest that the effects of lead on HFS-LTP and 2-DG-LTP are the result of different sites of lead toxicity.

Vasopressin reverses aluminum-induced impairment of synaptic plasticity in the rat dentate gyrus in vivo.

Aluminum (Al), an important neurotoxin, contributes to a variety of cognitive dysfunction and mental diseases. Previous studies have demonstrated that Al impairs hippocampal long-term potentiation (LTP) in vitro and in vivo. In the present study, both LTP and LTD (long-term depression) were recorded in the same animal to investigate the Al-induced impairment of synaptic plasticity. Another aim of the present research was to verify whether the impairment of synaptic plasticity induced by Al could be reversed by vasopressin (VP) treatment. Neonatal Wistar rats were exposed to Al from parturition through adulthood (pre- and post-weaning) by the drinking of 0.3% aluminum chloride (AlCl(3)) solution. The input-output (I/O) function, paired-pulse reaction (PPR), excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude were measured in the dentate gyrus (DG) of adult rats (60-90 days) in response to stimulation applied to the lateral perforant path. The results showed: (1) Al reduced the amplitudes of both EPSP LTP (control: 132+/-7%, n=7; Al-exposed: 115+/-10%, n=8, P<0.05) and PS LTP (control: 242+/-18%, n=7; Al-exposed: 136+/-7%, n=8, P<0.01) significantly. The amplitudes of EPSP LTD (control: 82+/-6%, n=7; Al-exposed: 92+/-7%, n=8, P<0.05) and PS LTD (control: 81+/-4%, n=7; Al-exposed: 98+/-5%, n=8, P<0.05) were also decreased by Al treatment. The Al-induced impairments of PS LTP and PS LTD were more serious than that of EPSP LTP and EPSP LTD. (2) In control rats, VP had an increase in the PS LTP amplitude (control: 242+/-18%, n=7; control+VP: 358+/-23%, n=6, P<0.01), while it had no significant effects on PS LTD (control: 81+/-4%, n=7; control+VP: 76+/-7%, n=6, P>0.05). (3) In Al-exposed rats, VP had a significant increase in the amplitudes of both PS LTP (Al-exposed: 136+/-7%, n=8, Al-exposed+VP: 255+/-16%, n=6, P<0.01) and PS LTD (Al-exposed: 98+/-5%, n=8; Al-exposed+VP: 81+/-6%, n=6, P<0.05). After the application of VP, the range of synaptic plasticity (PS LTP+PS LTD) in Al-exposed rats increased from 38% to 174%, which surpassed that in control rats (161%). It was suggested that VP could reverse Al-induced impairment of synaptic plasticity and might be an effective medicine to cure Al-induced neurological disorders.

Two components of long-term depression are impaired by chronic lead exposure in area CA1 and dentate gyrus of rat hippocampus in vitro.

Previous studies have demonstrated that low-level lead exposure can impair the induction of long-term depression (LTD) in area CA1 and dentate gyrus (DG) of rat hippocampus in vitro and in vivo. The induction of LTD in area CA1 and DG has been shown to associate with N-methyl-D-aspartate receptors (NMDARs) and voltage-gated calcium channel (VGCC). In this study, the relative contributions of NMDARs-dependent and VGCC-dependent components in the induction of LTD in the hippocampus and the impairments of these two components of LTD by chronic low-level lead exposure were investigated. Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams drinking 0.2% lead acetate solution. Field excitatory postsynaptic potentials (EPSPs) were recorded in area CA1 and DG before and after two 15-min trains of 1-Hz low-frequency stimulation (LFS) (2x900 pulses). In area CA1, the amplitude of NMDARs-dependent LTD (NMDA-LTD), in the presence of 10 microM nimodipine (a blocker of L-type Ca(2+) channels), was 80.05+/-2.54% (n=8) and 94.58+/-10.57% (n=8) in the control and lead-exposed rats, respectively. The amplitude of VGCC-dependent LTD (VGCC-LTD), in the presence of 50 microM (-)-2-amino-5-phosphonopentanoic acid (AP5), was 80.36+/-4.08% (n=10) and 93.91+/-7.85% (n=10) in the control and lead-exposed rats, respectively. In area DG the amplitude of NMDA-LTD, with both 50 microM Ni(2+) (a blocker of T-type Ca(2+) channels) and 10 microM nimodipine present, in the control rats (79. 97+/-4.30%, n=8) was significantly larger than that in the lead-exposed rats (91.24+/-11.08%, n=10, P<0.001). The amplitude of VGCC-LTD, with 50 microM AP5 present, was significantly larger in the control rats (70.80+/-3.64%, n=9) than that in the lead-exposed rats (87.60+/-9.00%, n=10, P<0.001). The results suggested that chronic lead exposure affected two components of LTD induction in area CA1 and DG. Furthermore, the impairment of two components by lead exposure might be similar in area CA1, while the impairment of VGCC-LTD might be more serious in DG of hippocampus.

Impairment of the Ca2+-permeable AMPA/kainate receptors by lead exposure in organotypic rat hippocampal slice cultures.

Previous studies have demonstrated that chronic lead exposure may impair neuronal process underlying synaptic plasticity via a direct interaction with N-methyl-D-aspartate (NMDA) receptors. The present study was carried out to investigate the effects of lead exposure on non-NMDA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, AMPA/kainate) receptors of rat hippocampus. Ca2+-permeable AMPA/kainate receptors in organotypic slice cultures were evaluated by using cobalt uptake, a histochemical method that identifies cells expressing Ca2+-permeable non-NMDA receptors. Ten mM L-glutamate-induced cobalt accumulation was enriched in area CA1, area CA3 and in dentate gyrus, which was totally blocked by 100 microM DL-2-amino-5-phosphonovaleric acid (AP5) and 100 microM 6-cyano-7-nitroquinoxaline-2, 3-dione (CNQX). Three hundred microM NMDA-induced cobalt accumulation was in area CA1, area dentate gyrus and was blocked by AP5 or CNQX. One hundred microM AMPA had effects in area CA1, area CA3 and in dentate gyrus, which were blocked by CNQX, not by AP5. Furthermore, cobalt accumulations induced by NMDA and AMPA in the lead-exposed rats decreased significantly than those in the controls. The results indicate that AMPA receptors enriched in area CA1, area CA3, area dentate gyrus and kainate receptors enriched in area CA1, area dentate gyrus are impaired by lead exposure.

Age-related impairment of long-term depression in area CA1 and dentate gyrus of rat hippocampus following developmental lead exposure in vitro.

Chronic developmental lead exposure is known to be associated with cognitive dysfunction in children. Impairment of the induction of long-term depression (LTD) has been reported in area CA1 and dentate gyrus (DG) of rat hippocampus following chronic lead exposure. The present study was carried out to investigate age-related alterations of LTD in area CA1 and DG of rat hippocampus following developmental lead exposure in vitro. Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams drinking 0.2% lead acetate solution. Field excitatory postsynaptic potentials (EPSPs) were recorded in hippocampal slices at various postnatal ages: postnatal day (PND) 17-23, 27-33, and 57-63. Following low-frequency stimulation (LFS, 900 pulses/1 Hz), the average magnitude of LTD is age related. In the controls, LTD magnitude in area CA1 decreased with age, whereas in DG it increased with age. In the lead-exposed groups, the magnitude of LTD declined during development in both area CA1 and DG. The differences of LTD magnitude between the control and lead-exposed rats were 27.26 +/- 9.15% (PND 17-23), 21.59 +/- 12.93% (PND 27-33), and 16.96 +/- 9.33% (PND 57-63) in area CA1, and were 6.95 +/- 9.26%, 17.60 +/- 3.91%, and 33.63 +/- 10.47% in DG, respectively. These results demonstrated that the lead-induced impairment of LTD magnitude was an age-related decline in area CA1 and an age-related increase in area DG of rat hippocampus. Published by Elsevier Science Inc.

Effects of chronic lead exposure on short-term and long-term depression in area CA1 of the rat hippocampus in vivo.

Chronic developmental lead (Pb) exposure to the rat has been reported to impair the long-term potentiation (LTP) in area CA1 and DG of the hippocampus. The present study was performed to investigate the effects of chronic Pb exposure on homosynaptic short-term depression (STD) and long-term depression (LTD) of population spikes (PS) in area CA1 of the rat hippocampus in vivo. Neonatal Wistar rats were exposed to Pb from parturition to weaning via the milk of dams fed with 0.2% lead acetate solution. The input/output (I/O) function, paired-pulse reaction (PPR), the PS were measured in the area CA1 in response to low frequency stimulation (LFS). The results showed that the homo-STD amplitude of PS depotentiation in Pb-exposed rats (87.48 +/- 7.44%, n = 14) was less significant than that in control rats (72.34 +/- 6.05%, n = 18, P<0.05), and the homo-LTD amplitude of PS depotentiation in Pb-exposed rats (72.80 +/- 5.86%, n = 14) was even less significant than that in control rats (47.80 +/- 5.03%, n = 18, P<0.01). The results suggest that chronic Pb exposure in neonatal rats caused impairments in the STD and LTD of area CA1 of hippocampus.

The effects of chronic lead exposure on long-term depression in area CA1 and dentate gyrus of rat hippocampus in vitro.

Long-term potentiation (LTP) and long-term depression (LTD), two forms of synaptic plasticity, are believed to underlie the mechanisms of learning and memory. Previous studies have demonstrated that low-level lead exposure can impair the induction and maintenance of LTP in vivo and in vitro. The present study was carried out to investigate whether the low-level lead exposure affected the induction and maintenance of LTD. Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams drinking 0.2% lead acetate solution. Field excitatory postsynaptic potentials (EPSPs) were recorded in hippocampal slices in adult rats (50-65 days) to study the alterations of LTD in area CA1 and dentate gyrus (DG) of hippocampus following chronic lead exposure. The input-output (I/O) curves before conditioning in both areas showed no evident alterations in basic synaptic transmission between the control and lead exposure groups. In area CA1, the mean amplitude of EPSP slope in control rats (61+/-11%, n=15) decreased significantly greater than that in lead-exposed rats (78+/-8%, n=8, P<0.05) following low frequency stimulation (LFS, 1 Hz, 15 min), which lasted at least 45 min. In area DG, with application of the same LFS, the LTD was induced in control rats (72+/-22%, n=8), while the LFS failed to induce LTD in lead-exposed rats (100+/-26%, n=8). These results showed that chronic lead exposure affected the induction of LTD in both area CA1 and DG. The effect of lead on synaptic plasticity in area CA1 was also investigated. The alteration of the amplitude of LTP in hippocampal slices caused by lead was reexamined in order to compare with that on LTD (control: 189+/-23, n=5; lead-exposed: 122+/-12, n=10). The result demonstrated that low-level lead exposure could reduce the range of synaptic plasticity, which might underlie the dysfunction of learning and memory caused by chronic lead exposure.

Impairment of long-term potentiation and paired-pulse facilitation in rat hippocampal dentate gyrus following developmental lead exposure in vivo.

Neonatal rats were exposed to lead from parturition to weaning via the milk of dams drinking 0.2% lead acetate solution. The alterations of long-term potentiation (LTP) and paired-pulse facilitation (PPF) of hippocampal dentate gyrus in adult rats (90-115 days) following developmental lead exposure were studied in vivo. Input/output (I/O) function, paired-pulse facilitation (PPF), excitatory postsynaptic potential (EPSP) and population spike (PS) amplitude were measured in the dentate gyrus (DG) in response to stimulation applied to the lateral perforant path. The results showed that LTP was induced in control rats with an average PS potentiation of 321.1+/-50.0% (n=18), which was significantly greater than the increase in PS potentiation (173.5+/-30.0%, n=17, p<0.001) in lead-exposed rats after tetanizing stimulation. The mean EPSP potentiation increased to 172.4+/-27.0% (n=18) in control and 138.8+/-21.4% (n=17) in lead-exposed rats after tetanizing stimulation. The lead-induced impairment of LTP of PS potentiation was more serious than that of EPSP potentiation. Following pairs stimulation of perforant fiber at 250 microA and an interpulse interval (IPI) of 10-1000 ms, the average peak facilitation of PS was 211.3+/-25.0% (n=13) in control and 187.7+/-23.0% (n=11) in lead-exposed rats. The average facilitation period duration of PS was 243.0+/-35.8 ms (n=13) in control and 138.0+/-24.4 ms (n=11) in lead-exposed rats. These results suggested that developmental lead exposure in neonatal rats caused impairments in LTP and PPF of hippocampal dentate gyrus.

Influences of area 17 on neuronal activity of simple and complex cells of area 18 in cats.

To understand the influence of the ascending path linking area 17 to area 18 of visual cortices, experiments were carried out in which a small neuronal population of area 17 was inactivated with GABA, while unitary responses were recorded in area 18. In the latter, cells are identified as belonging to the simple or complex family according to their firing pattern evoked in response to sine-wave gratings scrolling through the receptive fields. Anesthetized cats were prepared for single-cell recordings. In area 17, a GABA-containing pipette was placed in superficial layers in order to inactivate reversibly a small neuronal population. Prior to blockade, the orientation tuning curves were obtained in both areas and the difference in optimal orientation between areas 17 and 18 was recorded. In area 18, cells were classified as simple or complex. The strategy was to study the reaction of neurons in area 18 prior to, during and after area 17 depression. In most simple cells, whenever the difference in orientation was in the iso-range, that is when the difference in optimal orientations of the injected site (in area 17) and of the neuron in area 18 was less than 30 degrees, the GABA application produced a decline of the evoked discharges, whereas GABA injection augmented the evoked firing rate when the difference was in the cross-range (>60 degrees). In contrast to simple cells, GABA depression enhanced the responses in the majority of complex cells with like orientations in both areas. When the difference between recording sites was in the cross-range, then area 17 depression produced weaker evoked firing. A tangential penetration of the injecting pipette, allowing injection of different orientation sites while testing the same unit in area 18, revealed that the latter could react with an enhancement or a decline of the responses as the injecting pipette shifted from iso (or cross) to cross (or iso) disparity in optimal orientations between areas 17 and 18. These results suggest that the path connecting area 17 to area 18 may be functionally discriminated on the basis of the orientation domain and cell types. In addition, our data suggest that the ascending visual streams are required to generate orientation specificity in area 18.