Transmission In CA1 Pyramidal Neurons Research Articles

Median raphe glutamatergic neuron-mediated enhancement of GABAergic transmission and suppression of long-term potentiation in the hippocampus

The ascending neuromodulatory pathway from the median raphe nucleus (MRN) extends widely throughout midline/para-midline regions and robustly innervates the hippocampus. This neuromodulatory pathway is believed to be critical for regulating emotional and affective behaviors. Although the MRN primarily contains serotoninergic (5-HTergic), GABAergic, and glutamatergic neurons, glutamatergic neurons expressing vesicular glutamate transporter 3 (VGLUT3) form the primary MRN input to the hippocampus. Despite the earlier demonstration of the robust MRN VGLUT3 innervation of the hippocampus, little is known about how this MRN glutamatergic input modulates synaptic transmission and plasticity in the hippocampus. Our studies show that MRN VGLUT3 neurons activate serotonin 3a receptor (5-HT3aR)-expressing GABAergic neurons, including VGLUT3-expressing neurons, at the stratum radiatum (SR)/stratum lacunosum moleculare (SLM) border. This MRN VGLUT3 neuron-mediated glutamatergic transmission onto SR/SLM 5-HT3aR neurons is negatively regulated by 5-HT through 5-HT1B receptors. In agreement with the MRN VGLUT3 neuron-mediated activation of the 5-HT3aR GABAergic neurons, activation of MRN VGLUT3 projections induces a long-lasting increase in GABAergic transmission but not glutamatergic transmission in CA1 pyramidal neurons from male but not female mice. Consistent with the MRN VGLUT3 neuron-mediated enhancement of GABAergic transmission in male mice, activation of MRN VGLUT3 projections suppresses Schaffer collateral (SC)-CA1 long-term potentiation (LTP) in male but not female mice. Thus, our results show that MRN VGLUT3 neurons modulate the dorsal hippocampus by augmenting synaptic inhibition of CA1 pyramidal neurons and by suppressing SC-CA1 LTP in a sex-specific manner.

A glibenclamide-sensitive TRPM4-mediated component of CA1 excitatory postsynaptic potentials appears in experimental autoimmune encephalomyelitis

The transient receptor potential melastatin 4 (TRPM4) channel contributes to disease severity in the murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and to neuronal cell death in models of excitotoxicity and traumatic brain injury. As TRPM4 is activated by intracellular calcium and conducts monovalent cations, we hypothesized that TRPM4 may contribute to and boost excitatory synaptic transmission in CA1 pyramidal neurons of the hippocampus. Using single-spine calcium imaging and electrophysiology, we found no effect of the TRPM4 antagonists 9-phenanthrol and glibenclamide on synaptic transmission in hippocampal slices from healthy mice. In contrast, glibenclamide but not 9-phenanthrol reduced excitatory synaptic potentials in slices from EAE mice, an effect that was absent in slices from EAE mice lacking TRPM4. We conclude that TRPM4 plays little role in basal hippocampal synaptic transmission, but a glibenclamide-sensitive TRPM4-mediated contribution to excitatory postsynaptic responses is upregulated at the acute phase of EAE.

Increasing astrogenesis in the developing hippocampus induces autistic-like behavior in mice via enhancing inhibitory synaptic transmission.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized primarily by impaired social communication and rigid, repetitive, and stereotyped behaviors. Many studies implicate abnormal synapse development and the resultant abnormalities in synaptic excitatory–inhibitory (E/I) balance may underlie many features of the disease, suggesting aberrant neuronal connections and networks are prone to occur in the developing autistic brain. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function during a critical developmental period may also contribute to the pathogenesis of ASD. Here, we report that increasing hippocampal astrogenesis during development induces autistic‐like behavior in mice and a concurrent decreased E/I ratio in the hippocampus that results from enhanced GABAergic transmission in CA1 pyramidal neurons. Suppressing the aberrantly elevated GABAergic synaptic transmission in hippocampal CA1 area rescues autistic‐like behavior and restores the E/I balance. Thus, we provide direct evidence for a developmental role of astrocytes in driving the behavioral phenotypes of ASD, and our results support that targeting the altered GABAergic neurotransmission may represent a promising therapeutic strategy for ASD.

A novel therapeutic approach for treatment of catamenial epilepsy

Many women with epilepsy experience perimenstrual seizure exacerbation, referred to as catamenial epilepsy. There is no effective treatment for this condition, proposed to result from withdrawal of neurosteroid-mediated effects of progesterone. A double-blind, multicenter, phase III, clinical trial of catamenial epilepsy has failed to find a beneficial effect of progesterone. The neurosteroid-mediated effects of progesterone have been extensively studied in relation to catamenial epilepsy; however, the effects mediated by progesterone receptor activation have been overlooked. We determined whether progesterone increased excitatory transmission in the hippocampus via activation of progesterone receptors, which may play a role in regulating catamenial seizure exacerbation. In a double-blind study using a rat model of catamenial epilepsy, we found that treatment with RU-486, which blocks progesterone and glucocorticoid receptors, significantly attenuated neurosteroid withdrawal-induced seizures. Furthermore, progesterone treatment as well as endogenous rise in progesterone during estrous cycle increased the expression of GluA1 and GluA2 subunits of AMPA receptors in the hippocampi, and enhanced the AMPA receptor-mediated synaptic transmission of CA1 pyramidal neurons. The progesterone-induced plasticity of AMPA receptors was blocked by RU-486 treatment and progesterone also failed to increase AMPA receptor expression in progesterone receptor knockout mice. These studies demonstrate that progesterone receptor activation regulates AMPA receptor expression and may play a role in catamenial seizure exacerbation.

Streptozotocin Inhibits Electrophysiological Determinants of Excitatory and Inhibitory Synaptic Transmission in CA1 Pyramidal Neurons of Rat Hippocampal Slices: Reduction of These Effects by Edaravone

Background: Streptozotocin (STZ) has served as an agent to generate an Alzheimer's disease (AD) model in rats, while edaravone (EDA), a novel free radical scavenger, has recently emerged as an effective treatment for use in vivo and vitro AD models. However, to date, these beneficial effects of EDA have only been clearly demonstrated within STZ-induced animal models of AD and in cell models of AD. A better understanding of the mechanisms of EDA may provide the opportunity for their clinical application in the treatment of AD. Therefore, the purpose of this study was to investigate the underlying mechanisms of STZ and EDA as assessed upon electrophysiological alterations in CA1 pyramidal neurons of rat hippocampal slices. Methods: Through measures of evoked excitatory postsynaptic currents (eEPSCs), AMPAR-mediated eEPSCs (eEPSCs_AMPA), evoked inhibitory postsynaptic currents (eIPSCs), evoked excitatory postsynaptic current paired pulse ratio (eEPSC PPR) and evoked inhibitory postsynaptic current paired pulse ratio (eIPSC PPR), it was possible to investigate mechanisms as related to the neurotoxicity of STZ and reductions in these effects by EDA. Results: Our results showed that STZ (1000 µM) significantly inhibited peak amplitudes of eEPSCs, eEPSCs_AMPA and eIPSCs, while EDA (1000 µM) attenuated these STZ-induced changes at holding potentials ranging from -60mV to +40 mV for EPSCs and -60mV to +20 mV for IPSCs. Our work also indicated that mean eEPSC PPR were substantially altered by STZ, effects which were partially restored by EDA. In contrast, no significant effects upon eIPSC PPR were obtained in response to STZ and EDA. Conclusion: Our data suggest that STZ inhibits glutamatergic transmission involving pre-synaptic mechanisms and AMPAR, and that STZ inhibits GABAergic transmission by post-synaptic mechanisms within CA1 pyramidal neurons. These effects are attenuated by EDA.

Cadherin-13, a risk gene for ADHD and comorbid disorders, impacts GABAergic function in hippocampus and cognition.

Cadherin-13 (CDH13), a unique glycosylphosphatidylinositol-anchored member of the cadherin family of cell adhesion molecules, has been identified as a risk gene for attention-deficit/hyperactivity disorder (ADHD) and various comorbid neurodevelopmental and psychiatric conditions, including depression, substance abuse, autism spectrum disorder and violent behavior, while the mechanism whereby CDH13 dysfunction influences pathogenesis of neuropsychiatric disorders remains elusive. Here we explored the potential role of CDH13 in the inhibitory modulation of brain activity by investigating synaptic function of GABAergic interneurons. Cellular and subcellular distribution of CDH13 was analyzed in the murine hippocampus and a mouse model with a targeted inactivation of Cdh13 was generated to evaluate how CDH13 modulates synaptic activity of hippocampal interneurons and behavioral domains related to psychopathologic (endo)phenotypes. We show that CDH13 expression in the cornu ammonis (CA) region of the hippocampus is confined to distinct classes of interneurons. Specifically, CDH13 is expressed by numerous parvalbumin and somatostatin-expressing interneurons located in the stratum oriens, where it localizes to both the soma and the presynaptic compartment. Cdh13−/− mice show an increase in basal inhibitory, but not excitatory, synaptic transmission in CA1 pyramidal neurons. Associated with these alterations in hippocampal function, Cdh13−/− mice display deficits in learning and memory. Taken together, our results indicate that CDH13 is a negative regulator of inhibitory synapses in the hippocampus, and provide insights into how CDH13 dysfunction may contribute to the excitatory/inhibitory imbalance observed in neurodevelopmental disorders, such as ADHD and autism.

Increased excitability and excitatory synaptic transmission during in vitro ischemia in the neonatal mouse hippocampus

Objective: The present study tested the hypothesis that exposure to in vitro hypoxia–ischemia alters membrane properties and excitability as well as excitatory synaptic transmission of CA1 pyramidal neurons in the neonatal mouse. Methods: Experiments were conducted in hippocampal slices in P7–P9 C57Bl/6 mice using whole-cell patch clamp in current- and voltage-clamp mode. Passive membrane potential (Vm), input resistance (Rin) and active (action potential (AP) threshold and amplitude) membrane properties of CA1 pyramidal neurons were assessed at baseline, during 10min in vitro ischemia (oxygen-glucose deprivation (OGD)) and during reoxygenation. Spontaneous and miniature excitatory post-synaptic currents (s and mEPSCs) were studied under similar conditions. Results: OGD caused significant depolarization of CA1 pyramidal neurons as well as decrease in AP threshold and increase in AP amplitude. These changes were blocked by the application of tetrodotoxin (TTX), indicating Na+ channels’ involvement. Following 10min of reoxygenation, significant membrane hyperpolarization was noted and it was associated with a decrease in Rin. AP threshold and amplitude returned to baseline during that stage. sEPSC and mEPSC frequency increased during both OGD and reoxygenation but their amplitude remained unchanged. Additionally, we found that OGD decreases Ih (hyperpolarization activated current) in CA1 neurons from neonatal mice and this effect persists during reoxygenation. Significance: These results indicate that in vitro ischemia leads to changes in membrane excitability mediated by sodium and potassium channels. Further, it results in enhanced neurotransmitter release from presynaptic terminals. These changes are likely to represent one of the mechanisms of hypoxia/ischemia-mediated seizures in the neonatal period.

Galantamine prevents long-lasting suppression of excitatory synaptic transmission in CA1 pyramidal neurons of soman-challenged guinea pigs

Galantamine, a drug currently approved for the treatment of Alzheimer's disease, has recently emerged as an effective pretreatment against the acute toxicity and delayed cognitive deficits induced by organophosphorus (OP) nerve agents, including soman. Since cognitive deficits can result from impaired glutamatergic transmission in the hippocampus, the present study was designed to test the hypothesis that hippocampal glutamatergic transmission declines following an acute exposure to soman and that this effect can be prevented by galantamine. To test this hypothesis, spontaneous excitatory postsynaptic currents (EPSCs) were recorded from CA1 pyramidal neurons in hippocampal slices obtained at 1h, 24h, or 6–9 days after guinea pigs were injected with: (i) 1×LD50 soman (26.3μg/kg, s.c.); (ii) galantamine (8mg/kg, i.m.) followed 30min later by 1×LD50 soman, (iii) galantamine (8mg/kg, i.m.), or (iv) saline (0.5ml/kg, i.m.). In soman-injected guinea pigs that were not pretreated with galantamine, the frequency of EPSCs was significantly lower than that recorded from saline-injected animals. There was no correlation between the severity of soman-induced acute toxicity and the magnitude of soman-induced reduction of EPSC frequency. Pretreatment with galantamine prevented the reduction of EPSC frequency observed at 6–9 days after the soman challenge. Prevention of soman-induced long-lasting reduction of hippocampal glutamatergic synaptic transmission may be an important determinant of the ability of galantamine to counter cognitive deficits that develop long after an acute exposure to the nerve agent.

The Reduction of EPSC Amplitude in CA1 Pyramidal Neurons by the Peroxynitrite Donor SIN-1 Requires Ca2+ Influx Via Postsynaptic Non-L-Type Voltage Gated Calcium Channels

The peroxynitrite free radical (ONOO(-)) modulation of miniature excitatory postsynaptic currents (mEPSCs) and spontaneous excitatory postsynaptic currents (sEPSCs) was investigated in rat CA1 pyramidal neurons using the whole-cell patch clamp technique. SIN-1(3-morpholino-sydnonimine), which can lead the simultaneous generation of superoxide anion and nitric oxide, and then form the highly reactive species ONOO(-), induced dose-dependent inhibition in amplitudes of both mEPSCs and sEPSCs. The SIN-1 action on mEPSC amplitude was completely blocked by U0126, a selective MEK inhibitor, suggesting that MEK contributed to the action of ONOO(-) on mEPSCs. The effect of SIN-1 was completely occluded either in the presence of the calcium chelator EGTA or the non-selective calcium channel antagonist Cd(2+). Furthermore, the application of nifedipine (20μM), the L-type calcium channel blocker, had no effect on the ONOO(-)-induced decrease in mEPSC amplitude, excluding a role for L-type voltage-gated Ca(2+) channels in this process. SIN-1 inhibited the frequency of sEPSCs but had no effect on mEPSC frequency, which suggested a presynaptic action potential-dependent the action of ONOO(-) at CA1 pyramidal neuron synapses. The best-known glutamatergic input to CA1 pyramidal neurons is via Schaffer collaterals from CA3 area. However, no changes were observed in slices treated with SIN-1 on the spontaneous firing rates of CA3 pyramidal neurons. These findings suggested that SIN-1 inhibited glutamatergic synaptic transmission of CA1 pyramidal neurons by a postsynaptic non-L-type voltage gated calcium channel-dependent mechanism.

Estradiol Attenuates Ischemia-Induced Death of Hippocampal Neurons and Enhances Synaptic Transmission in Aged, Long-Term Hormone-Deprived Female Rats

BackgroundTransient global forebrain ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons, and the ovarian hormone 17β-estradiol (E2) reduces neuronal loss in young and middle-aged females. The neuroprotective efficacy of E2 after a prolonged period of hormone deprivation is controversial, and few studies examine this issue in aged animals given E2 treatment after induction of ischemia.Methodology/Principal FindingsThe present study investigated the neuroprotective effects of E2 administered immediately after global ischemia in aged female rats (15–18 months) after 6 months of hormone deprivation. We also used electrophysiological methods to assess whether CA1 synapses in the aging hippocampus remain responsive to E2 after prolonged hormone withdrawal. Animals were ovariohysterectomized and underwent 10 min global ischemia 6 months later. A single dose of E2 (2.25 µg) infused intraventricularly after reperfusion significantly increased cell survival, with 45% of CA1 neurons surviving vs 15% in controls. Ischemia also induced moderate loss of CA3/CA4 pyramidal cells. Bath application of 1 nM E2 onto brain slices derived from non-ischemic aged females after 6 months of hormone withdrawal significantly enhanced excitatory transmission at CA1 synapses evoked by Schaffer collateral stimulation, and normal long-term potentiation (LTP) was induced. The magnitude of LTP and of E2 enhancement of field excitatory postsynaptic potentials was indistinguishable from that recorded in slices from young rats.Conclusions/SignificanceThe data demonstrate that 1) acute post-ischemic infusion of E2 into the brain ventricles is neuroprotective in aged rats after 6 months of hormone deprivation; and 2) E2 enhances synaptic transmission in CA1 pyramidal neurons of aged long-term hormone deprived females. These findings provide evidence that the aging hippocampus remains responsive to E2 administered either in vivo or in vitro even after prolonged periods of hormone withdrawal.

Astroglial networks scale synaptic activity and plasticity

Astrocytes dynamically interact with neurons to regulate synaptic transmission. Although the gap junction proteins connexin 30 (Cx30) and connexin 43 (Cx43) mediate the extensive network organization of astrocytes, their role in synaptic physiology is unknown. Here we show, by inactivating Cx30 and Cx43 genes, that astroglial networks tone down hippocampal synaptic transmission in CA1 pyramidal neurons. Gap junctional networking facilitates extracellular glutamate and potassium removal during synaptic activity through modulation of astroglial clearance rate and extracellular space volume. This regulation limits neuronal excitability, release probability, and insertion of postsynaptic AMPA receptors, silencing synapses. By controlling synaptic strength, connexins play an important role in synaptic plasticity. Altogether, these results establish connexins as critical proteins for extracellular homeostasis, important for the formation of functional synapses.

AMPA Receptor Subunits Get Their Share of the Pie

Determining the precise subunit composition of AMPARs in situ has been an enduring challenge. In this issue of Neuron, Lu et al. make significant headway into this pesky problem by using a clever single-cell genetic knockout approach. In a Herculean effort, they provide the field with the completeness of a pie chart outlining the contribution of each AMPAR subunit to basal synaptic transmission at CA1 hippocampus synapses--and we get a pie chart for somatic extrasynaptic receptors, too.

Age‐dependent enhancement of inhibitory synaptic transmission in CA1 pyramidal neurons via GluR5 kainate receptors

Changes in hippocampal synaptic networks during aging may contribute to age-dependent compromise of cognitive functions such as learning and memory. Previous studies have demonstrated that GABAergic synaptic transmission exhibits age-dependent changes. To better understand such age-dependent changes of GABAergic synaptic inhibition, we performed whole-cell recordings from pyramidal cells in the CA1 area of acute hippocampal slices on aged (24-26 months old) and young (2-4 months old) Brown-Norway rats. We found that the frequency and amplitude of spontaneous inhibitory postsynaptic current (IPSCs) were significantly increased in aged rats, but the frequency and amplitude of mIPSCs were decreased. Furthermore, the regulation of GABAergic synaptic transmission by GluR5 containing kainate receptors was enhanced in aged rats, which was revealed by using LY382884 (a GluR5 kainate receptor antagonist) and ATPA (a GluR5 kainate receptor agonist). Moreover, we demonstrated that vesicular glutamate transporters are involved in the kainate receptor dependent regulation of sIPSCs. Taken together, these results suggest that GABAergic synaptic transmission is potentiated in aged rats, and GluR5 containing kainate receptors regulate the inhibitory synaptic transmission through endogenous glutamate. These alterations of GABAergic input with aging could contribute to age-dependent cognitive decline.

Chronic benzodiazepine-induced reduction in GABA A receptor-mediated synaptic currents in hippocampal CA1 pyramidal neurons prevented by prior nimodipine injection

One week oral flurazepam (FZP) administration in rats results in reduced GABA A receptor-mediated synaptic transmission in CA1 pyramidal neurons associated with benzodiazepine tolerance in vivo and in vitro. Since voltage-gated calcium channel (VGCC) current density is enhanced twofold during chronic FZP treatment, the role of L-type VGCCs in regulating benzodiazepine-induced changes in CA1 neuron GABA A receptor-mediated function was evaluated. Nimodipine (10 mg/kg, i.p.) or vehicle (0.5% Tween 80, 2 ml/kg) was injected 1 day after ending FZP treatment and 24 h prior to hippocampal slice preparation for measurement of mIPSC characteristics and in vitro tolerance to zolpidem. The reduction in GABA A receptor-mediated mIPSC amplitude and estimated unitary channel conductance measured 2 days after drug removal was no longer observed following prior nimodipine injection. However, the single nimodipine injection failed to prevent in vitro tolerance to zolpidem's ability to prolong mIPSC decay in FZP-treated neurons, suggesting multiple mechanisms may be involved in regulating GABA A receptor-mediated synaptic transmission following chronic FZP administration. As reported previously in recombinant receptors, nimodipine inhibited synaptic GABA A receptor currents only at high concentrations (>30 μM), significantly greater than attained in vivo (1 μM) 45 min after a single antagonist injection. Thus, the effects of nimodipine were unlikely to be related to direct effects on GABA A receptors. As with nimodipine injection, buffering intracellular free [Ca 2+] with BAPTA similarly prevented the effects on GABA A receptor-mediated synaptic transmission, suggesting intracellular Ca 2+ homeostasis is important to maintain GABA A receptor function. The findings further support a role for activation of L-type VGCCs, and perhaps other Ca 2+-mediated signaling pathways, in the modulation of GABA A receptor synaptic function following chronic benzodiazepine administration, independent of modulation of the allosteric interactions between benzodiazepine and GABA binding sites.

Effects of emodin on synaptic transmission in rat hippocampal CA1 pyramidal neurons in vitro

Rhubarb extracts provide neuroprotection after brain injury, but the mechanism of this protective effect is not known. The present study tests the hypothesis that rhubarb extracts interfere with the release of glutamate by brain neurons and, therefore, reduce glutamate excitotoxicity. To this end, the effects of emodin, an anthraquinone derivative extracted from Rheum tanguticum Maxim. Ex. Balf, on the synaptic transmission of CA1 pyramidal neurons in rat hippocampus were studied in vitro. The excitatory postsynaptic potential (EPSP) was depressed by bath-application of emodin (0.3–30 μM). Paired-pulse facilitation (PPF) of the EPSP was significantly increased by emodin. The monosynaptic inhibitory postsynaptic potential (IPSP) recorded in the presence of glutamate receptor antagonists (DNQX and AP5) was not altered by emodin. Emodin decreased the frequency, but not the amplitude, of the miniature EPSP (mEPSP). The inhibition of the EPSP induced by emodin was blocked by either 8-CPT, an adenosine A 1 receptor antagonist, or by adenosine deaminase. These results suggest that emodin inhibits the EPSP by decreasing the release of glutamate from Schaffer collateral/commissural terminals via the activation of adenosine A 1 receptors in rat hippocampal CA1 area and that the neuroprotective effects of rhubarb extracts may result from decreased glutamate excitotoxicity.

The Tokyo Attacks in Retrospect: Sarin Leads to Memory Loss

Science SelectionsOpen AccessThe Tokyo Attacks in Retrospect Sarin Leads to Memory Loss E Hood E Hood Search for more papers by this author Published:1 November 2001https://doi.org/10.1289/ehp.109-a542aCited by:10AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InRedditEmail "The Tokyo Attacks in Retrospect Sarin Leads to Memory Loss." Environmental Health Perspectives, 109(11), p. A542FiguresReferencesRelatedDetailsCited By Deshpande L, Blair R, Huang B, Phillips K and DeLorenzo R (2016) Pharmacological blockade of the calcium plateau provides neuroprotection following organophosphate paraoxon induced status epilepticus in rats, Neurotoxicology and Teratology, 10.1016/j.ntt.2016.05.002, 56, (81-86), Online publication date: 1-Jul-2016. Deshpande L, Blair R, Phillips K and DeLorenzo R (2016) Role of the calcium plateau in neuronal injury and behavioral morbidities following organophosphate intoxication, Annals of the New York Academy of Sciences, 10.1111/nyas.13122, 1374:1, (176-183), Online publication date: 1-Jun-2016. Phillips K and Deshpande L (2016) Repeated low-dose organophosphate DFP exposure leads to the development of depression and cognitive impairment in a rat model of Gulf War Illness, NeuroToxicology, 10.1016/j.neuro.2015.11.014, 52, (127-133), Online publication date: 1-Jan-2016. Kassa J, Bajgar J, Kuca K and Jun D (2015) Behavioral Toxicity of Nerve Agents Handbook of Toxicology of Chemical Warfare Agents, 10.1016/B978-0-12-800159-2.00035-X, (477-487), . Alexandrova E, Alkondon M, Aracava Y, Pereira E and Albuquerque E (2014) Galantamine prevents long-lasting suppression of excitatory synaptic transmission in CA1 pyramidal neurons of soman-challenged guinea pigs, NeuroToxicology, 10.1016/j.neuro.2014.07.005, 44, (270-278), Online publication date: 1-Sep-2014. Deshpande L, Phillips K, Huang B and DeLorenzo R (2014) Chronic behavioral and cognitive deficits in a rat survival model of paraoxon toxicity, NeuroToxicology, 10.1016/j.neuro.2014.08.008, 44, (352-357), Online publication date: 1-Sep-2014. Mamczarz J, Kulkarni G, Pereira E and Albuquerque E (2011) Galantamine counteracts development of learning impairment in guinea pigs exposed to the organophosphorus poison soman: Clinical significance, NeuroToxicology, 10.1016/j.neuro.2011.07.001, 32:6, (785-798), Online publication date: 1-Dec-2011. Kassa J, Bajgar J, Kuca K and Jun D (2009) Behavioral Toxicity of Nerve Agents Handbook of Toxicology of Chemical Warfare Agents, 10.1016/B978-012374484-5.00033-X, (481-492), . Genovese R, Benton B, Lee E, Shippee S and Jakubowski E (2007) Behavioral and biochemical evaluation of sub-lethal inhalation exposure to VX in rats, Toxicology, 10.1016/j.tox.2006.12.015, 232:1-2, (109-118), Online publication date: 1-Mar-2007. Genovese R, Benton B, Shippee S, Jakubowski E and Bonnell J (2007) Effects of Low-level Inhalation Exposure to Cyclosarin on Learned Behaviors in Sprague-Dawley Rats, Journal of Toxicology and Environmental Health, Part A, 10.1080/15287390600748153, 69:24, (2167-2180), Online publication date: 1-Jun-2006. Vol. 109, No. 11 November 2001Metrics About Article Metrics Publication History Originally published1 November 2001Published in print1 November 2001 Financial disclosures License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Chronic intermittent ethanol exposure alters CA1 synaptic transmission in rat hippocampal slices

We investigated the neuroadaptive changes in synaptic transmission in the CA1 region of the hippocampus as a result of chronic intermittent ethanol exposure. Male Wistar rats were exposed daily (14 h) to ethanol vapors (blood alcohol levels=150–200 mg%) for 12–14 days, and synaptic field potentials elicited by Schaffer collateral stimulation were compared in hippocampal slices from control and chronic ethanol-treated rats. Excitatory postsynaptic responses of slices were recorded under three conditions: (i) normal physiological saline; (ii) continued presence of 33 mM (150 mg%) ethanol (chronic ethanol-treated rats only); (iii) acute exposure to 33 mM ethanol. When recorded in ethanol-free physiological saline, the mean amplitude of the dendritic synaptic potential and the somatic population spike were significantly smaller in slices from chronic ethanol-treated rats compared to slices from control rats. Under conditions of continuous ethanol exposure, somatic and dendritic synaptic responses of slices taken from chronic ethanol-treated rats were further depressed, suggesting that neural pathways in area CA1 remained sensitive to ethanol. Acute application of ethanol led to a more pronounced reduction of the mean somatic population spike amplitude in slices from chronic ethanol-treated rats than in slices from control rats. However, dendritic synaptic responses were unaffected by acute ethanol in slices from both control and chronic ethanol-treated rats. In addition, we examined the involvement of presynaptic mechanisms in the effects of chronic intermittent ethanol using paired-pulse protocols. When recorded in the continued presence of ethanol, slices from chronic ethanol-treated rats exhibited a significant reduction in paired-pulse facilitation of the dendritic synaptic response compared to slices from control rats, indicating a presynaptic component to the neuroadaptive effects of chronic intermittent ethanol exposure. Conversely, acute ethanol exposure resulted in an enhancement of paired-pulse facilitation of the dendritic synaptic response, an effect that was similar in slices from both control and chronic ethanol-treated rats. Paired-pulse facilitation of the somatic population spike amplitude was not altered by chronic ethanol treatment. However, acute ethanol exposure significantly enhanced paired-pulse facilitation of the somatic population spike in slices from chronic ethanol-treated rats. This effect of acute ethanol was not observed in slices from control rats. Paired-pulse inhibition was not significantly altered in slices from chronic ethanol-treated rats, suggesting that GABAergic inhibitory mechanisms were not involved in the neuroadaptive effects of chronic intermittent ethanol exposure. We suggest that chronic intermittent ethanol exposure can induce multiple neuroadaptive changes in synaptic transmission of CA1 pyramidal neurons that are detectable at both the pre- and postsynaptic levels. Alterations in paired-pulse facilitation indicate presynaptic changes involving the release of the excitatory neurotransmitter glutamate, whereas changes in dendritic synaptic responses suggest postsynaptic changes in the responsiveness of neurons to synaptic input. Moreover, differential effects of chronic ethanol treatment on synaptic responses recorded in the dendrites versus the somatic region implicate additional effects of ethanol on somatically located mechanisms of CA1 pyramidal neurons. Furthermore, we suggest that complete tolerance to ethanol does not occur in the CA1 region of the hippocampus following chronic intermittent ethanol exposure.

Prolonged enhancement and depression of synaptic transmission in CA1 pyramidal neurons induced by transient forebrain ischemia in vivo

Evoked postsynaptic potentials of CA1 pyramidal neurons in rat hippocampus were studied during 48 h after severe ischemic insult using in vivo intracellular recording and staining techniques. Postischemic CA1 neurons displayed one of three distinct response patterns following contralateral commissural stimulation. At early recirculation times (0–12 h) approximately 50% of neurons exhibited, in addition to the initial excitatory postsynaptic potential, a late depolarizing postsynaptic potential lasting for more than 100 ms. Application of dizocilpine maleate reduced the amplitude of late depolarizing postsynaptic potential by 60%. Other CA1 neurons recorded in this interval failed to develop late depolarizing postsynaptic potentials but showed a modest blunting of initial excitatory postsynaptic potentials (non-late depolarizing postsynaptic potential neuron). The proportion of recorded neurons with late depolarizing postsynaptic potential characteristics increased to more than 70% during 13–24 h after reperfusion. Beyond 24 h reperfusion, ∼20% of CA1 neurons exhibited very small excitatory postsynaptic potentials even with maximal stimulus intensity. The slope of the initial excitatory postsynaptic potentials in late depolarizing postsynaptic potential neurons increased to ∼150% of control values up to 12 h after reperfusion indicating a prolonged enhancement of synaptic transmission. In contrast, the slope of the initial excitatory postsynaptic potentials in non-late depolarizing postsynaptic potential neurons decreased to less than 50% of preischemic values up to 24 h after reperfusion indicating a prolonged depression of synaptic transmission. More late depolarizing postsynaptic potential neurons were located in the medial portion of CA1 zone where neurons are more vulnerable to ischemia whereas more non-late depolarizing postsynaptic potential neurons were located in the lateral portion of CA1 zone where neurons are more resistant to ischemia. The result from the present study suggests that late depolarizing postsynaptic potential and small excitatory postsynaptic potential neurons may be irreversibly injured while non-late depolarizing postsynaptic potential neurons may be those that survive the ischemic insult. Alterations of synaptic transmission may be associated with the pathogenesis of postischemic neuronal injury.

Differential modulation by serotonin of GABA-mediated inhibitory postsynaptic currents recorded from layer V pyramidal neurons in the rat visual cortex

Rhubarb extracts provide neuroprotection after brain injury, but the mechanism of this protective effect is not known. The present study tests the hypothesis that rhubarb extracts interfere with the release of glutamate by brain neurons and, therefore, reduce glutamate excitotoxicity. To this end, the effects of emodin, an anthraquinone derivative extracted from Rheum tanguticum Maxim. Ex. Balf, on the synaptic transmission of CA1 pyramidal neurons in rat hippocampus were studied in vitro. The excitatory postsynaptic potential (EPSP) was depressed by bath-application of emodin (0.3–30 μM). Paired-pulse facilitation (PPF) of the EPSP was significantly increased by emodin. The monosynaptic inhibitory postsynaptic potential (IPSP) recorded in the presence of glutamate receptor antagonists (DNQX and AP5) was not altered by emodin. Emodin decreased the frequency, but not the amplitude, of the miniature EPSP (mEPSP). The inhibition of the EPSP induced by emodin was blocked by either 8-CPT, an adenosine A1 receptor antagonist, or by adenosine deaminase. These results suggest that emodin inhibits the EPSP by decreasing the release of glutamate from Schaffer collateral/commissural terminals via the activation of adenosine A1 receptors in rat hippocampal CA1 area and that the neuroprotective effects of rhubarb extracts may result from decreased glutamate excitotoxicity.

Depression of early and late monosynaptic inhibitory postsynaptic potentials in hippocampal CA1 neurons following prolonged benzodiazepine administration: role of a reduction in Cl- driving force.

GABAergic synaptic responses were studied by direct, monosynaptic activation of GABAergic interneurons in the CA1 region of in vitro hippocampal slices from rats made tolerant to the benzodiazepine, flurazepam. Monosynaptic IPSPs were elicited in CA1 pyramidal neurons, following 1 week oral flurazepam administration, by electrical stimulation at the stratum oriens/stratum pyramidale or stratum radiatum/ stratum-lacanosum border < or = 0.5 mm from the recording electrode plane. Excitatory input to pyramidal cells and interneurons was eliminated by prior superfusion of the glutamate receptor antagonists, APV (50 microM) and DNQX (10 microM). GABAA receptor-mediated early IPSPs were further isolated by perfusion of the GABAB antagonist, CGP 35348 (25 microM) or by diffusion of Cs- from the recording electrode. GABAB receptor-mediated late IPSPs were pharmacologically isolated by perfusion of the GABAA antagonist, picrotoxin (50 microM). There was a significant decrease in the amplitude of pharmacologically isolated early and late IPSPs in FZP-treated neurons without a change in passive membrane properties. A shift of the early IPSP, but not the late IPSP, reversal potential in FZP-treated neurons suggested that a change in the driving force for anions, presumably Cl, in CA1 neurons was one important factor related to the decreased early IPSP amplitude after prolonged activation of GABAA receptors by flurazepam. A decreased early IPSP amplitude accompanied by a decreased late IPSP amplitude suggested that presynaptic GABA release onto FZP-treated pyramidal cells may also be reduced. We conclude from these data that an impairment of GABAergic transmission in CA1 pyramidal neurons associated with the development of tolerance during chronic benzodiazepine treatment may be related to the regulation of both pre- and postsynaptic mechanisms at the GABA synapse.