scholarly journals The Creation of A Negative Slope Conductance Region by the activation of The Persistent Sodium Current Prolongs Near-Threshold Synaptic Potentials

2016 ◽  
Author(s):  
Cesar C. Ceballos ◽  
Antonio C. Roque ◽  
Ricardo M. Leão
Keyword(s):  
Temporal Integration ◽  
Brain Slices ◽  
Membrane Potentials ◽  
Negative Slope ◽  
Leak Current ◽  
Firing Threshold ◽  
Voltage Dependent ◽  
Negative Conductance ◽  
The Impact ◽  
Near Threshold

ABSTRACTA change of the input resistance (Rin) of the neuron involves a change in the membrane conductances by opening and closing of ion channels. In passive membranes, i.e., membranes with only linear leak conductances, the increase or decrease of these conductances leads to a decrease or increase of the Rin and the membrane time constant (τm). However, the presence of subthreshold voltage dependent currents can produce non-linear effects generating deviations from this relationship, especially the contradictory effect of negative conductances, as produced by the sodium-persistent current (INaP), on the Rin. In this work we aimed to analyze experimentally and theoretically the impact of the negative conductance produced by INaP on Rin. Experiments of whole-cell patch-clamp conducted in CA1 hippocampus pyramidal cells from brain slices showed a paradoxical voltage-dependent decrease of the Rin and the τm in subthreshold membrane potentials close to the firing threshold after the perfusion with TTX, which inhibits INaP. This effect is postulated to be a result of the negative slope conductance in the subthreshold region produced by this conductance. The analysis of the experimental data, together with simulations found that the slope conductance of INaP is negative for subthreshold membrane potentials and its magnitude is voltage dependent in the same range observed for the voltage-dependence of Rin and τm. The injection of an artificial INaP using dynamic-clamp in the presence of TTX restored the Rin and τm to its original values. Additionally the injection of an artificial leak current with a negative conductance in the presence of TTX restored the Rin and τm as the artificial Inap did. On the other hand, the injection of an artificial leak current with a positive conductance in the presence of TTX had no effect on the Rin and τm. We conclude that INaP increases the Rin and τm by the negative slope conductance observed in its non-monotonic I-V relationship. These results demonstrate that the effect of Inap on Rin and τm is stronger in potentials near the firing threshold, which could potentiate the temporal summation of the EPSPs increasing their temporal integration and facilitating action potential firing. Because of its negative slope conductance, INaP is more effective in increasing excitability near threshold than a depolarizing leak current.

Ca2+ Ions Block and Permeate Serotonin 5-HT3 Receptor Channels in Rat Hippocampal Interneurons

2003 ◽  
Vol 89 (4) ◽  
pp. 1864-1869 ◽  
Author(s):  
Johannes A. van Hooft ◽  
Wytse J. Wadman
Keyword(s):  
Binding Sites ◽  
Membrane Potentials ◽  
Ion Current ◽  
Stratum Radiatum ◽  
Negative Slope ◽  
Rate Theory ◽  
Dependent Manner ◽  
Site Model ◽  
Hippocampal Ca1 ◽  
Voltage Dependent

The serotonin 5-HT3receptor native to rat hippocampal CA1 stratum radiatum interneurons is blocked by Ca2+ ions in a dose- and voltage-dependent manner, which is reflected by a region of negative slope conductance in the I-V curve. The steep dependence on the extracellular Ca2+concentration suggests that the channel contains more than one binding site for Ca2+. A three barrier-two site model, based on Eyring rate theory, was used to describe the I-Vcurves. When extra- and intracellular K+ and Cs+ were substituted with Na+, the I-V curves were accurately fit by the model, unlike the I-V curves recorded under standard ionic conditions. This suggests that the K+ and Cs+ permeabilities are small compared with that of Na+. The distribution of the energy barriers and binding sites for Ca2+ and Na+ showed that the binding sites are located at approximately the 13′ and the –4′ position in the ion channel. The model predicts that at large hyperpolarized membrane potentials (more negative than −120 mV), the fractional Ca2+ current amounts to approximately 1% of the total ion current. However, at physiologically relevant membrane potentials, the fractional Ca2+ current is smaller (<0.1%) and the relative Ca2+permeability ( P Ca/ P Na) is estimated to be 0.10 at –60 mV.

Differential effects of cAMP and serotonin on membrane current, action-potential duration, and excitability in somata of pleural sensory neurons of Aplysia

1990 ◽  
Vol 64 (3) ◽  
pp. 978-990 ◽  
Author(s):  
D. A. Baxter ◽  
J. H. Byrne
Keyword(s):  
Voltage Clamp ◽  
Sensory Neurons ◽  
Slow Component ◽  
Membrane Potentials ◽  
Membrane Current ◽  
Negative Slope ◽  
Independent Effect ◽  
Current Response ◽  
Voltage Dependent ◽  
K Current

1. In somata of sensory neurons in the pleural ganglia of Aplysia californica, serotonin (5-HT) modulates at least three K+ currents: the S K+ current (IK,S), a slow component of the Ca2(+)-activated K+ current (IK,Ca), and the delayed or voltage-dependent K+ current (IK,V). The modulation of IK,S and the slow component of IK,Ca by 5-HT has been shown previously to be mediated via adenosine 3',5'-cyclic monophosphate (cAMP). To determine whether the modulation of IK,V by 5-HT also is mediated via cAMP, we used two-electrode voltage-clamp techniques to compare the modulation of membrane current by cAMP and 5-HT. 2. Current responses were elicited by brief (200 ms) voltage-clamp pulses before and after the bath application of analogues of cAMP. At all voltage-clamp potentials examined (-40-30 mV), analogues of cAMP reduced the amplitude of the current response. The properties of the cAMP-sensitive component of membrane current were revealed by computer subtraction of current responses elicited in the presence of the analogue of cAMP from current responses elicited before application of the analogue. The characteristics of the resulting cAMP difference current (IcAMP) suggested that cAMP modulated a component of membrane current that was relatively voltage independent, did not inactivate, and was active over a wide range of membrane potentials. In addition, the current-voltage (I-V) relationship of the cAMP difference current had a positive slope. These properties of the cAMP difference current were consistent with those of IK,S but did not indicate that IK,V was modulated by cAMP. 3. The cAMP-independent modulation of membrane current by 5-HT was examined by eliciting current responses first in the presence of an analogue of cAMP and again after the addition of 5-HT to the bath, which still contained the analogue. The presence of the analogue of cAMP occluded further modulation of IK,S by 5-HT. However, the analogue of cAMP did not occlude the modulation of IK,V by 5-HT. This cAMP-independent effect of 5-HT on membrane current was revealed by computer subtraction of current responses elicited in the presence of 5-HT from current responses elicited before the application of 5-HT (the analogue of cAMP was present throughout). The resulting cAMP-independent 5-HT difference current (I5-HT) was highly voltage dependent, had complex kinetics, and its I-V relationship had a negative slope at membrane potentials above 0 mV.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals The Impact of Intervention-Related Risk Factors on the Risk of Ventilator-Associated Pneumonia Is High in a Neurosurgical Intensive Care Unit

2020 ◽  
Vol 41 (S1) ◽  
pp. s407-s409
Author(s):  
Ksenia Ershova ◽  
Oleg Khomenko ◽  
Olga Ershova ◽  
Ivan Savin ◽  
Natalia Kurdumova ◽  
...  
Keyword(s):  
Risk Factors ◽  
Mechanical Ventilation ◽  
Negative Slope ◽  
Infection Prevention And Control ◽  
Ventilator Associated Pneumonia ◽  
Related Factors ◽  
Icu Patients ◽  
The Impact ◽  
Adf Test ◽  
Over Time

Background: Ventilator-associated pneumonia (VAP) represents the highest burden among all healthcare-associated infections (HAIs), with a particularly high rate in patients in neurosurgical ICUs. Numerous VAP risk factors have been identified to provide a basis for preventive measures. However, the impact of individual factors on the risk of VAP is unclear. The goal of this study was to evaluate the dynamics of various VAP risk factors given the continuously declining prevalence of VAP in our neurosurgical ICU. Methods: This prospective cohort unit-based study included neurosurgical patients who stayed in the ICU >48 consecutive hours in 2011 through 2018. The infection prevention and control (IPC) program was implemented in 2010 and underwent changes to adopt best practices over time. We used a 2008 CDC definition for VAP. The dynamics of VAP risk factors was considered a time series and was checked for stationarity using theAugmented Dickey-Fuller test (ADF) test. The data were censored when a risk factor was present during and after VAP episodes. Results: In total, 2,957 ICU patients were included in the study, 476 of whom had VAP. Average annual prevalence of VAP decreased from 15.8 per 100 ICU patients in 2011 to 9.5 per 100 ICU patients in 2018 (Welch t test P value = 7.7e-16). The fitted linear model showed negative slope (Fig. 1). During a study period we observed substantial changes in some risk factors and no changes in others. Namely, we detected a decrease in the use of anxiolytics and antibiotics, decreased days on mechanical ventilation, and a lower rate of intestinal dysfunction, all of which were nonstationary processes with a declining trend (ADF testP > .05) (Fig. 2). However, there were no changes over time in such factors as average age, comorbidity index, level of consciousness, gender, and proportion of patients with brain trauma (Fig. 2). Conclusions: Our evidence-based IPC program was effective in lowering the prevalence of VAP and demonstrated which individual measures contributed to this improvement. By following the dynamics of known VAP risk factors over time, we found that their association with declining VAP prevalence varies significantly. Intervention-related factors (ie, use of antibiotics, anxiolytics and mechanical ventilation, and a rate of intestinal dysfunction) demonstrated significant reduction, and patient-related factors (ie, age, sex, comorbidity, etc) remained unchanged. Thus, according to the discriminative model, the intervention-related factors contributed more to the overall risk of VAP than did patient-related factors, and their reduction was associated with a decrease in VAP prevalence in our neurosurgical ICU.Funding: NoneDisclosures: None

Presynaptic inhibition produced by an identified presynaptic inhibitory neuron. I. Physiological mechanisms

1986 ◽  
Vol 55 (1) ◽  
pp. 113-130 ◽  
Author(s):  
R. Kretz ◽  
E. Shapiro ◽  
E. R. Kandel
Keyword(s):  
Voltage Clamp ◽  
Presynaptic Inhibition ◽  
Inhibitory Neuron ◽  
Outward Current ◽  
Membrane Potentials ◽  
Slow Inward Current ◽  
Synaptic Potential ◽  
Synaptic Current ◽  
Voltage Dependent ◽  
Stimulation Of

We have examined the synaptic conductance mechanisms underlying presynaptic inhibition in Aplysia californica in a circuit in which all the neural elements are identified cells (Fig. 1). L10 makes connections to identified follower cells (RB and left upper quadrant cells, L2-L6). These connections are presynaptically inhibited by stimulating cells of the L32 cluster (4). L32 cells produce a slow inhibitory synaptic potential on L10. This inhibitory synaptic potential is associated with an apparent increased membrane conductance in L10. Both the inhibitory postsynaptic potential (IPSP) and the conductance increase are voltage dependent; the IPSP could not be reversed by hyperpolarizing the membrane potentials to - 120 mV. The hyperpolarization of L10 induced by L32 reduces the transmitter output of L10 and thereby contributes to presynaptic inhibition. However, this hyperpolarization accounts for about 30% of the effect because presynaptic inhibition can still be observed even when the hyperpolarization of L10 by L32 is prevented by voltage clamping. When L10 is voltage clamped, stimulation of L32 produces a slow outward synaptic current associated with an apparent increased conductance. Both the synaptic current and conductance change measured under clamp are voltage dependent, and the outward current could not be reversed. This synaptic current is not mediated by an increase in C1- conductance. It is sensitive to external K+ concentration, especially at hyperpolarized membrane potentials. With L10 under voltage clamp, stimulation of L32 also reduces a slow inward current in L10. This current has time and voltage characteristics similar to those of the Ca2+ current. Presynaptic inhibition is still produced by L32 when L10 is voltage clamped, and transmitter release is elicited by depolarizing voltage-clamp pulses. This component of presynaptic inhibition, which accounts for approximately 70% of the inhibition, appears to be due to a decrease in the Ca2+ current in the presynaptic neuron.

scholarly journals Characterization of receptors mediating the actions of dopamine on an identified inhibitory motoneurone of the cockroach

1991 ◽  
Vol 155 (1) ◽  
pp. 203-217 ◽  
Author(s):  
J. P. Davis ◽  
R. M. Pitman
Keyword(s):  
Periplaneta Americana ◽  
Voltage Dependence ◽  
Negative Resistance ◽  
Membrane Potentials ◽  
Dopaminergic Agonists ◽  
Current Voltage ◽  
Voltage Dependent ◽  
Inward Currents ◽  
Ly 171555 ◽  
Relationship Of

1. The effects of a number of dopaminergic agonists and antagonists upon the soma of a prothoracic inhibitory motoneurone of the cockroach (Periplaneta americana) have been recorded under voltage-clamp conditions. 2. Dopamine generates inward currents that are extremely voltage-dependent: currents increase rapidly at membrane potentials more negative than about −120 to −150 mV and also show a peak at membrane potentials of approximately −20 mV. As a result of this voltage-dependence, dopamine induces a region of negative resistance in the current-voltage relationship of the neurone. 3. The dopaminergic agonists apomorphine, bromocriptine, ergometrine and A-6,7-DTN mimic the action of dopamine on this neurone, all having a similar voltage-dependence to that of dopamine. The selective D-1 receptor agonist SK&F82526 and the D-2 agonist LY 171555, however, were both inactive on the preparation. 4. Responses to dopamine were suppressed by a number of D-1 and D-2 receptor antagonists, indicating that the pharmacological profile of the dopamine-sensitive receptor in this insect preparation is different from that of vertebrate dopamine receptors.

scholarly journals LRRC52 regulates BK channel function and localization in mouse cochlear inner hair cells

2019 ◽  
Vol 116 (37) ◽  
pp. 18397-18403 ◽  
Author(s):  
Christopher J. Lingle ◽  
Pedro L. Martinez-Espinosa ◽  
Aizhen Yang-Hood ◽  
Luis E. Boero ◽  
Shelby Payne ◽  
...  
Keyword(s):  
Hair Cells ◽  
Glutamate Release ◽  
Nerve Fibers ◽  
Bk Channels ◽  
Bk Channel ◽  
Membrane Potentials ◽  
Macromolecular Complex ◽  
Inner Hair Cells ◽  
Channel Function ◽  
Voltage Dependent

The perception of sound relies on sensory hair cells in the cochlea that convert the mechanical energy of sound into release of glutamate onto postsynaptic auditory nerve fibers. The hair cell receptor potential regulates the strength of synaptic transmission and is shaped by a variety of voltage-dependent conductances. Among these conductances, the Ca2+- and voltage-activated large conductance Ca2+-activated K+channel (BK) current is prominent, and in mammalian inner hair cells (IHCs) displays unusual properties. First, BK currents activate at unprecedentedly negative membrane potentials (−60 mV) even in the absence of intracellular Ca2+elevations. Second, BK channels are positioned in clusters away from the voltage-dependent Ca2+channels that mediate glutamate release from IHCs. Here, we test the contributions of two recently identified leucine-rich-repeat–containing (LRRC) regulatory γ subunits, LRRC26 and LRRC52, to BK channel function and localization in mouse IHCs. Whereas BK currents and channel localization were unaltered in IHCs fromLrrc26knockout (KO) mice, BK current activation was shifted more than +200 mV in IHCs fromLrrc52KO mice. Furthermore, the absence of LRRC52 disrupted BK channel localization in the IHCs. Given that heterologous coexpression of LRRC52 with BK α subunits shifts BK current gating about −90 mV, to account for the profound change in BK activation range caused by removal of LRRC52, we suggest that additional factors may help define the IHC BK gating range. LRRC52, through stabilization of a macromolecular complex, may help retain some other components essential both for activation of BK currents at negative membrane potentials and for appropriate BK channel positioning.

Modulation of the delayed rectifier, IK, by cadmium in cat ventricular myocytes

1992 ◽  
Vol 262 (1) ◽  
pp. C75-C83 ◽  
Author(s):  
C. H. Follmer ◽  
N. J. Lodge ◽  
C. A. Cullinan ◽  
T. J. Colatsky
Keyword(s):  
Voltage Clamp ◽  
Ventricular Myocytes ◽  
Outward Current ◽  
Membrane Potentials ◽  
Delayed Rectifier ◽  
Voltage Range ◽  
Control Value ◽  
Current Voltage ◽  
Voltage Dependent ◽  
Slope Factor

The effects of cadmium on the delayed outward potassium current (IK) were investigated in isolated cat ventricular myocytes using the single suction pipette voltage-clamp technique. IK activation was examined using peak tail currents elicited after 750-ms voltage-clamp steps to selected membrane potentials from a holding potential of -40 mV. In the presence of Cd2+ (0.2 mM), peak tail currents increased from a control value of 85 +/- 12 to 125 +/- 18 pA (n = 4). Activation curves constructed from the average peak tail-current measurements in all experiments showed that Cd2+ shifted the voltage dependence of activation to more positive potentials by 16.4 +/- 2.0 mV and increased the slope factor of the activation curve from 6.1 +/- 0.2 to 6.9 +/- 0.2 mV. In the absence of Cd2+, increases in holding potential from -30 to -70 mV had no effect on the magnitude of the peak tail currents, suggesting that the Cd(2+)-induced increase was not the result of a voltage-dependent increase in the number of available K+ channels at the holding potential. Slow voltage ramps from -70 to +70 mV revealed that Cd2+ increased the outward current at membrane potentials positive to +20 mV and shifted the voltage range in which IK inwardly rectified to more positive potentials. The fully activated current-voltage relationship was also shifted to more positive potentials by Cd2+. Cd2+ did not alter channel selectivity for K+.(ABSTRACT TRUNCATED AT 250 WORDS)

Ethacizin blockade of calcium channels: a test of the guarded receptor hypothesis

1989 ◽  
Vol 257 (5) ◽  
pp. H1693-H1704
Author(s):  
C. F. Starmer ◽  
A. I. Undrovinas ◽  
F. Scamps ◽  
G. Vassort ◽  
V. V. Nesterenko ◽  
...  
Keyword(s):  
Calcium Channels ◽  
Cell Voltage ◽  
Membrane Potentials ◽  
Specific Rate ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Channel Inactivation ◽  
Ventricular Cells ◽  
Channel Blocking ◽  
Voltage Dependent

The effect on calcium channels of the sodium channel antagonist, ethacizin, was studied in isolated frog ventricular cells using the whole cell voltage-clamp methodology. Ethacizin was found to block inward calcium current in a frequency-, voltage-, and concentration-dependent manner. The frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage-dependent mixture of calcium channels harboring either an accessible or an inaccessible binding site. With repetitive stimulation, the pulse-to-pulse reduction in peak current is shown to be exponential, with a rate linearly related to the interstimulus interval and the drug concentration. Observed frequency- and concentration-dependent blocks were consistent with the predictions of the model, and mixture-specific rate constants were estimated from these data. The negligible shift in channel inactivation and the reduction of apparent binding and unbinding rates with more polarized membrane potentials imply the active moiety of ethacizin blocks open channels and is trapped within the channel at resting membrane potentials. The binding rate at 0 mV is similar to that observed in studies of interactions of other open channel blocking agents with voltage- and ligand-gated channels.

scholarly journals S13. IMPACT OF POLYGENIC AND POLY-ENVIRONMENTAL RISK FACTORS ON A PSYCHOSIS RISK PHENOTYPE EXPLAINED THROUGH BRAIN STRUCTURE

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S35-S36
Author(s):  
Tina Meller ◽  
Simon Schmitt ◽  
Frederike Stein ◽  
Katharina Brosch ◽  
Dominik Grotegerd ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cognitive Function ◽  
Environmental Risk ◽  
Brain Structure ◽  
Negative Slope ◽  
Mediation Model ◽  
Moderated Mediation Model ◽  
Main Effect ◽  
Psychosis Risk ◽  
The Impact

Abstract Background While single (genetic and environmental) risk factors for psychosis have been studied for their impact on brain structure and function, there is little understanding of how they interact to generate psychosis liability on the neural level. Direct associations between cumulative genetic risk scores and risk phenotypes are often weak, and analyses of G×E interactions are scarce. We developed and tested a multivariate model, in which the effects of cumulative environmental and genetic risk on a dimensional phenotype are mediated by brain structural variation. Methods In a data set of 440 non-clinical subjects, we tested a moderated mediation model with an interaction of an environmental (ERS) and a polygenic risk score (PRS) for schizophrenia, impacting on the subclinical psychosis spectrum phenotype schizotypy. We propose this effect to be mediated by grey matter volume variation, derived from voxel-based morphometry. In addition, cognitive function (CF) was considered as a potential moderator. Results Firstly, in a whole-brain analysis, we detected a significant interaction effect of PRS×ERS in a cluster (k=910, x/y/z=-4/-50/33, p=0.024 FWE cluster-level corrected) including the left precuneus (Pc, 64%) and posterior cingulate gyrus (pcG, 33%). Secondly, cluster values were extracted and entered into a multivariate moderated mediation model. This model was significant, showing that Pc/pcG volume mediated the impact of a PRS×ERS interaction on positive schizotypy (R2=10.91%, p=4.9×10–5). In predicting Pc/pcG variation (R2=51.69%), neither PRS (b=0.638, p=0.830) nor ERS had a main effect on grey matter variation, but their interaction was significant (b=-3.13, p=0.002): The intensity and direction of the PRS effect is moderated by the level of ERS, with a positive slope for low ERS (i.e., low environmental risk), and a negative slope for high ERS. In predicting positive schizotypy, the direct effects of PRS (b=6.116, p=0.477) and ERS (b=0.006, p=0.068) were not significant. However, we demonstrate an indirect effect through brain structural variation, showing a significant mediation (index=0.223, bootstrapped confidence interval 0.004–0.542). Cluster variation had a significant main effect on positive schizotypy (b=-0.277, p=0.049), but was modulated by the level of cognitive function, with a positive slope for low CF, and a negative slope for high CF, showing a second significant interaction (b=-0.070, p=0.027). Discussion Our finding is the first to integrate polygenic and poly-environmental markers with MRI parameters to demonstrate that the interaction of these cumulated risk factors leads to the emergence of subclinical symptoms through changes in brain structure. Furthermore, our model confirms cognition as a protective factor, indicating that above-average levels of cognitive function can compensate for dysfunctional processes that arise from altered neurodevelopment. Such compensatory mechanisms are crucial for understanding resilience, explaining high (positive) symptom load in unaffected individuals. Conventional diathesis-stress models propose increased vulnerability specifically to adverse events – our model extends this to suggest an inverted effect for high PRS and low ERS subjects. Under favourable environmental conditions, an increased genetic load might paradoxically result in low psychopathology outcomes or gain of function, supporting the notion of genes associated with schizophrenia as “plasticity genes” rather than simple risk factors. In sum, the present study provides proof for a multivariate model predicting the impact of genetic and environmental risk on a psychosis risk phenotype, extendable to other clinical spectra.

Hippocampal Interneurons Are Excited Via Serotonin-Gated Ion Channels

1997 ◽  
Vol 78 (5) ◽  
pp. 2493-2502 ◽  
Author(s):  
Lori L. McMahon ◽  
Julie A. Kauer
Keyword(s):  
Ion Channels ◽  
Synaptic Transmission ◽  
Dentate Gyrus ◽  
Granule Cells ◽  
Brain Slices ◽  
Pyramidal Cells ◽  
Stratum Radiatum ◽  
Negative Slope ◽  
Patch Clamp Recording ◽  
Gated Ion Channels

McMahon, Lori L. and Julie A. Kauer. Hippocampal interneurons are excited via serotonin-gated ion channels. J. Neurophysiol. 78: 2493–2502, 1997. Serotonergic neurons of the median raphe nucleus heavily innervate hippocampal GABAergic interneurons located in stratum radiatum of area CA1, suggesting that this strong subcortical projection may modulate interneuron excitability. Using whole cell patch-clamp recording from interneurons in brain slices, we tested the effects of serotonin (5-HT) on the physiological properties of these interneurons. Serotonin produces a rapid inward current that persists when synaptic transmission is blocked by tetrodotoxin and cobalt, and is unaffected by ionotropic glutamate and γ-aminobutyric acid (GABA) receptor antagonists. The 5-HT–induced current was independent of G-protein activation. Pharmacological evidence indicates that 5-HT directly excites these interneurons through activation of 5-HT3 receptors. At membrane potentials negative to −55 mV, the current-voltage ( I-V) relationship of the 5-HT current displays a region of negative slope conductance. Therefore the response of interneurons to 5-HT strongly depends on membrane potential and increases greatly as cells are depolarized. Removal of extracellular calcium, but not magnesium, increases the amplitude of 5-HT–induced currents and removes the region of negative slope conductance, thereby linearizing the I-V relationship. The axons of 5-HT–responsive interneurons ramify widely within CA1; some of these interneurons also project to and arborize extensively in the dentate gyrus. The organization of these inhibitory connections strongly suggests that these cells regulate excitability of both CA1 pyramidal cells and dentate granule cells. As our results indicate that 5-HT may mediate fast excitatory synaptic transmission onto these interneurons, serotonergic inputs can simultaneously modulate the output of both hippocampus and dentate gyrus.

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