Anoxic depression of excitatory and inhibitory postsynaptic potentials in rat neocortical slices

1. The effects of brief anoxia (4-6 min replacement of O2 by N2) on synaptic potentials evoked from layer IV and/or the white matter were studied in pyramidal neurons of layers II-III from rat neocortical slices. 2. The early and late components of excitatory postsynaptic potentials (EPSPs) showed differential sensitivity to anoxia: within 2 min the late EPSP (lEPSP) disappeared, whereas the amplitude of the early EPSP (eEPSP) decreased by 70% at 5 min of anoxia. Recovery was complete within 4-11 min. 3. Both fast and slow inhibitory postsynaptic potentials (IPSPs) were extremely sensitive to lack of O2 and were abolished earlier than the lEPSP evoked by the same stimulus. As well, recovery of the IPSPs was always more delayed than that of the EPSPs. 4. A transient increase in excitability during early anoxia and/or midrecovery, manifested as enhanced probability of spiking in 25% of neurons, is attributed to the higher sensitivity of IPSPs compared with EPSPs. 5. The anoxic-induced depression of the lEPSP and IPSPs, which are generated close to the soma, is not due to depolarization-induced occlusion; however, occlusion may cause an attenuation of the eEPSP at dendritic sites. 6. The depression of the EPSPs is not a result of a decreased transmembrane Na+ gradient after inactivation of Na-K-adenosine triphosphatase (Na-K-ATPase). Although ouabain induced a depolarization similar to that of anoxia, it did not affect EPSP amplitude.(ABSTRACT TRUNCATED AT 250 WORDS)     

Active summation of excitatory postsynaptic potentials in hippocampal CA3 pyramidal neurons

The manner in which the thousands of synaptic inputs received by a pyramidal neuron are summed is critical both to our understanding of the computations that may be performed by single neurons and of the codes used by neurons to transmit information. Recent work on pyramidal cell dendrites has shown that subthreshold synaptic inputs are modulated by voltage-dependent channels, raising the possibility that summation of synaptic responses is influenced by the active properties of dendrites. Here, we use somatic and dendritic whole-cell recordings to show that pyramidal cells in hippocampal area CA3 sum distal and proximal excitatory postsynaptic potentials sublinearly and actively, that the degree of nonlinearity depends on the magnitude and timing of the excitatory postsynaptic potentials, and that blockade of transient potassium channels linearizes summation. Nonlinear summation of synaptic inputs could have important implications for the computations performed by single neurons and also for the role of the mossy fiber and perforant path inputs to hippocampal area CA3.     

Integration of excitatory postsynaptic potentials in dendrites of motoneurons of rat spinal cord slice cultures

We examined the attenuation and integration of spontaneous excitatory postsynaptic potentials (sEPSPs) in the dendrites of presumed motoneurons (MNs) of organotypic rat spinal cord cultures. Simultaneous whole cell recordings in current-clamp mode were made from either the soma and a dendrite or from two dendrites. Direct comparison of the two voltage recordings revealed that the membrane potentials at the two recording sites followed each other very closely except for the fast-rising phases of the EPSPs. The dendritic recording represented a low-pass filtered version of the somatic recording and vice versa. A computer-assisted method was developed to fit the sEPSPs with a generalized alpha-function for measuring their amplitudes and rise times (10-90%). The mean EPSP peak attenuation between the two recording electrodes was determined by a maximum likelihood analysis that extracted populations of similar amplitude ratios from the fitted events at each electrode. For each pair of recordings, the amplitude attenuation ratio for EPSP traveling from dendrite to soma was larger than that traveling from soma to dendrite. The linear relation between mean ln attenuation and distance between recording electrodes was used to map 1/e attenuations into units of distance (micron). For EPSPs with typical time course traveling from the somatic to the dendritic recording electrode, the mean 1/e attenuation corresponded to 714 micron for EPSPs traveling in the opposite direction, the mean 1/e attenuation corresponded to 263 micron. As predicted from cable analysis, fast EPSPs attenuated more in both the somatofugal and somatopetal direction than did slow EPSPs. For EPSPs with rise times shorter than approximately 2.0 ms, the attenuation factor increased steeply. Compartmental computer modeling of the experiments with biocytin-filled and reconstructed MNs that used passive membrane properties revealed amplitude attenuation ratios of the EPSP traveling in both the somatofugal and somatopetal direction that were comparable to those observed in real experiments. The modeling of a barrage of sEPSPs further confirmed that the somato-dendritic compartments of a MN are virtually isopotential except for the fast-rising phase of EPSPs. Large, transient differences in membrane potential are locally confined to the site of EPSP generation. Comparing the modeling results with the experiments suggests that the observed attenuation ratios are adequately explained by passive membrane properties alone.     

Determinants of voltage attenuation in neocortical pyramidal neuron dendrites

How effectively synaptic and regenerative potentials propagate within neurons depends critically on the membrane properties and intracellular resistivity of the dendritic tree. These properties therefore are important determinants of neuronal function. Here we use simultaneous whole-cell patch-pipette recordings from the soma and apical dendrite of neocortical layer 5 pyramidal neurons to directly measure voltage attenuation in cortical neurons. When combined with morphologically realistic compartmental models of the same cells, the data suggest that the intracellular resistivity of neocortical pyramidal neurons is relatively low ( approximately 70 to 100 Omegacm), but that voltage attenuation is substantial because of nonuniformly distributed resting conductances present at a higher density in the distal apical dendrites. These conductances, which were largely blocked by bath application of CsCl (5 mM), significantly increased steady-state voltage attenuation and decreased EPSP integral and peak in a manner that depended on the location of the synapse. Together these findings suggest that nonuniformly distributed Cs-sensitive and -insensitive resting conductances generate a "leaky" apical dendrite, which differentially influences the integration of spatially segregated synaptic inputs.     

Effects of PKA and PKC on miniature excitatory postsynaptic currents in CA1 pyramidal cells

Protein kinases play an important role in controlling synaptic strength at excitatory synapses on CA1 pyramidal cells. We examined the effects of activating cAMP-dependent protein kinase or protein kinase C (PKC) on the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) with perforated patch recording techniques. Both forskolin and phorbol-12,13-dibutryate (PDBu) caused a large increase in mEPSC frequency, but only PDBu increased mEPSC amplitude, an effect that was not observed when standard whole cell recording was performed. These results support biochemical observations indicating that PKC, similar to calcium/calmodulin-dependent protein kinase II, has an important role in controlling synaptic strength via modulation of AMPA receptor function, potentially through the direct phosphorylation of the GluR1 subunit.     

Serotonin modulates spike backpropagation and associated [Ca2+]i changes in the apical dendrites of hippocampal CA1 pyramidal neurons

The effect of serotonin (5-HT) on somatic and dendritic properties was analyzed in pyramidal neurons from the CA1 region in slices from the rat hippocampus. Bath-applied 5-HT (10 microM) hyperpolarized the soma and apical dendrites and caused a conductance increase at both locations. In the dendrites (200-300 microm from the soma) trains of antidromically activated, backpropagating action potentials had lower peak potentials in 5-HT than in normal artificial cerebrospinal fluid. Spike amplitudes were about the same in the two solutions. Similar results were found when the action potentials were evoked synaptically with stimulation in the stratum oriens. In the soma, spike amplitudes increased in 5-HT, with only a small decrease in the peak potential. Calcium concentration measurements, made with bis-fura-2 injected through patch electrodes, showed that the amplitude of the [Ca2+]i changes was reduced at all locations in 5-HT. The reduction of the [Ca2+]i change in the soma was confirmed in slices where cells were loaded with fura-2-AM. The reduction at the soma in 5-HT, where the spike amplitude increased, suggests that the reduction is due primarily to direct modulation of Ca2+ channels. In the dendrites, the reduction is due to a combination of this channel modulation and the lowering of the peak potential of the action potentials.     

Estimating the time course of the excitatory synaptic conductance in neocortical pyramidal cells using a novel voltage jump method

We introduce a method that permits faithful extraction of the decay time course of the synaptic conductance independent of dendritic geometry and the electrotonic location of the synapse. The method is based on the experimental procedure of Pearce (1993), consisting of a series of identical somatic voltage jumps repeated at various times relative to the onset of the synaptic conductance. The progression of synaptic charge recovered by successive jumps has a characteristic shape, which can be described by an analytical function consisting of sums of exponentials. The voltage jump method was tested with simulations using simple equivalent cylinder cable models as well as detailed compartmental models of pyramidal cells. The decay time course of the synaptic conductance could be estimated with high accuracy, even with high series resistances, low membrane resistances, and electrotonically remote, distributed synapses. The method also provides the time course of the voltage change at the synapse in response to a somatic voltage-clamp step and thus may be useful for constraining compartmental models and estimating the relative electrotonic distance of synapses. In conjunction with an estimate of the attenuation of synaptic charge, the method also permits recovery of the amplitude of the synaptic conductance. We use the method experimentally to determine the decay time course of excitatory synaptic conductances in neocortical pyramidal cells. The relatively rapid decay time constant we have estimated (tau approximately 1.7 msec at 35 degrees C) has important consequences for dendritic integration of synaptic input by these neurons.     

Monosynaptic GABA-mediated inhibitory postsynaptic potentials in CA1 pyramidal cells of hyperexcitable hippocampal slices from kainic acid-treated rats

To examine the mechanisms underlying chronic epileptiform activity, field potentials were first recorded to identify hyperexcitable hippocampal slices from kainic acid-treated rats. Intracellular recordings were then obtained from CA1 pyramidal cells in the hyperexcitable areas. Twenty-two of the 47 cells responded to electrical stimulation of the stratum radiatum with a burst of two or more action potentials and reduced early inhibitory postsynaptic potentials, and were considered hyperexcitable. The remaining 25 cells were not hyperexcitable, displaying a single action potential and biphasic inhibitory postsynaptic potentials after stimulation, like control cells (n = 20). A long duration, voltage-sensitive component was associated with subthreshold excitatory postsynaptic potentials in the majority of hyperexcitable (12/15) and non-hyperexcitable (3/5) cells examined from kainic acid-treated animals, but not from cells (1/10) of control animals. Stimulation of stratum radiatum during pharmacological blockade of ionotropic excitatory amino acid synaptic transmission elicited biphasic monosynaptic inhibitory postsynaptic potentials in all hyperexcitable (n = 9) and non-hyperexcitable (n = 9) cells tested from kainate-treated animals, as well as in control cells (n = 8). The mean amplitude, latency to peak, equilibrium potential, and conductance changes of early and late monosynaptic inhibitory postsynaptic potentials were not different between cells of kainic acid-treated and control animals. In seven hyperexcitable cells tested, the early component of monosynaptic inhibitory postsynaptic potentials was significantly reduced by the GABAA receptor antagonist bicuculline (100-200 microM). The late component was significantly decreased by the GABAB receptor antagonist 2-hydroxysaclofen (1-2 mM; n = 3). Comparable effects were observed on early and late monosynaptic inhibitory postsynaptic potentials in non-hyperexcitable cells (n = 4) from kainic acid-treated animals and control cells (n = 5). These results suggest that GABAergic synapses on hyperexcitable hippocampal pyramidal cells of kainate-treated rats are intact and functional. Therefore, epileptiform activity in the kainate-lesioned hippocampus may not arise from a disconnection of GABAergic synapses made by inhibitory interneurons on pyramidal cells. The hyperexcitability may be due to underactivation of inhibitory interneurons and/or reorganization of excitatory inputs to pyramidal cells since, in kainate-treated animals, pyramidal cells appear to express additional excitatory mechanisms.     

Cholinergic excitation of dendrites in neocortical neurons

Discharge patterns were studied in response to iontophoretic application of acetylcholine to the soma and dendrites of 128 neocortical pyramidal neurons of layer V. Extracellular recordings were obtained from slices of the guinea-pig parietal cortex. All responses found were excitatory and were better expressed in spontaneously firing cells than in silent ones. Sensitivity to acetylcholine was approximately the same at somatic and dendritic sites in all the cells. Activation of muscarinic receptors gave rise to firing patterns with equal latencies and intensities when applied to both soma and dendrites. The latter suggests that membrane excitation elicited in dendrites by binding of acetylcholine to muscarinic cholinoreceptors is likely to propagate towards the soma through intracellular biochemical processes. Modulating effect of acetylcholine on output firing patterns, elicited by dendritic application of excitatory amino acids, included shortening of the somatic response latency and increase of response intensity and duration. We propose that, in contrast to glutamatergic excitation, the spread of cholinergic excitation along dendrites involves intra-cellular chemical signalling and results in changing the electrical properties of dendrites all over their length.     

Spontaneous excitatory postsynaptic currents in hippocampal CA1 pyramidal neurons of the gerbil after transient ischemia

The changes in the spontaneous excitatory postsynaptic currents (sEPSCs) after transient cerebral ischemia were studied using whole-cell recording from CA1 pyramidal neurons in the gerbil. In neurons recorded 1-2 days after ischemia, sEPSCs had a slowed time course with the decay time constant fitted by a single exponential and it progressively increased after ischemia. Frequency and amplitude distribution of sEPSCs in ischemic neurons were not significantly different from those in the control neurons. The results support the view that abnormal non-N-methyl-D-aspartic acid currents originate at the degenerated postsynaptic site, unrelated to the presynaptic releasing mechanisms.     

Calcium dynamics in single spines during coincident pre- and postsynaptic activity depend on relative timing of back-propagating action potentials and subthreshold excitatory postsynaptic potentials

We compared the transient increase of Ca2+ in single spines on basal dendrites of rat neocortical layer 5 pyramidal neurons evoked by subthreshold excitatory postsynaptic potentials (EPSPs) and back-propagating action potentials (APs) by using calcium fluorescence imaging. AP-evoked Ca2+ transients were detected in both the spines and in the adjacent dendritic shaft, whereas Ca2+ transients evoked by single EPSPs were largely restricted to a single active spine head. Calcium transients elicited in the active spines by a single AP or EPSP, in spines up to 80 micro(m) for the soma, were of comparable amplitude. The Ca2+ transient in an active spine evoked by pairing an EPSP and a back-propagating AP separated by a time interval of 50 ms was larger if the AP followed the EPSP than if it preceded it. This difference reflected supra- and sublinear summation of Ca2+ transients, respectively. A comparable dependence of spinous Ca2+ transients on relative timing was observed also when short bursts of APs and EPSPs were paired. These results indicate that the amplitude of the spinous Ca2+ transients during coincident pre- and postsynaptic activity depended critically on the relative order of subthreshold EPSPs and back-propagating APs. Thus, in neocortical neurons the amplitude of spinous Ca2+ transients could encode small time differences between pre- and postsynaptic activity.     

Large amplitude miniature excitatory postsynaptic currents in hippocampal CA3 pyramidal neurons are of mossy fiber origin

Neonatal (P0) gamma-irradiation was used to lesion selectively the mossy fiber (MF) synaptic input to CA3 pyramidal cells. This lesion caused a > 85% reduction in the MF input as determined by quantitative assessment of the number of dynorphin immunoreactive MF boutons. The gamma-irradiation lesion caused a reduction in the mean number of miniature excitatory postsynaptic currents (mEPSCs) recorded from CA3 pyramidal cells (2,292 vs. 1,429/3-min period; n = 10). The lesion also caused a reduction in the mean mEPSC peak amplitude from 19.1 +/- 0.45 to 14.6 +/- 0.49 pA (mean +/- SE; peak conductance 238.8 +/- 5.6 to 182.0 +/- 6.1 pS). Similarly, there was a reduction in the mean 10-85% rise time from 1.72 +/- 0.02 ms to 1.42 +/- 0.04 ms. The effects of the gamma-irradiation on both mEPSC amplitude and 10-85% rise time were significant at P < 0.002 and P < 0.005 (2-tailed Kolmogorov-Smirnov test). Based on the selectively of the gamma-irradiation, MF and non-MF mEPSC amplitude and 10-85% rise-time distributions were calculated. Both the amplitude and 10-85% rise-time distributions showed extensive overlap between the MF and non-MF mediated mEPSCs. The MF mEPSC distributions had a mean peak amplitude of 24.6 pA (307.5 pS) and a mean 10-85% rise time of 2.16 ms. THe non-MF mEPSC distributions had a mean peak amplitude of 12.2 pA (152.5 pS) and 10-85% rise time of 1.26 ms. The modes of the amplitude distributions were the same at 5 pA (62 pS). The MF and non-MF mEPSC amplitude and 10-85% rise-time distributions were significantly different at P < 0.001 (1-tailed, large sample Kolmogorov-Smirnov test). The data demonstrate that the removal of the MF synaptic input to CA3 pyramidal cells leads to the absence of the large amplitude mEPSCs that are present in control recordings.     

Neuroactive steroids induce GABA(A) receptor-mediated depolarizing postsynaptic potentials in hippocampal CA1 pyramidal cells of the rat

Intracellular recordings were performed in area CA1 pyramidal cells of rat hippocampal slices to determine the effects of certain steroids on inhibitory postsynaptic potentials/currents (IPSP/Cs) mediated by GABA(A) receptors. Following application of the steroids 5alpha-pregnan-3alpha,21-diol-20-one (5alpha-THDOC), alphaxalone and 5beta-pregnan-3alpha-ol-20-one (pregnanolone) hyperpolarizing PSPs developed into biphasic responses consisting of an early hyperpolarizing and a late depolarizing PSP sequence. Steroid-induced depolarizing PSPs could be elicited in the presence of antagonists to non-NMDA, NMDA, and GABA(B) receptors, indicating that these receptor types do not contribute significantly to the initiation of these responses. Depolarizing PSPs were completely blocked by both GABA(A) receptor antagonists bicuculline and t-butylbicyclophosphorothionat (TBPS) providing evidence for their mediation by GABA(A) receptors. The reversal potential of steroid-induced late inward PSCs, measured in single-electrode voltage clamp, was -29.9+/-5.3 mV, whereas the early outward current, which corresponded to the early hyperpolarizing component of PSPs, reversed at -68.2+/-1.5 mV. Depolarizing PSPs and late inward PSCs were sensitive to reduction of extracellular [HCO3-] and block of carbonic anhydrase by application of acetazolamide. The results suggest that certain neuroactive steroids can induce GABA(A) receptor-mediated depolarizing PSPs, which are dependent on HCO3-.     

Differential impact of miniature synaptic potentials on the soma and dendrites of pyramidal neurons in vivo

We studied the impact of transmitter release resistant to tetrodotoxin (TTX) in morphologically identified neocortical pyramidal neurons recorded intracellularly in barbiturate-anesthetized cats. It was observed that TTX-resistant release occurs in pyramidal neurons in vivo and at much higher frequencies than was previously reported in vitro. Further, in agreement with previous findings indicating that GABAergic and glutamatergic synapses are differentially distributed in the somata and dendrites of pyramidal cells, we found that most miniature synaptic potentials were sensitive to gamma-aminobutyric acid-A (GABA(A)) or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists in presumed somatic and dendritic impalements, respectively. Pharmacological blockage of spontaneous synaptic events produced large increases in input resistance that were more important in dendritic (approximately 50%) than somatic (approximately 10%) impalements. These findings imply that in the intact brain, pyramidal neurons are submitted to an intense spike-independent synaptic bombardment that decreases the space constant of the cells. These results should be taken into account when extrapolating in vitro findings to intact brains.     

Purinergic fast excitatory postsynaptic potentials in myenteric neurons of guinea pig: distribution and pharmacology

BACKGROUND & AIMS: Adenosine triphosphate (ATP) acting at P2 receptors mediates some fast excitatory postsynaptic potentials (fEPSPs) in myenteric neurons of guinea pig ileum. The present studies investigate the distribution of purinergic fEPSPs along the length of the gut and characterize the P2-receptor subtype mediating fEPSPs. METHODS: Conventional intracellular electrophysiological methods were used to record from myenteric neurons in vitro. RESULTS: At a membrane potential of -97 +/- 1 mV, the amplitude (25 +/- 1 mV; n = 307) of fEPSPs was similar along the gut. Hexamethonium (100 micromol/L) inhibited fEPSPs in the gastric corpus by 98% +/- 1% (n = 31) and in the duodenum, ileum, taenia coli, proximal colon, and distal colon by 42%-55%. In the presence of hexamethonium, suramin (100 micromol/L) or the P2X antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS, 10 micromol/L) reduced the control fEPSP amplitude in the duodenum, ileum, taenia coli, proximal colon, and distal colon by 71%-84%. The pharmacology of the purinergic fEPSPs was investigated in detail in the ileum. Noncholinergic fEPSPs were concentration-dependently (1-30 micromol/L) inhibited by PPADS (50%-inhibitory concentration, 3 micromol/L). In addition, alpha,beta-methylene 5'-adenosine triphosphate (1 micromol/L) also reduced purinergic fEPSPs. CONCLUSIONS: Fast EPSPs mediated in part through P2X receptors are prominent in myenteric neurons along the small and large intestines but are rare in the gastric corpus.     

Calcium electrogenesis in neocortical pyramidal neurons in vivo

Much of what is known about Ca2+ electrogenesis in neocortical cells has been derived from in vitro studies. Since Ca2+ currents are controlled by various modulators, comparing these findings to in vivo data is essential. Here, we analysed tetrodotoxin (TTX)-resistant, presumably Ca2+-mediated potentials in intracellularly recorded neocortical neurons in vivo. TTX was applied locally to block Na+ channels. Its effectiveness was demonstrated by the elimination of fast spikes and orthodromic responses. In response to depolarizing current pulses bringing the membrane potential beyond approximately -33 mV, 71% of neurons generated high-threshold Ca2+ spikes averaging 17 mV. This is in contrast with in vitro findings, where high-threshold spikes could only be elicited following the blockade of K+ conductances. Consistent with this, neurons dialysed with K+ channel blockers in vivo generated high-threshold spikes that had a lower threshold (approximately -40 mV) and, with intracellular Cs+, a larger amplitude, indicating the presence of K+ currents opposing the activation of Ca2+ channels. Only 15% of cortical cells displayed low-threshold Ca2+ spikes. To compare high-threshold Ca2+ spikes evoked by synaptic stimuli or current injection, another group of cortical neurons was dialysed with QX-314 and Cs+, in the absence of extracellular TTX. Synaptic stimuli applied on a background of membrane depolarization elicited presumed Ca2+ spikes whose amplitude varied in a stepwise fashion. Thus, although there are numerous similarities between in vivo and in vitro data, some significant differences were found, which suggest that the high-voltage activated Ca2+ currents and/or the K+ conductances that oppose them are subjected to different modulatory influences in vivo than in vitro.     

Low ethanol concentrations enhance GABAergic inhibitory postsynaptic potentials in hippocampal pyramidal neurons only after block of GABAB receptors

Despite considerable evidence that ethanol can enhance chloride flux through the gamma-aminobutyric acid type A (GABA/A/) receptor-channel complex in several central neuron types, the effect of ethanol on hippocampal GABAergic systems is still controversial. Therefore, we have reevaluated this interaction in hippocampal pyramidal neurons subjected to local monosynaptic activation combined with pharmacological isolation of the various components of excitatory and inhibitory synaptic potentials, using intracellular current- and voltage-clamp recording methods in the hippocampal slice. In accord with our previous findings, we found that ethanol had little effect on compound inhibitory postsynaptic potentials/currents (IPSP/Cs) containing both GABA/A/ and GABA/B/ components. However, after selective pharmacological blockade of the GABA/B/ component of the IPSP (GABA/B/-IPSP/C) by CGP-35348, low concentrations of ethanol (22-66 mM) markedly enhanced the peak amplitude, and especially the area, of the GABA/A/ component (GABA/A/-IPSP/C) in most CA1 pyramidal neurons. Ethanol had no significant effect on the peak amplitude or area of the pharmacologically isolated GABA/B/-inhibitory postsynaptic current (IPSC). These results provide new data showing that activation of GABAB receptors can obscure ethanol enhancement of GABA/A/ receptor function in hippocampus and suggest that similar methods of pharmacological isolation might be applied to other brain regions showing negative or mixed ethanol-GABA interactions.     

Inhibitory control of somatodendritic interactions underlying action potentials in neocortical pyramidal neurons in vivo: an intracellular and computational study

The effect of synaptic inputs on somatodendritic interactions during action potentials was investigated, in the cat, using in vivo intracellular recording and computational models of neocortical pyramidal cells. An array of 10 microelectrodes, each ending at a different cortical depth, was used to preferentially evoke synaptic inputs to different somatodendritic regions. Relative to action potentials evoked by current injection, spikes elicited by cortical microstimuli were reduced in amplitude and duration, with stimuli delivered at proximal (somatic) and distal (dendritic) levels evoking the largest and smallest decrements, respectively. When the inhibitory postsynaptic potential reversal was shifted to around -50 mV by recording with KCl pipettes, synaptically-evoked spikes were significantly less reduced than with potassium acetate or cesium acetate pipettes, suggesting that spike decrements are not only due to a shunt, but also to voltage-dependent effects. Computational models of neocortical pyramidal cells were built based on available data on the distribution of active currents and synaptic inputs in the soma and dendrites. The distribution of synapses activated by extracellular stimulation was estimated by matching the model to experimental recordings of postsynaptic potentials evoked at different depths. The model successfully reproduced the progressive spike amplitude reduction as a function of stimulation depth, as well as the effects of chloride and cesium. The model revealed that somatic spikes contain an important contribution from proximal dendritic sodium currents up to approximately 100 microm and approximately 300 microm from the soma under control and cesium conditions, respectively. Proximal inhibitory postsynaptic potentials can present this dendritic participation thus reducing the spike amplitude at the soma. The model suggests that the somatic spike amplitude and shape can be used as a "window" to infer the electrical participation of proximal dendrites. Thus, our results suggest that inhibitory postsynaptic potentials can control the participation of proximal dendrites in somatic sodium spikes.     

Progressive atrophy of pyramidal neuron dendrites in autoimmune MRL-lpr mice

The autoimmune-prone MRL-lpr substrain of mice develop an autoimmunity-associated behavioral syndrome (AABS) which resembles in many respects the behavior of animals exposed to chronic stress. The present study examined whether these mice show changes in the morphology of neuronal dendrites, as found in animals exposed to chronic stress. A modified Golgi-Cox procedure was used to visualize the dendrites of pyramidal neurons in the parietal cortex and in the CA1 hippocampal field of 5-week and 14-week old MRL-lpr mice and MRL + / + controls. Reduced dendritic branching and length, and an up to 20% loss of dendritic spines were observed in parietal and hippocampal pyramidal neurons of MRL-lpr mice at both ages. In the parietal cortex, there was an age-dependent potentiation in the reduction of basilar, but not apical, dendrite branching and length, as well as in the loss of spines on basilar segments. Loss of spines in the hippocampus followed an age-related course for apical but not basilar dendrites. Moreover, compared to age-matched controls, brain weight was smaller in MRL-lpr mice at 14 but not 5 weeks of age. Considering that dendritic atrophy becomes more extensive when autoimmune disease is florid in MRL-lpr mice, it is proposed that immune/inflammatory factor(s) produce dendritic loss. Reduced dendritic complexity may represent, at least in part, a structural basis for the altered behavioral profile of MRL-lpr mice.