Institute of Physiology, University of Bern, Bühlplatz 5, CH 3012 Bern, Switzerland
Address correspondence to Dr Thomas Berger, Institute of Physiology, University of Bern, Bühlplatz 5, CH-3012 Bern, Switzerland. Email: berger{at}pyl.unibe.ch.
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Abstract |
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Introduction |
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In order to study the impact of GABAA receptors and Ih on synaptic integration and coincidence detection, we activated synaptic inputs in layer V pyramidal cells using extracellular stimulation. This induced a barrage of excitatory and inhibitory events, which were spatially distributed over the entire neuron. Such a heterogeneous situation may actually reflect the physiological input of a pyramidal cell at a given time. This experimental approach enabled us to assess true conductance changes in contrast to direct current injection into a neuron. Under these conditions, activation of GABAA receptors and deactivation of Ih influenced the localization of spike generation and defined the width and symmetry of the time window for coincidence detection.
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Materials and Methods |
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Parasagittal slices (300 µm thick) of the somatosensory cortex were prepared from 2835-day-old Wistar rats according to national and institutional guidelines. Preparations were carried out in ice-cold extracellular solution using a vibratome (752M, Campden Instruments, Loughborough, UK, or Microslicer DTK-1000, Dosaka, Kyoto, Japan). Slices were incubated at 37°C for 3060 min and then left at room temperature until recording. Layer V pyramidal neurons from the somatosensory area with a thick apical dendrite were visualized by infrared differential interference contrast videomicroscopy utilizing a Newvicon camera (C2400; Hamamatsu, Hamamatsu City, Japan) and an infrared filter (RG9; Schott, Mainz, Germany) mounted on an upright microscope (Axioskop FS Zeiss, Oberkochen, Germany).
Recordings
Current-clamp whole-cell recordings were either made from the soma alone or simultaneously from the soma and apical dendrite of layer V pyramidal neurons. Simultaneous somatic and dendritic recordings were made to estimate the location of the activated synapses and to study the origin of action potentials. An Axoprobe-1A amplifier (Axon Instruments, Foster City, CA) was used. Resistance compensation and capacitance neutralization were applied. Electrodes were made from borosilicate glass tubing with or without 20% PbO (Hilgenberg, Malsfeld, Germany). The resistance was 35 M for somatic and 611 M
for dendritic recording pipettes. All experiments were carried out at
34°C. Data were low-pass filtered at 5 kHz using the internal filter of the amplifier. The sampling frequency was twice the filter frequency. Data were digitized and stored on-line using Clampex8 (Axon Instruments) connected to a personal computer. Data were analyzed off-line with Clampfit8. Pooled data are expressed as mean ± standard deviation (SD) and statistical significance was assessed by one-way analysis of variance (ANOVA) with significance levels of 0.05 or 0.01.
Stimulation
Bipolar stimulation electrodes were made from twisted pairs of insulated nickelchromium wire (diameter 25 mm; Goodfellow, Cambridge, UK). Two of these stimulation electrodes were glued into one pipette and their distance was adjusted to 600 mm. Prior to recording, their tips were placed on the surface of the slice at the border between layers I and II in such a way that the apical dendrite had a horizontal distance of
300 mm from each of the electrodes. Because we did not cut the slice from white matter to layer II/III (Cauller and Connors, 1994
; Zhu, 2000
), synaptic inputs were likely activated in all layers along the somatodendritic axis of the cell under study (Yuste et al., 1994
). Consequently, the PSP elicited by one stimulation electrode consisted of excitatory and inhibitory inputs from different regions of the cell. In order to make the coincidence detection window under control and blocking conditions comparable, we adjusted the stimulation intensity in such a way that the spiking probability in the postsynaptic neuron was
50% with simultaneous stimulation of the two sites (threshold criterion; see Fig. 6
) (Pouille and Scanziani, 2001
).
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Slices were continuously superfused with a physiological extracellular solution (containing, in mM: NaCl, 125; NaHCO3, 25; KCl, 2.5; NaH2PO4, 1.25; CaCl2, 2; MgCl2, 1; glucose, 20), bubbled with 95% O2 and 5% CO2. The pipette solution contained (in mM): K-gluconate, 110; KCl, 30; EGTA, 10; HEPES, 10; Mg-ATP, 4; Na2-GTP, 0.3; Na2-phosphocreatine, 10; the solution was pH adjusted to 7.3 with KOH.
ZD7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyridinium chloride] was a generous gift of Astra-Zeneca (Macclesfield, UK). CNQX [6-cyano-7-nitroquinoxaline-2,3-dione] and gabazine [6-imino-3-(4-methoxyphenyl)-1(6H)-pyridazinebutanoic acid hydrobromide] were bought from Tocris Cookson (Bristol, UK). All other drugs and chemicals were from Sigma or Merck. Stock solutions of 50 mM ZD7288, 10 mM bicuculline methiodide and 3 mM gabazine were prepared in bidistilled water; a stock solution of 10 mM CNQX was made in dimethylsulfoxide. Dilution in the extracellular solution provided the final concentrations given in the Results section.
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Results |
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Localization of the Input and Spike Initiation Zone
We activated synaptic inputs with extracellular stimulation electrodes situated at the border between layers I and II one on either side of the cell (Fig. 1A). The composite postsynaptic potentials (PSPs) induced by one stimulation electrode had a mean amplitude of 11.8 ± 3.7 mV (n = 116 inputs) at the soma (membrane potential at the soma = -68.4 ± 6.4 mV, n = 58 cells). In simultaneous somatic and dendritic recordings (range of the interelectrode distances 200430 µm, mean distance ± SD = 320 ± 76 mm, n = 17 cells), we could identify the approximate origin of the majority of the activated synaptic inputs (Berger et al., 2001
). For PSPs originating distally or close to the dendritic electrode (e.g. in the tuft), the amplitude attenuated, while time to peak and latency of the PSPs increased from the distal to the somatic recording site (Fig. 1B). PSPs generated primarily at the basal dendrites and the soma showed the opposite behavior (Fig. 1C
). Activation of all 17 proximally located inputs with a suprathreshold stimulation intensity induced a somatic spike and a resulting back-propagating dendritic action potential (Fig. 1E
). In contrast, in eight out of seventeen distally located inputs, suprathreshold stimulation intensity induced a dendritic, forward-propagated sodium-calcium action potential (Larkum et al., 2001
), which was followed by a somatic sodium spike (Fig. 1D
). However, activation of the other nine distally located inputs resulted in a somatic action potential, which back-propagated into the dendrite (not shown).
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The stimulation strength (40300 mA, 100500 ms) was adjusted in such a way that the activation of a single stimulation electrode (input) did not evoke an action potential, while the simultaneous activation of both stimulation electrodes elicited a spike with a probability of 50%. The stimulation intensity had to be adjusted under certain blocking conditions (see below) to match this threshold criterion. To exclude the possibility that the activation of one input led to the presynaptic refractoriness of the other input, a slope ratio was calculated see Fig. 2A,B
(Pouille and Scanziani, 2001
). The slope (
V/
t) of the averaged PSP was determined during the first millisecond of the rise after the onset of the PSP. The two inputs were considered to be independent, i.e. two different sets of synapses were activated, if the slope of the PSP after simultaneous activation resulted in a value of at least 80% of the arithmetic sum of the slopes of the two individual inputs (Fig. 2A
). In 13 out of 58 cells studied a lower slope ratio was found, suggesting that the two inputs were partially overlapping (Fig. 2B
). Only the data from independent inputs were used.
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GABAA Receptors and Spike Initiation
In eight cells it was impossible to induce spikes even with very high stimulation intensities (5001000 mA, 500 ms). When these cells were depolarized with constant DC current injection, the PSP induced by both stimulation electrodes reversed its sign at 49 ± 6 mV, i.e. close to the Nernst potential for Cl- (ECl- 40 mV with the solutions used). After the application of 10 µM bicuculline, the reversal potential of the PSP shifted to 0 mV (n = 2 out of 2 tested), the reversal potential of ionotropic glutamate receptors. This suggests that in these cells a prominent GABAA conductance shortened the decaying phase of the EPSP (cf. Fig. 3A,B
) and thus prevented the generation of action potentials.
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GABAA receptor blockade by bicuculline or gabazine (with 1 µM CNQX) could switch the origin of spike generation and reverse the direction of propagation by enabling somatic PSP summation. In five somatodendritic recordings, summation of the PSPs from both inputs was much less pronounced in the soma than in the dendrite (Fig. 3A). In these cases, somatic sodium action potentials were only induced when a local dendritic sodiumcalcium spike (Larkum et al., 2001
) brought the soma suprathreshold (forward-propagated action potential; Fig. 3C
, inset). The lack of somatic summation and its inability to produce spikes could be abolished by the application of 10 µM bicuculline (Fig. 3B,D
). Under these conditions, the dendritic sodiumcalcium spike was seen after the beginning of the somatic burst (back-propagating action potential; Fig. 3D
, inset). The presence of a strong GABAergic input located mainly on the soma was most likely responsible for this observation.
In the majority of the cells, 1 mM bicuculline (n = 5 out of 6) or 10 µM bicuculline (n = 9 out of 9) changed the spiking behavior from single spikes to bursts (Figs 3C,D and 4A,B). In addition, the subthreshold PSP showed a multiphasic rise under bicuculline, which could be due to presynaptic burst activity or polysynaptic inputs (Fig. 3B
). The number of spikes per burst and the delay between both inputs was negatively correlated. However, epileptic activity or spontaneous bursts were not seen. The integral below the MSPdelay curve was taken as a measure of the overall spiking probability and thus of the general excitation due to the activation of the cells inputs. The overall spiking probability was increased to 257 ± 103% (n = 4) and 488 ± 202% (n = 9) of control for 1 or 10 µM bicuculline, respectively.
GABAA Receptors and Coincidence Detection
In order to investigate the importance of GABAA receptor activation for coincidence detection, both inputs were activated as described above. The time window for the generation of spikes and bursts became broader under 1 µM bicuculline (n = 2 cells; not shown), while in two cells no effect was seen. Under 10 µM bicuculline, the time window was always broadened (n = 9 out of 9 cells; Figs 3C,D and 4). The MSPdelay plots were fitted with a Gaussian function and the SD of this fitted curve increased from 2.8 (n = 13) to 7.6 (n = 4) and 9.5 ms (n = 9) for 1 or 10 µM bicuculline, respectively (P < 0.05 using the F-distribution test; Fig. 6A,B
). Thus, block of the GABAergic input impaired coincidence detection in the cells under study.
The MSP reflects the probability of eliciting an action potential in a given cell excited by two groups of composite inputs of unknown excitatory and inhibitory contribution. It was not necessarily the case that the MSP was highest when both inputs were activated simultaneously (Fig. 4A). In about half of the cells tested (n = 26 out of 45 cells), an uneven summation of both inputs was found, resulting in an asymmetric MSPdelay plot (Fig. 4C
). The mean delay for the peak of the MSP was 9.4 ± 5.1 ms (range 2.522.5 ms) in these 26 cells. A shift of the plot from an asymmetric situation to a symmetric one was seen in all cells under 10 µM bicuculline or 3 mM gabazine (n = 5 out of 5 cells; Fig. 4B,C
). In order to compare the coincidence detection window of an asymmetric MSP plot under control conditions and the corresponding symmetric MSP plot after blockade of the GABAergic input, we aligned both plots along the time axis. Therefore, their maximal MSP was set to a delay of 0 ms. An asymmetric plot reflects most likely an uneven activation of GABAergic interneurons by the different stimulation electrodes and therefore a different ability of the two inputs to shunt each other.
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In order to study the effect of the hyperpolarization-activated cationic current Ih on coincidence detection, 10 or 100 µM of the specific blocker ZD7288 (Harris and Constanti, 1995) was added to the bath solution. Separate activation of both inputs was carried out under control conditions and in the presence of ZD7288 (Fig. 5A,B
). With 10 µM ZD7288, the stimulation strength was always left unchanged (n = 8 inputs). In contrast, with 100 µM ZD7288, the stimulation strength was changed to 93 ± 19% (n = 28 inputs) of the control value to match the threshold criterion. The hyperpolarization of
10 mV induced by ZD7288 (Berger et al., 2001
) was always compensated by DC current injection. The monoexponentially fitted mean PSP decay time constant increased to 67.1 ± 23.2 and 81.5 ± 34.2 ms for 10 or 100 µM ZD7288 in comparison to a control value of 32.2 ± 13.9 ms (P < 0.01; n = 8 inputs and n = 28 inputs, respectively; Fig. 5B
).
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In one out of three cells with forward-propagated dendritic spikes, application of 100 mM ZD7288 reversed the propagation direction (Fig. 5D, lower four traces). In contrast, in two other cells, 100 µM ZD7288 did not induce a change from forward- to back-propagating spikes (not shown).
The results show that coincidence detection in layer V pyramidal cells of the somatosensory cortex is influenced by at least two conductances. GABAA receptors as well as Ih sharpen the time window for coincidence detection by curtailing the decaying phase of the PSP. In addition, an unbalanced activation of GABAergic neuron populations can shift the time window for coincidence detection. Bicuculline or ZD7288 can switch the action potential initiation zone from dendrite to soma, with a concomitant reversal in the direction of spike propagation in the apical dendrite.
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Discussion |
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Methodological Considerations
In vivo recordings from layer II/III and layer V pyramidal cells in anesthetized rats show spontaneous as well as whisker-deflection-correlated synaptic activity with low frequency and high amplitude (Helmchen et al., 1999; Svoboda et al., 1999
; Zhu and Connors, 1999
). This pattern reflects a highly synchronous input, which can result, at least in layer V pyramidal cells, in the generation of complex sodiumcalcium spikes (Helmchen et al., 1999
). A comparable behavior with low EPSP and spiking frequencies was also found in layer II/III and V pyramidal cells of awake rats during whisking periods (Margrie et al., 2002
). In order to imitate these in vivo patterns, we used high-amplitude PSPs, which brought the cell from rest close to threshold.
Direct intracellular current injection was used in the majority of studies dealing with integrative processes in layer V dendrites (Berger et al., 2001; Larkum et al., 2001
, Williams and Stuart, 2002
), but not all (Pouille and Scanziani, 2001
). This has the advantage that the exact localization of the induced potential changes is known. However, injection of currents instead of using conductance changes has the disadvantage that currents are not limited by their reversal potential and that shunting is neglected. For the study of the effects of shunting and leak conductances such as GABAA receptors and Ih we decided therefore to use extracellular stimulation in order to induce conductance changes. The response of each cell was calibrated in a such way that a threshold regime was reached where 50% of the trials resulted in a spike. If this maximal spiking probability was similar under control conditions and after application of a blocker, the width of the MSPdelay plot reflected the time window for coincidence detection. The inputs to layer V pyramidal cells were activated with stimulation electrodes positioned at the border between layers I and II. Under these conditions, stimulation could have led to the distal activation of layer V pyramidal cells via the excitatory fibers in layer I. However, activation of layer II/III pyramidal cells or of distally located GABAergic interneurons could indirectly activate more proximally situated synapses. In spite of the heterogeneity of the activated synaptic inputs, we found a relatively homogeneous effect of GABAA receptor activation and Ih on the coincidence detection window. This suggests that the detailed localization and composition of the synaptic inputs are of minor importance for the results reported in this study.
GABAA Receptors and Synaptic Integration in Layer V Pyramidal Cells
In this study, GABAergic input could completely prevent axonal action potential generation. This could be the result of a direct activation of the somatic GABAergic synapses (White, 1989) shunting the axonal sodium spike initiation and curtailing the synaptic event (Pouille and Scanziani, 2001
). Under these conditions, distal PSPs could, however, evoke a dendritic spike (Williams and Stuart, 2002
). In about half of our experiments with distal inputs, we found such a forward-propagating dendritic spike, while in the other half a back-propagating sodium spike was seen (Larkum et al., 2001
). Blocking the GABAA receptors changed this pattern only in a subset of cells. In these cells, extracellular stimulation resulted in the generation of somatic, back-propagating spikes. However, burst firing was seen in nearly all cells under block of the GABAA receptors. This correlates well with the observation that GABA receptors exert a veto effect on back-propagating action-potential-activated calcium spike firing (BAC-firing) in these cells (Larkum et al., 1999
). An alternative or additional mechanism would be a stronger excitatory drive with polysynaptic effects resulting in burst firing.
GABAA Receptors and Coincidence Detection in Layer V Pyramidal Cells
GABAergic input to layer V pyramidal cells is generated by a heterogeneous group of interneurons. Their axons terminate along the whole somatodendritic axis of the pyramidal cells (Somogyi et al., 1998; Gupta et al., 2000
). However, there is a clear distribution of inhibitory and excitatory inputs: the overwhelming majority of the synapses on the soma and the dendritic shaft is GABAergic, while the majority of the excitatory synapses sits on spines (White, 1989
; Keller, 1995
). This distinguished position of the GABAergic input and the organization of interneurons as networks connected via both electrical and chemical synapses (Galarreta and Hestrin, 1999
; Gibson et al., 1999
) can exert a strong influence on the summation properties and thus on coincidence detection. Bicuculline at 1 and 10 µM led to a broadening of the coincidence detection window for two incoming PSPs by factors of 1.9 and 3.4, respectively. This effect was also seen in hippocampal CA1 pyramidal cells (Pouille and Scanziani, 2001
), while GABA application sharpened the time window for coincidence detection in neurons of the chicken nucleus laminaris (Funabiki et al., 1998
). Iontophoretic application of bicuculline broadened and GABA sharpened the selectivity of the interaural time difference in the owls midbrain (Fujita and Konishi, 1991
), pointing to the importance of GABAA receptors for discrimination in the bird auditory system. The broadening of the coincidence detection window in layer V pyramidal cells was correlated with a prolongation of the decaying phase of the PSP an effect which was not seen in all cells. This heterogeneity can be explained by a varying contribution of GABAA receptor activation to the PSP waveform. Activation of excitatory and inhibitory neurons can lead to an EPSPIPSP sequence where the IPSP curtails the EPSP (Pouille and Scanziani, 2001
). Alternatively, activation of GABAA receptors leads to a shunting of EPSPs by decreasing the cells input resistance, resulting in a reduction of the membrane time constant and a consecutive acceleration of the EPSP decay time constant.
In contrast to what one would expect intuitively, in 58% of the cells studied the highest probability for eliciting an action potential was not found when both PSPs were activated simultaneously. If bicuculline or gabazine were applied to these asymmetric cells, the coincidence plot became symmetric to the origin in all cells tested. Such an asymmetric GABAergic activation and the consecutive shunting of one input by the other one could be well explained if one stimulation electrode activated a larger population of GABAergic cells than the other. In addition, unbalanced activation of GABAergic synapses along the somatodendritic axis of the cell could lead to asymmetric coincidence detection as well. Asymmetric activation of GABAergic networks could well serve as a physiological mechanism to control the time delay between two inputs leading to action potential generation. Such an asymmetric GABAergic activation was not seen in CA1 pyramidal cells after coincident Schaffer collateral activation (Pouille and Scanziani, 2001). These authors stimulated directly an excitatory input which was followed by di-synaptic feed-forward inhibition. In the present study, the extracellular stimulation activated directly both excitatory and inhibitory axons of unknown origins, resulting in a heterogeneous pattern of symmetric and asymmetric responses.
Ih and Coincidence Detection in Layer V Pyramidal Cells
Similar to GABAA receptor activation, Ih exerted its effects on coincidence detection via the active shortening of the decaying phase of the PSP (Nicoll et al., 1993). In addition, blockade of Ih increased the input resistance of neocortical pyramidal cell dendrites (Berger et al., 2001
). However, due to their opposing spatial distributions along the somatodendritic axis, modulation of GABAA receptors and Ih should result in different shunting patterns. Due to the high density of Ih channels in the distal apical dendrite, the effect will be more pronounced for distal than for proximal inputs. The resulting reduction of temporal summation in pyramidal cells (Magee, 1998
; Williams and Stuart, 2000
, 2002
; Berger et al., 2001
) makes the temporal influence of each EPSP more precise with regard to synaptic integration. In contrast to GABAA receptors, block of Ih always led to a prolongation of the PSP decaying phase. This is due to the fact that all layer V pyramidal cells contain Ih channels, while the proportion of active GABAA receptors was variable, depending on the stimulation situation.
Functional Implications
Layer V pyramidal cells handle the integration of signals from thousands of spatially distributed excitatory and inhibitory synapses. These cells can detect highly coincident excitatory inputs using voltage- and ligand-gated conductances such as Ih and GABAA receptors. In addition, these pyramidal cells respond with a qualitatively different spiking pattern if inputs to distal and proximal regions of the cell are activated within a narrow time window BAC firing (Larkum et al., 1999). A single spike is generated if the sodium spike initiation zone is activated alone. In contrast, simultaneous activation of both the axonal and dendritic spike initiation zones results in a burst discharge (Larkum et al., 1999
). The coincident activation of the different cell compartments leads therefore to a change of the output, reflecting the importance of this associative process. For an effective detection of coincident proximal and distal inputs, a narrow time window is essential. This can be achieved by synaptic events with a fast decay time course, which allow summation only during a short time period. Distal synaptic events are shortened by Ih channels located on the apical dendrite (Berger et al., 2001
), while proximal synaptic events are curtailed by somatically localized GABAA receptors. As a consequence, abolishing these PSP-curtailing mechanisms would lead to a strong broadening of the time window for BAC firing and therefore to a loss of the precision of this process. Because BAC firing provides a potential mechanism for binding the information from different brain areas (Singer and Gray, 1995
), precise coincidence detection seems to be an essential mechanism during the integration of sensory information in layer V pyramidal cells. In addition, the observed time shifts in coincidence detection due to unbalanced activation of inhibitory input could provide the basis for encoding temporal and spatial sensory information (Ahissar and Arieli, 2001
).
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Footnotes |
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