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REPORT
2-Adrenergic Receptors Modify Dendritic Spike Generation Via HCN Channels in the Prefrontal CortexInstitute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
Submitted 21 August 2007; accepted in final form 8 November 2007
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ABSTRACT |
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2-adrenergic receptors could also shift the frequency domain of spike induction to lower frequencies. Our data suggest that noradrenergic activity in the prefrontal cortex influences dendritic Ih and extends the zone of dendritic spikes in the apical dendrite via 2-adrenergic receptors. This mechanism might be one cellular correlate of the 2-receptor–mediated actions on working memory. |
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INTRODUCTION |
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). Plastic processes of dendrites are shaped by the interaction of backpropagating action potentials (bAPs), synaptic events, and local spikes in dendrites (Hausser et al. 2000). Distant synapses of pyramidal neurons are difficult to reach by bAPs because of their distance- and activity-dependent attenuation (Golding et al. 2002; Helmchen et al. 1999; Spruston et al. 1995; Svoboda et al. 1999). Dendritic spikes recently gained special attention because they can control distal signal integration (Lisman and Spruston 2005). High-intensity distal synaptic stimulation could induce dendritic spikes in apical, basal, and oblique dendrites of CA1 pyramidal neurons (Golding and Spruston 1998; Golding et al. 2002; Kampa and Stuart 2006; Losonczy and Magee 2006), in neocortical pyramidal neurons (Polsky et al. 2004), and in granule cells of olfactory bulb (Zelles et al. 2006). Dendritic spikes can also be produced by high-frequency bAP trains in apical and basal dendrites (Kampa and Stuart 2006; Larkum et al. 1999a,b; Perez-Garci et al. 2006). Ca2+ transients, which appear as all-or-none responses at particular sites of the dendrite with a threshold, can be considered as dendritic spikes (Stuart et al. 1997). Dendritic spikes, generated by synaptic activation and dendritic current injection, exist in PFC layer 5 neurons (Seamans et al. 1997).
Although high-amplitude Ca2+ responses have been observed during high-frequency bursts in pyramidal neurons of the PFC (Gulledge and Stuart 2003) and the somatosensory cortex (Larkum et al. 1999a; Perez-Garci et al. 2006), very little is known about the transitions between frequency profiles of Ca2+ responses along the dendrite. This information is essential, however, when studying the modulation of evoked Ca2+ transients in the dendrite following receptor activation. Here, we aim to explore the distance-dependent scaling of Ca2+ dynamics along the entire length of the apical dendrite at various bAP frequencies in PFC layer 5 pyramidal neurons. Recent studies have established a model that 2A-adrenergic receptors and hyperpolarization-activated current (Ih) interact at the level of dendritic spines to enhance working memory (Arnsten 2007; Wang et al. 2007). The distribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which mediate Ih, was found to be skewed to a preferentially distal localization in subicular and in cortical pyramidal neurons (Lorincz et al. 2002; Notomi and Shigemoto 2004). Ih was recently shown to interact with dendritic spike initiation in layer 5 pyramidal neurons of the somatosensory cortex (Berger et al. 2003; Kole et al. 2007). 2-Adrenergic receptors were detected on apical dendrites of PFC pyramidal neurons (Aoki et al. 1998; Wang et al. 2007). In this report, we uncovered an Ih-mediated mechanism by which 2-adrenergic receptors can shift the frequency profile of bAP-evoked Ca2+ responses along the apical dendrite in the PFC.
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METHODS |
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All experiments were carried out in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC) and all efforts were made to minimize animal suffering, to reduce the number of animals used. Postnatal day (P) 18 to P23 male Wistar rats were killed by decapitation and slices (300 µm) containing the prefrontal cortex were prepared using a vibratome (Vibratome 3000 Plus Sectioning System, Vibratome, St. Louis, MO). Brain slices were placed in artificial cerebrospinal fluid containing (in mM) 127 NaCl, 25 NaHCO3, 25 D-glucose, 2.5 KCl, 2 CaCl2, 1 MgCl2, and 1.25 NaH2PO4 (all from Sigma), and incubated for 30 min at 32°C. Slices were left at room temperature for 
45 min before use.
Electrophysiology
Layer 5 pyramidal neurons in the PFC were visualized using video infrared-differential interference contrast. Patch pipettes were pulled from borosilicate glass (1.2-mm OD; Harvard Instruments, Tübingen, Germany). For whole cell recordings 2–4 M
electrodes were filled with 125 mM K-gluconate, 20 mM KCl, 10 mM HEPES, 10 mM di-Tris-salt phosphocreatine, 0.3 mM Na-GTP, 4 mM Mg-ATP, 10 mM NaCl (all from Sigma), and 100 µM Oregon Green BAPTA-1 (from Molecular Probes). ZD7288 [4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyridinium chloride] was purchased from Tocris. Current- and voltage-clamp recordings were made with an Axopatch 1D amplifier (Axon Instruments, Foster City, CA). Cells with an initial resting membrane potential that was more negative than –60 mV were accepted. During voltage-clamp recordings series resistance (typically 8–15 M) was monitored but not compensated. Cells in which the series resistance increased by 15% were discarded. Leak current was not subtracted. Signals were sampled at 10 kHz with a Digidata 1322A interface (Axon Instruments) and low-pass filtered at 1 kHz (four-pole low-pass Bessel). Data acquisition and analysis were performed using pClamp8 (Axon Instruments). In current-clamp experiments in most cases, 5 bAPs were evoked by somatic current injections (five stimuli, 1,800 pA, 2–4 ms) to induce dendritic Ca2+ responses. Spike half-width did not change significantly during the experiment. All experiments were done at 32–34°C.
Two-photon laser scanning imaging
Imaging was performed using a custom-made two-photon laser scanning system consisting of a modified confocal microscope (Olympus FluoView, Munich, Germany) and a titanium–sapphire laser (Millenia/Tsunami, Spectra Physics, Stratford, CT) described previously (Rozsa et al. 2004). Briefly, fluorescent indicators were excited at 810-nm wavelength. Detection was performed in both epi- and a transfluorescence mode using external photomultiplier tubes (R3896, Hamamatsu, Hamburg, Germany). To minimize photodamage, the intensity of the excitation laser light was always maintained at the minimum required to attain sufficient signal-to-noise ratio. High time-resolution fluorescence measurements were obtained in line-scan mode (2-ms maximal temporal resolution) after zooming onto a dendritic section. Data recording was started 40 min following break-in. At the end of each experiment, a series of images across the depth of the volume encompassing the imaged neuron were taken. Image data were analyzed off-line using a custom-made program written in Matlab.
Calculations
Fluorescence traces are expressed as relative fluorescence changes [
F/F = (F – F0)/F0], where F0 is the background-corrected mean prestimulus fluorescence and F is the background-corrected fluorescence. The amplitude of the Ca2+ transient was determined by the averaging of 15 data points around the largest F/F value of the transient. In some cases frequency dependence was calculated as the amplitude difference between the smallest and the largest frequency bAP-evoked Ca2+ transients. Recordings from dendritic sites were separated into groups according to their distance from the soma. Because of the variation in critical frequencies of control, data of treatment cases were normalized to the critical frequency of the same cell under control condition and expressed as 10-Hz differences compared with the critical frequency of the control experiment.
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RESULTS |
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To map the dendritic scaling of Ca2+ responses evoked by bAPs we applied trains of 5 APs at different frequencies and imaged the apical dendrite of PFC layer 5 pyramidal neurons at various distances from the soma (Fig. 1A). We applied a range of frequencies (10–100 Hz) to reveal the transitions between frequency profiles of different sites. At the most proximal sites (0–50 µm), Ca2+ transients showed weak frequency dependence (difference between the lowest- and the highest-frequency bAP train in F/F: 26%, n = 7). Moving distally along the apical dendrite, the amplitude of the evoked Ca2+ transients gradually increased as a function of bAP frequency (Fig. 1B). At far distal sites, Ca2+ responses had a binary outcome: low-frequency, subcritical stimuli caused no response but after passing a critical frequency (CF) of the bAP train, a stable-amplitude Ca2+ transient was detected (Fig. 1, B–D). The difference between the smallest and largest transients was maximal and stable at these distal responses (Fig. 1D). This all-or-none feature of distal Ca2+ transients and the existence of the threshold stimulation correspond well with the characteristics of dendritic regenerative events, i.e., dendritic spikes (Golding and Spruston 1998; Larkum et al. 1999a). Although the CF for one cell was stable during the control experiments, we observed a considerable variation of the CF across different cells (mean CF: 71 Hz, range: 40–110 Hz, n = 49, Fig. 1E). The large variability of the CF in the PFC may reflect a physiologically active mechanism that sets the actual threshold of dendritic spike generation in the dendrite. Ca2+ transients associated with dendritic spikes were also recorded in adjacent dendrite/spine pairs (Fig. 1F). We found strict correlation between amplitudes of supracritical Ca2+ responses measured in dendrites and spines (r = 0.74), suggesting that dendritic spikes reliably invade all spines in distal dendrites.
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Imaging dendritic sites at high spatial resolution, we could reliably explore the transitions between different frequency profiles. Corroborating the findings of earlier experiments (Berger et al. 2003; Larkum et al. 1999a; Perez-Garci et al. 2006; Stuart et al. 1997), at low stimulation frequencies the amplitude of the bAP-evoked Ca2+ transients declined with distance from the soma (n = 45; Fig. 2A). However, supracritical Ca2+ transients associated with dendritic spikes showed a substantially different scaling: the plot of amplitudes over distance exhibited a maximum in the apical dendrite (Fig. 2A). Different morphologies of layer 5 pyramidal neurons may influence the site of the dendritic spike generation (Spruston et al. 1995; Waters et al. 2003). Plotting the soma distance of the main bifurcation along the apical dendrite for each cell revealed that the supracritical maximum greatly overlapped the bifurcation sites (maximum: 415 ± 21 µm, bifurcation: 431 ± 42 µm; means ± SE) (Fig. 2, A and D).
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Ih shifts the threshold of dendritic spikes
After the characterization of Ca2+ responses associated with distal dendritic spikes, we investigated the possible modulation of frequency profiles of evoked Ca2+ transients. We applied ZD7288 to remove Ih and studied the generation of dendritic Ca2+ transients. In accordance with earlier reports (Berger et al. 2001), application of ZD7288 (50 µM, 8-min perfusion) caused hyperpolarization at the soma (–6.7 ± 0.7 mV, n = 6; data not shown), confirming its action on Ih in our experiments. Then, we determined the frequency profile of bAP-evoked Ca2+ responses at distal dendritic sites (350–720 µm) in control and ZD7288-treated cases (n = 17). The block of Ih by ZD7288 decreased the frequency threshold of dendritic spikes: low-frequency bAP trains, which normally fail to evoke the large-amplitude, all-or-none Ca2+ transients, became able to induce suprathreshold responses (Fig. 3, Aa and Ab). This was particularly evident for the 50-µM dose of ZD7288; the CF decreased from the control 81.8 ± 3.8 to 45.5 ± 4.1 Hz by ZD7288 (means ± SE, n = 11; P < 0.001). ZD7288 (20 µM) produced a smaller (18.3 Hz) but significant shift in CF (n = 6; P < 0.05; Fig. 3Ba). After lowering the concentration of ZD7288 to 10 µM, we observed a minimal (10-Hz) shift for lower stimulating bAP frequencies (n = 7; P < 0.05; Fig. 3Ba). The effect was the most visible at frequencies that were just subcritical in control but became supracritical in the presence of the ZD7288 (CFZD – CFCtrl). The amplitude increase by 50 µM ZD7288 was highly significant in this group (n = 11; P < 0.001; Fig. 3Bb). In addition, removal of Ih also increased the amplitude of the Ca2+ transient associated with dendritic spikes at supracritical frequencies (P = 0.01; Fig. 3Bb), indicating that the block of Ih could also amplify dendritic spikes at suprathreshold bAP frequencies. To ensure that the elapsed time between control and treatment periods did not influence the frequency dependence of dendritic spike generation, we applied the same protocol (10–100 Hz) at three consecutive time points with intervals identical to the ZD experiments (10 min). In contrast to the effect of ZD, the CF did not change significantly under control conditions (P > 0.2, n = 4; Fig. 3C). At proximal sites, 50 µM ZD7288 enhanced Ca2+ transients (Fig. 3D), suggesting that forward propagation of dendritic spikes may also be enhanced under the block of HCN channels.
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; Kole et al. 2007).
2-Adrenergic regulation of distal dendritic Ca2+ responses
Ih activation is linked to downstream elevation of 3',5'-cyclic adenosine (cAMP) level and subsequent intracellular pathways (Ludwig et al. 1998). Thus neurotransmitters, known to act by changing cAMP levels, are expected to influence Ih and, consequently, the initiation of dendritic spikes. PFC layer 5 pyramidal neurons express 2-adrenergic receptors (Aoki et al. 1998; Wang et al. 2007). To address the possibility that activation of 2-adrenergic receptors can shift the frequency domain of dendritic spike initiation, we applied clonidine, a specific agonist of 2-adrenergic receptors, at 100 µM concentrations for 9 min and recorded Ca2+ responses evoked by bAPs with various frequencies. Similarly to the Ih block, clonidine enhanced Ca2+ transients by lowering the threshold for all-or-none Ca2+ transients evoked by dendritic spikes (Fig. 4, A and B). The frequency shift to the left was smaller than that produced by ZD7288 at 50 µM. Nevertheless, at stimulatory frequencies of 10 Hz less than the CF of control, the clonidine-induced increase in the amplitude of the evoked Ca2+ response was marked and highly significant (P = 0.006; Fig. 4, A and B). Next, we studied whether the effect of clonidine was indeed mediated by specific 2-adrenergic receptors. Application of 100 µM RX 821002, a specific antagonist of 2-adrenergic receptors, inhibited the stimulatory effect of clonidine (n = 3, P < 0.05; Fig. 4C). The similarities between clonidine and ZD7288-mediated action (hyperpolarization at the soma, shift of CF) suggested the potential role of Ih in the action of clonidine. To investigate this interaction, we applied clonidine in the presence of ZD7288. Clonidine was not able to change the frequency profile in the presence of 50 µM ZD7288 (Fig. 4, D and E). In contrast, applying a lower concentration of ZD7288 (20 µM), which itself produces a small shift in frequency, the effect of clonidine was additive and produced a further 12-Hz shift in the CF (Fig. 4E). The assumption that clonidine acted through the inhibition of Ih was further supported by voltage-clamp experiments using hyperpolarizing voltage steps. Ih was reduced by 100 µM clonidine (15% drop, P = 0.01, n = 5; Fig. 4F). The decrease in current amplitude by clonidine was not attributable to rundown of Ih within the time window of drug application in our study (2% drop in control, P = 0.32, n = 10, paired t-test; Fig. 4G). ZD7288 at 10 µM mimicked the effect of 100 µM clonidine (Fig. 4G). Taken together, these data strongly suggest that the 2-adrenergic receptor agonist clonidine shifted the frequency domain of Ca2+ transients associated with dendritic spikes to the left by inhibiting Ih.
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DISCUSSION |
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2-adrenergic receptor function in layer 5 pyramidal neurons of the PFC. We explored the transitions between frequency profiles along the apical dendrite from graded-type to all-or-none Ca2+ responses. The existence of the CF and the all-or-none Ca2+ transients at far distal sites indicated that the suprathreshold Ca2+ signals we observed in this study were indeed induced by dendritic spikes. The scaling of suprathreshold Ca2+ signals had a maximum in the middle part of the apical dendrite. For layer 5 neurons, it has been raised that the generation of dendritic Ca2+ spikes is located near the main bifurcation (Helmchen et al. 1999). Corroborating this, in layer 2/3 pyramidal neurons, extralinear Ca2+ influxes and dendritic regenerative potentials also localize to the main bifurcation (Waters et al. 2003). We have shown that suprathreshold bAP trains could initiate dendritic spikes both before and after the bifurcations. Our data suggest that the initiation zone of dendritic spikes is located at the area of the main bifurcation. Ih is a modulatory factor for the initiation of dendritic spikes
In our study, the CF substantially varied among layer 5 neurons of the PFC (40–100 Hz), indicating a naturally active cellular mechanism, which sets the CF for a given neuron. One possible candidate for shifting the CF is the modulation of HCN channels by neurotransmitter receptors. The assumption that Ih can influence dendritic spike initiation comes from structural and functional data showing higher Ih density at distal sites than at proximal sites of the apical dendrite (Berger et al. 2001; Kole et al. 2006; Lorincz et al. 2002; Wang et al. 2007). In addition, the vast majority of the pyramidal cells in the prelimbic and infralimbic cortex showed detectable levels of HCN1 mRNA (Day et al. 2005). HCN1 channels require the least amount of hyperpolarization to open among HCN channel subtypes, and weakly modulated by cAMP (Santoro et al. 1998). HCN2 channels need stronger hyperpolarizations, but are strongly modulated by cAMP (Ludwig et al. 1998). Formation of heteromultimers between HCN1 and HCN2 subunits may endow channels with a greater sensitivity to cAMP modulation (Chen et al. 2001). Furthermore, the cAMP-sensitive HCN2 and HCN3 isoforms are also detected in the PFC (Day et al. 2005; Franz et al. 2000). Weak staining for HCN3 and HCN4 was found in the somatosensory cortex. It has been shown earlier that the block of HCN channels by ZD7288 reduces the CF of spike generation in dendritic patch recording of layer 5 pyramidal neurons of the somatosensory cortex (Berger et al. 2003; Kole et al. 2007). In addition, our data suggest that the forward propagation and the amplitude of Ca2+ transients associated with dendritic spikes were also facilitated when Ih was blocked. Ultimately, in accordance with findings of other laboratories (Berger et al. 2003; Kole et al. 2007), our Ca2+ imaging data suggest that dendritic spikes originating in far distal sites have relatively high probability of reaching the soma when the distal HCN channels are blocked. Our results revealed that the removal of Ih can induce large Ca2+ transients associated with dendritic spikes at lower-frequency stimulation.
Adrenergic inputs can modify Ca2+ signaling associated with dendritic spikes
The consequence of shifting the frequency domain of dendritic spike initiation via Ih might be the adaptation to the changing extracellular transmitter levels that reflect network activity. How can this mechanism be regulated physiologically? Increases in cAMP levels facilitate Ih by direct binding of the cyclic nucleotide to the channel (Ludwig et al. 1998; Pape 1996). This feature raises the possibility that receptor modulation can influence HCN function through cAMP formation. Given the well-known negative coupling of 2-adrenergic receptors to adenylate cyclase via a heterotrimeric G protein (Docherty 1998), any reduction in the cAMP level would decrease Ih. Thus it is reasonable to assume that cAMP-dependent HCN channels are available for noradrenergic inhibition via dendritic 2-adrenergic receptors. We showed for the first time that clonidine, an 2-adrenergic agonist, produced a shift to lower critical frequencies, similarly to Ih blockade. The inhibition of Ih by ZD7288 in CA1 pyramidal neurons was about 60 and 80% for 20- and 50-µM concentrations, respectively (Gasparini and DiFrancesco 1997; Kole et al. 2006). This is in good agreement with our data: we found that the occlusion of HCN channels was not complete using 20 µM ZD7288. Supporting the earlier observations we also found that 50 µM ZD7288 could cause an occlusion of HCN channels; thus clonidine was no longer able to shift the CF. Further supporting the model of cooperation, 2-adrenergic receptors and HCN channels have been shown in dominantly extra- and perisynaptic localization in spines of PFC pyramidal neurons (Wang et al. 2007). It is now accepted that postsynaptic 2-adrenergic receptors (Aoki et al. 1998) are involved in the cellular processes of the PFC (Li et al. 1999) and strongly influence working memory (Wang et al. 2007). Noradrenaline increases delay-related firing for the preferred spatial direction via 2-adrenergic receptors (Arnsten 2007). Supporting the local adrenergic effects, noradrenergic fibers densely innervate the PFC (Lewis and Morrison 1989). Considering that dendritic spikes reach the soma with higher probability during the block of Ih, the clonidine-induced leftward shift in bAP frequencies for producing Ca2+ transients associated with spikes should have consequence for the in vivo firing properties of these neurons, supporting the model of HCN-2A coupling (Wang et al. 2007). Based on the known relationship between firing properties of pyramidal neurons and working memory in the PFC (Wang et al. 2007), we propose that shifting the frequency profile of dendritic spike generation through the inhibition of HCN channels could be one potential cellular-level mechanism by which noradrenaline can improve working memory. In addition, the lower threshold and facilitated propagation of dendritic spike initiation may result in an expansion of the area where they act as a regenerative signal. Ultimately, the autonomy of the distal part of the dendritic tree would be boosted with the reduced activity of Ih in the case of high noradrenergic activity in the PFC.
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FOOTNOTES |
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Address for reprint requests and other correspondence: B. Lendvai, Institute of Experimental Medicine, H-1083 Budapest, Szigony u. 43., Hungary (E-mail: lendvai{at}koki.hu)
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ABSTRACT
INTRODUCTION
