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Dendritic Spikes Mediate Negative Synaptic Gain Control in Cerebellar Purkinje Cells

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Dendritic Spikes Mediate Negative Synaptic Gain Control in Cerebellar Purkinje Cells Dendritic spikes mediate negative synaptic gain control in cerebellar Purkinje cells Ede A. Rancza,b,1 and Michael Häussera aWolfson Institute for Biomedical Research and Research Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom; and bDivision of Neurophysiology, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom Edited* by Rodolfo R. Llinás, New York University Medical Center, New York, NY, and approved November 8, 2010 (received for review June 28, 2010) Dendritic spikes appear to be a ubiquitous feature of dendritic dendritic spikes and axonal AP output in Purkinje cells by using excitability. In cortical pyramidal neurons, dendritic spikes increase simultaneous dendritic and somatic whole-cell recordings. Our the efficacy of distal synapses, providing additional inward current results show that a dendritic spike transiently increases synaptic to enhance axonal action potential (AP) output, thus increasing efficacy by promoting short bursts of somatic APs but dampen AP synaptic gain. In cerebellar Purkinje cells, dendritic spikes can trigger output over longer timescales. The interplay between these two synaptic plasticity, but their influence on axonal output is not well effects during sustained parallel fiber input results in a “clamping” understood. We have used simultaneous somatic and dendritic of Purkinje cells output over long timescales and, thus, a flattening patch-clamp recordings to directly assess the impact of dendritic of synaptic gain, in striking contrast to pyramidal cells (9). calcium spikes on axonal AP output of Purkinje cells. Dendritic spikes evoked by parallel fiber input triggered brief bursts of somatic APs, Results followed by pauses in spiking, which cancelled out the extra spikes in Single Dendritic Spikes Differentially Affect Axonal Output on the burst. As a result, average output firing rates during trains of Different Timescales. We made simultaneous somatic and den- input remained independent of the input strength, thus flattening dritic recordings (average distance 141 ± 11 μm, n = 9, range 102– synaptic gain. We demonstrate that this “clamping” of AP output 194 μm) from Purkinje neurons in rat cerebellar slices. Purkinje by the pause following dendritic spikes is due to activation of high cells were spontaneously active (28), and somatic APs were se- conductance calcium-dependent potassium channels by dendritic verely attenuated at dendritic recording sites (17, 19). To test the NEUROSCIENCE spikes. Dendritic spikes in Purkinje cells, in contrast to pyramidal cells, effect of dendritic spikes on somatic AP output, we evoked ex- thus have differential effects on temporally coded and rate coded citatory postsynaptic potentials (EPSPs) by stimulating parallel information: increasing the impact of transient parallel fiber input, fibers close to the dendritic recording electrode (Fig. 1A). Stim- while depressing synaptic gain for sustained parallel fiber inputs. ulus intensity was carefully adjusted to reach dendritic spike threshold (13), such that dendritic spikes were only triggered in cerebellum | patch clamp | dendrite | synaptic integration some trials at identical stimulus strengths (Fig. 1B). Dendritic spikes triggered a brief burst of somatic APs (2.46 ± 0.18 APs, n C D fi hallmark of active dendrites is their ability to produce re- = 9; Fig. 1 and ) at high instantaneous ring rates (maximum fi ± ± generative events known as dendritic spikes (1–8). In pyra- ring rate 367 52 Hz with dendritic spikes vs. 236 26 Hz A n P < E midal neurons, the inward currents associated with dendritic without dendritic spikes, =9, 0.02; Fig. 1 ). However, the burst of APs was followed by a prolonged pause that was not spikes provide a strong local depolarization that can boost distal C synaptic inputs and enhance their effect on axonal action potential observed in the response to subthreshold EPSPs (Fig. 1 ). The (AP) output (1–4), particularly during burst generation (5, 6). longest somatic interspike intervals (ISIs) were identical before and after EPSPs, which did not trigger dendritic spikes (44 ± 4.6 Furthermore, dendritic spikes can enhance the precision of axonal ± n P APs in hippocampal pyramidal neurons (7) as well as in neo- ms vs. 44 5.4 ms, respectively, =9, = 0.99). In contrast, EPSPs which triggered dendritic spikes were followed by sub- cortical pyramidal cells in vivo (8). Dendritic spikes thus have stantially longer maximal somatic ISIs (71 ± 11 ms, n =9;P < 0.02 a boosting effect on the output of pyramidal cells, thus enhancing compared with subthreshold EPSPs; Fig. 1E). The effects of the gain of the synaptic input-output (I/O) function (9, 10). In dendritic spikes on somatic firing were independent of the loca- contrast, the effect of dendritic spikes on AP output in Purkinje tion of the synaptic input (recording distance along the dendrite, cells is not well understood. Purkinje cell dendritic spikes, origi- range 102–194 μm; r = 0.17; r = −0.12). nally discovered in alligator Purkinje cells (11, 12), can be triggered (evoked spikes) (pause) fi fi The net effect of an input on AP output (stimulus-evoked by strong parallel ber (PF) activation (11, 13) or climbing ber spikes) can be quantified by integrating the poststimulus time activation (14, 15) and are due solely to activation of dendritic histograms (PSTH) and subtracting spontaneous activity (Meth- – voltage-gated calcium channels (13, 16 18), because Purkinje cells ods and refs. 29 and 30). This analysis confirmed that dendritic lack dendritic voltage-gated sodium channels and active back- spikes resulted in an increase in the peak number of somatic APs fl propagation of APs (17, 19). Calcium in ux driven by dendritic triggered by the stimulus (Fig. 1F). On average, EPSPs triggering – spikes has an important role in triggering synaptic plasticity (20 dendritic spikes added significantly more somatic APs immedi- 22) and dendritic release of neurotransmitters and neuro- ately following the stimulus than subthreshold EPSPs (2.3 ± 0.3 modulators (13, 23, 24). Dendritic spikes triggered by climbing APs vs. 1.7 ± 0.4 APs, n =9,P < 0.01; Fig. 1F). However, the fiber input have virtually no effect on the somatic complex spike increase in somatic AP output was transient, because after a few waveform, probably due to the large synaptic and intrinsic con- ductances activated during the complex spike (14). However, the functional role of parallel fiber-driven dendritic spikes in regulat- Author contributions: E.A.R. and M.H. designed research; E.A.R. performed research; ing axonal output has not been addressed directly. This distinction E.A.R. analyzed data; and E.A.R. and M.H. wrote the paper. is crucial, because the state of the Purkinje cell dendritic tree is The authors declare no conflict of interest. very different during climbing fiber and parallel fiber excitation *This Direct Submission article had a prearranged editor. (25), and because climbing fiber input occurs only at ≈1 Hz in vivo 1To whom correspondence should be addressed. E-mail: [email protected]. fi (26, 27), whereas parallel ber input occurs continuously at high This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. rates. We have therefore directly probed the relationship between 1073/pnas.1008605107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1008605107 PNAS Early Edition | 1of6 Downloaded by guest on September 27, 2021 dendrite, 184 µm A dendritic stimulation B EPSP + dendritic spike recording electrode electrode 10 mV somatic subthreshold EPSP recording (no dendritic spike) PC electrode 25 ms Fig. 1. Single dendritic spikes enhance AP output PF. stim. on short, but not long, timescales. (A) Simultaneous whole-cell recordings were made from the soma No dendritic spikes Dendritic spikes C PF. stim. D PF. stim. and dendrite of the same Purkinje cell while stim- ulating PFs close to the dendritic recording site. (B) Stimulating PFs at the threshold for dendritic spike generation resulted in subthreshold EPSPs (black) or dendritic spikes (red, same traces as in C and D). (C) Somatic (dotted line) and dendritic (thick line) 20 mV voltage recording during a single parallel fiber 50 ms stimulus (arrow) not triggering a dendritic spike. The raster plot and the PSTH contain 10 trials; bin size is 2 ms. (D) Same as in C, except the synaptic stimulus triggered a dendritic spike. The raster plot shows 10 trials, the PSTH contains 45 trials; bin size is 2 ms. Note the somatic AP burst associated with 0.2 the dendritic spike and the following pause in so- matic firing. (E) Pooled averages of maximum so- matic instantaneous firing rates and maximum somatic ISIs (n = 9). Black bars show the effect of E F G EPSPs without dendritic spikes, red bars show the ** 3 * 3 effect of EPSPs with dendritic spikes, and the blue 400 80 1.5 bar represents the average maximal somatic ISI during spontaneous activity showing no significant 1.0 F spont. ISI 2 2 pauses are present without dendritic spikes. ( )The C D 0.5 PSTHs in and were integrated then normalized 200 40 to trial number and spontaneous firing rate, thus dendritic spikes 1 1 0 no dendritic spikes only showing the stimulus-evoked spikes. (G) Bar maximal firing rate graphs showing the pooled averages of maximum stimulus evoked spikes 0 100 200 300 400 sustained added spikes maximum added spikes stim. evoked pause (ms) number of stimulus added spikes and the number of 0 0 time (ms) 0 0 d-sp. d-sp. d-sp. d-sp. sustained added spikes (in a 100-ms window start- no. d-sp. no. d-sp. no. d-sp. no. d-sp. ing 100 ms after the stimulus, n = 9). *P < 0.02. tens of milliseconds, there was no significant difference between however, the average somatic firing rate decreased from 241 ± 8 the effect of suprathreshold and subthreshold EPSPs (1.6 ± 0.2 Hz to 187 ± 12 Hz (P < 0.005, n = 5; Fig.
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