Cell-Specific, Spike Timing–Dependent Plasticities in the Dorsal Cochlear Nucleus

ARTICLES Cell-specific, spike timing–dependent plasticities in the dorsal cochlear nucleus Thanos Tzounopoulos1,Yuil Kim1,Donata Oertel2 & Laurence O Trussell1 In the dorsal cochlear nucleus, long-term synaptic plasticity can be induced at the parallel fiber inputs that synapse onto both fusiform principal neurons and cartwheel feedforward inhibitory interneurons. Here we report that in mouse fusiform cells, spikes evoked 5 ms after parallel-fiber excitatory postsynaptic potentials (EPSPs) led to long-term potentiation (LTP), whereas spikes evoked 5 ms before EPSPs led to long-term depression (LTD) of the synapse. The EPSP-spike protocol led to LTD in cartwheel cells, but no synaptic changes resulted from the reverse sequence (spike-EPSP). Plasticity in fusiform and cartwheel cells therefore followed Hebbian and anti-Hebbian learning rules, respectively. Similarly, spikes generated by summing EPSPs from different groups of parallel fibers produced LTP in fusiform cells, and LTD in cartwheel cells. LTD could also be induced in glutamatergic inputs of cartwheel cells by pairing parallel-fiber EPSPs with depolarizing glycinergic PSPs from neighboring cartwheel cells. Thus, synaptic learning rules vary with the postsynaptic cell, and may require the interaction of different http://www.nature.com/natureneuroscience transmitter systems. The mammalian dorsal cochlear nucleus (DCN) is the site of conver- The mammalian DCN resembles the electrosensory lobe of gence of multiple streams of neural information1,2.Disruption of this mormyrid fish, in which STDP has been documented14,15.Both are region causes deficits in the ability to orient the head to sounds3,4. cerebellum-like structures with similar cell types and possibly similar Spectral information is brought by auditory nerve fibers to the deep computational potential. In the present study, we examined the layer of the DCN; information from diverse sources, notably proprio- dependence of synaptic plasticity on spike timing in the DCN at both ceptive signals that convey head and ear position, are brought principal cells and interneurons. Whereas fusiform cells showed a through granule cells and their parallel fibers to the molecular layer. conventional STDP, plasticity in the cartwheel cell resembled that Fusiform cells, the principal neurons of the DCN, combine input observed in homologous cells in the electric fish. In exploring how from auditory nerve fibers and associated inhibitory interneurons on activation of different groups of synaptic inputs may induce STDP,we smooth basal dendrites, as well as from the axons of granule cells (the also found that depolarizing glycinergic contacts between cartwheel parallel fibers) and associated inhibitory interneurons on spiny apical cells may provide the spike trigger necessary for induction of LTD at © 2004 Nature Publishing Group dendrites (Fig. 1a). Cartwheel cells are glycinergic interneurons parallel fiber synapses. whose sole glutamatergic contacts are from the parallel fibers onto their spiny dendrites5.They are also excited by glycinergic input from RESULTS other cartwheel cells5,6.These cells provide powerful feedforward STDP differs in fusiform and cartwheel cells inhibition to fusiform cells7.Using conventional stimulus protocols Recordings were made from single cartwheel and fusiform cells in coro- that pair parallel fiber activation with various levels of postsynaptic nal slices of mouse brainstem. These cell types were identified by their depolarization, a previous study demonstrated both LTP and LTD in location in the densely cellular fusiform cell layer and by their charac- cartwheel and fusiform cells8.How more natural patterns of activity teristic responses to current injection (Fig. 1a,b). The larger cell bodies trigger synaptic plasticity is not known. in the fusiform cell layer are cartwheel and fusiform cells. Unlike In some neurons, long-term plasticity may be induced by pairing fusiform cells that fire regularly when they are depolarized, cartwheel EPSPs and postsynaptic action potentials in a critical timing relation- cells fire mixtures of simple and complex action potentials5,16,17. STDP ship, a process termed spike-timing dependent plasticity (STDP)9–12. was induced by pairing EPSPs with postsynaptic action potentials Although exact timing relationships vary, a common theme is that evoked by current injection through the recording electrode. Test EPSPs followed within a few milliseconds by spikes lead to LTP, EPSPs were delivered at 0.1 Hz. A pairing protocol consisted of a shock whereas reversing the sequence leads to LTD. In interneurons of the to parallel fibers followed 5 ms later by a suprathreshold current pulse electrosensory lobe of mormyrid electric fish, a different learning rule to the postsynaptic cell, causing the peak of an action potential to be holds, as yet undescribed in any mammalian circuit. In these neurons, produced ∼5 ms after the onset of the EPSP. For the 10-Hz protocol, spikes immediately following EPSPs lead to depression, but reversal of these pairs were delivered five times in 100-ms intervals, and followed the sequence does not produce an associative plasticity13. by a 5 s rest; this set was then repeated nine times (Fig. 2a,b). 1Oregon Hearing Research Center and Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA. 2Department of Physiology, University of Wisconsin Medical School, 1300 University Ave., Madison, Wisconsin 53706, USA. Correspondence should be addressed to T.T. ([email protected]). Published online 20 June 2004; doi:10.1038/nn1272 NATURE NEUROSCIENCE VOLUME 7 | NUMBER 7 | JULY 2004 719 ARTICLES a Figure 1 Parallel fibers and their targets in the DCN. (a) Parallel fibers, the axons of granule cells, contact spines on the dendrites of cartwheel cells and apical dendrites of fusiform cells. Cartwheel cells terminate locally with extensive terminal arbors, contacting fusiform cells and other cartwheel cells. (b) Characteristic responses to current injection in cells of the fusiform cell layer: cartwheel cells fire combinations of simple and complex spikes whereas fusiform cells fire regular simple spikes. Cartwheel cells are the only neurons of the DCN that show complex spikes16,17. b plasticity to parallel fiber stimuli (Fig. 3e). Thus, the learning rules for STDP at parallel fiber synapses depend upon the identity of the postsynaptic neuron. STDP in cortical pyramidal cells and in the mormyrid electrosensory lobe requires activation of NMDA receptors10,12,13,18,19. We repeated the EPSP-spike protocol with a 5-ms interval that produced LTP in fusiform and LTD in cartwheel cells under con- At synapses between parallel fibers and fusiform cells, pairing of trol conditions, while NMDA receptors were blocked by 100 µM EPSPs and postsynaptic spikes resulted in bidirectional plasticity. DL-APV. In the presence of DL-APV, no STDP was obtained (cart- When the onset of EPSPs preceded spikes by 5 ms, LTP was induced wheel, 104 ± 4%, n =6;fusiform, 97 ± 4%, n =4,data not shown). that lasted for the duration of the recordings ((post-pairing/con- This result suggests that increases in intracellular Ca2+ are trol)×100 = 134 ± 5%, n = 6; Fig. 2c,d). When the spike preceded the required to induce opposing plasticity in the two different cell EPSP by 5 ms, LTD was observed (73 ± 10%, n = 4). This synaptic types. In STDP of the electrosensory lobe, LTD required pairing plasticity is thus associative, requiring for its induction a specific synaptic stimuli with a broad Ca2+-dependent spike13.Since our http://www.nature.com/natureneuroscience timing and order between pre- and postsynaptic activity. Tests of the induction stimuli triggered broad, Ca2+-dependent, complex timing limits between EPSP and spike required for LTP and LTD spikes in cartwheel cells5,16,20,we asked if simple spikes could also revealed that no synaptic plasticity resulted when the interval trigger plasticity. To induce simple spikes without occasional sec- between EPSP and spike was longer than 20 ms (Fig. 2e). Mean ondary peaks, we followed the depolarizing current step with a delays between the onset of EPSPs and the peaks of the spikes are strong hyperpolarizing one. Figure 3g illustrates the waveform of a shown in Figure 2e. representative simple spike in the same temporal relationship as A different form of STDP was found at synapses between parallel the complex spike shown in Figure 3b.The simple spike supported fibers and cartwheel cells. LTD was observed when the conditioning LTD equally well as the complex spike (Fig. 3d,f). EPSP preceded the spike by ∼5 ms (71 ± 9%, n =9;Fig. 3a–d). When We further explored the properties of cartwheel SDTP by shorten- the spike preceded the EPSP by ∼5 ms, no change in synaptic strength ing the interval between delivery of EPSP-spike pairs from 100 ms to was observed (97 ± 4%, n = 6), despite the similar time course of the 25 ms (40 Hz). At this higher frequency, LTP was observed when the two events. The timing limits between EPSP and spike required for spike followed the EPSP by 5 ms (Fig. 4a,b). Thus, cartwheel cells can LTD were sharp. For 10-Hz pairs, even small deviations from the 5-ms show LTP with EPSP-spike pairs, providing a potential mechanism © 2004 Nature Publishing Group delay reduced or eliminated LTD (Fig. 3e). Comparison of the timing for reversing LTD in these cells8.However, when pairs were delivered limits for plasticity in cartwheel and fusiform cells emphasizes that with the reverse sequence, LTP was still obtained (Fig. 4c,d). Thus, for the 5-ms spike delay, the two cells exhibited opposite long-term STDP is dependent on the frequency of stimulation12. a b c Figure 2 STDP in fusiform cells. (a) Example of a cell’s responses to pairing of a subthreshold EPSP with a current-evoked spike delivered 5 ms later. (b) Plasticity was induced by a protocol comprising 5 such pairs delivered at 100 ms intervals followed by a 5-s pause, and repeated a total of 10 times.

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