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• W2998668254 abstract "•A phenomenological synaptic plasticity rule is applied to a pyramidal neuron model•Model reproduces rate-, timing-, and location-dependent plasticity results•Active dendrites allow plasticity via dendritic spikes and subthreshold events•Cooperative plasticity exists across the dendritic tree and within single branches A large number of experiments have indicated that precise spike times, firing rates, and synapse locations crucially determine the dynamics of long-term plasticity induction in excitatory synapses. However, it remains unknown how plasticity mechanisms of synapses distributed along dendritic trees cooperate to produce the wide spectrum of outcomes for various plasticity protocols. Here, we propose a four-pathway plasticity framework that is well grounded in experimental evidence and apply it to a biophysically realistic cortical pyramidal neuron model. We show in computer simulations that several seemingly contradictory experimental landmark studies are consistent with one unifying set of mechanisms when considering the effects of signal propagation in dendritic trees with respect to synapse location. Our model identifies specific spatiotemporal contributions of dendritic and axo-somatic spikes as well as of subthreshold activation of synaptic clusters, providing a unified parsimonious explanation not only for rate and timing dependence but also for location dependence of synaptic changes. A large number of experiments have indicated that precise spike times, firing rates, and synapse locations crucially determine the dynamics of long-term plasticity induction in excitatory synapses. However, it remains unknown how plasticity mechanisms of synapses distributed along dendritic trees cooperate to produce the wide spectrum of outcomes for various plasticity protocols. Here, we propose a four-pathway plasticity framework that is well grounded in experimental evidence and apply it to a biophysically realistic cortical pyramidal neuron model. We show in computer simulations that several seemingly contradictory experimental landmark studies are consistent with one unifying set of mechanisms when considering the effects of signal propagation in dendritic trees with respect to synapse location. Our model identifies specific spatiotemporal contributions of dendritic and axo-somatic spikes as well as of subthreshold activation of synaptic clusters, providing a unified parsimonious explanation not only for rate and timing dependence but also for location dependence of synaptic changes. Adaptive behavior, guided by learning and memory processes, can be seen as a macroscopic manifestation of microscopic long-term changes in synaptic strength (Bliss and Collingridge, 1993Bliss T.V.P. Collingridge G.L. A synaptic model of memory: long-term potentiation in the hippocampus.Nature. 1993; 361: 31-39Crossref PubMed Scopus (9540) Google Scholar). Such changes have been proposed to be related to the causal contribution of a presynaptic (pre) cell to the excitation of a postsynaptic (post) cell according to Hebbian theory (Hebb, 1949Hebb D.O. The Organization of Behaviour: A Neuropsychological Theory. John Wiley & Sons, 1949Google Scholar). Thus, a number of studies exploring various “spike timing-dependent plasticity” (STDP) (Abbott and Nelson, 2000Abbott L.F. Nelson S.B. Synaptic plasticity: taming the beast.Nat. Neurosci. 2000; 3: 1178-1183Crossref PubMed Scopus (1461) Google Scholar) protocols have investigated the relationship of the precise timing between presynaptic and postsynaptic action potentials (APs) on the efficacy of synapses. In the simplest arrangement, pre-APs preceding post-APs (pre-post, positive timing) by a few milliseconds typically result in synaptic long-term potentiation (LTP), whereas the opposite order (post-pre, negative timing) leads to long-term depression (LTD) (Bi and Poo, 1998Bi G.Q. Poo M.M. Synaptic modifications in cultured hippocampal neurons: dependence on spike timing, synaptic strength, and postsynaptic cell type.J. Neurosci. 1998; 18: 10464-10472Crossref PubMed Google Scholar, Markram et al., 1997Markram H. Lübke J. Frotscher M. Sakmann B. Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs.Science. 1997; 275: 213-215Crossref PubMed Scopus (2846) Google Scholar). However, each newly tested plasticity protocol has led to the discussion of new parameters. In particular, when bursts of APs are considered, the frequency of these bursts heavily influences the results of the simple STDP concept. Higher frequencies tend to increase the strength of LTP at positive timings (Markram et al., 1997Markram H. Lübke J. Frotscher M. Sakmann B. Regulation of synaptic efficacy by coincidence of postsynaptic APs and EPSPs.Science. 1997; 275: 213-215Crossref PubMed Scopus (2846) Google Scholar, Sjöström et al., 2001Sjöström P.J. Turrigiano G.G. Nelson S.B. Rate, timing, and cooperativity jointly determine cortical synaptic plasticity.Neuron. 2001; 32: 1149-1164Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar) and sometimes even convert LTD at negative timings into LTP, bypassing the pre-post timing requirement (Sjöström et al., 2001Sjöström P.J. Turrigiano G.G. Nelson S.B. Rate, timing, and cooperativity jointly determine cortical synaptic plasticity.Neuron. 2001; 32: 1149-1164Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar). Also, the location of synapses along the dendritic tree was shown to play an important role, with LTD often becoming more prominent in distal synapses (Froemke et al., 2005Froemke R.C. Poo M.-M. Dan Y. Spike-timing-dependent synaptic plasticity depends on dendritic location.Nature. 2005; 434: 221-225Crossref PubMed Scopus (300) Google Scholar, Sjöström and Häusser, 2006Sjöström P.J. Häusser M. A cooperative switch determines the sign of synaptic plasticity in distal dendrites of neocortical pyramidal neurons.Neuron. 2006; 51: 227-238Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar), a likely consequence of voltage attenuation of backpropagating action potentials (bAPs) in dendrites (Stuart et al., 1997Stuart G. Spruston N. Sakmann B. Häusser M. Action potential initiation and backpropagation in neurons of the mammalian CNS.Trends Neurosci. 1997; 20: 125-131Abstract Full Text Full Text PDF PubMed Scopus (594) Google Scholar), where LTP was recovered by boosting bAPs through dendritic current injection or cooperative synaptic inputs (Sjöström and Häusser, 2006Sjöström P.J. Häusser M. A cooperative switch determines the sign of synaptic plasticity in distal dendrites of neocortical pyramidal neurons.Neuron. 2006; 51: 227-238Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar). In addition to these effects of frequency and location on STDP, plasticity can also be induced by depolarization that originates from other sources besides bAPs in the postsynaptic neuron, e.g., dendritic Ca2+ spikes (Golding et al., 2002Golding N.L. Staff N.P. Spruston N. Dendritic spikes as a mechanism for cooperative long-term potentiation.Nature. 2002; 418: 326-331Crossref PubMed Scopus (495) Google Scholar, Kampa et al., 2006Kampa B.M. Letzkus J.J. Stuart G.J. Requirement of dendritic calcium spikes for induction of spike-timing-dependent synaptic plasticity.J. Physiol. 2006; 574: 283-290Crossref PubMed Scopus (140) Google Scholar, Letzkus et al., 2006Letzkus J.J. Kampa B.M. Stuart G.J. Learning rules for spike timing-dependent plasticity depend on dendritic synapse location.J. Neurosci. 2006; 26: 10420-10429Crossref PubMed Scopus (214) Google Scholar), N-methyl-D-aspartate (NMDA) spikes (Brandalise et al., 2016Brandalise F. Carta S. Helmchen F. Lisman J. Gerber U. Dendritic NMDA spikes are necessary for timing-dependent associative LTP in CA3 pyramidal cells.Nat. Commun. 2016; 7: 13480Crossref PubMed Scopus (52) Google Scholar, Gordon et al., 2006Gordon U. Polsky A. Schiller J. Plasticity compartments in basal dendrites of neocortical pyramidal neurons.J. Neurosci. 2006; 26: 12717-12726Crossref PubMed Scopus (131) Google Scholar), or excitatory postsynaptic potentials (EPSPs) alone (Sandler et al., 2016Sandler M. Shulman Y. Schiller J. A novel form of local plasticity in tuft dendrites of neocortical somatosensory layer 5 pyramidal neurons.Neuron. 2016; 90: 1028-1042Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, Weber et al., 2016Weber J.P. Andrásfalvy B.K. Polito M. Magó Á. Ujfalussy B.B. Makara J.K. Location-dependent synaptic plasticity rules by dendritic spine cooperativity.Nat. Commun. 2016; 7: 11380Crossref PubMed Scopus (71) Google Scholar). For all these reasons, the concept of classical STDP as a self-contained mechanism has been debated (Clopath and Gerstner, 2010Clopath C. Gerstner W. Voltage and spike timing interact in STDP—a unified model.Front. Synaptic Neurosci. 2010; 2: 25PubMed Google Scholar, Clopath et al., 2010Clopath C. Büsing L. Vasilaki E. Gerstner W. Connectivity reflects coding: a model of voltage-based STDP with homeostasis.Nat. Neurosci. 2010; 13: 344-352Crossref PubMed Scopus (389) Google Scholar, Goldberg et al., 2002Goldberg J. Holthoff K. Yuste R. A problem with Hebb and local spikes.Trends Neurosci. 2002; 25: 433-435Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, Lisman and Spruston, 2005Lisman J. Spruston N. Postsynaptic depolarization requirements for LTP and LTD: a critique of spike timing-dependent plasticity.Nat. Neurosci. 2005; 8: 839-841Crossref PubMed Scopus (197) Google Scholar, Shouval et al., 2010Shouval H.Z. Wang S.S.-H. Wittenberg G.M. Spike timing dependent plasticity: a consequence of more fundamental learning rules.Front. Comput. Neurosci. 2010; 4: 19PubMed Google Scholar). It stands to reason that the principle of STDP is only one manifestation of an underlying general plasticity framework (Feldman, 2012Feldman D.E. The spike-timing dependence of plasticity.Neuron. 2012; 75: 556-571Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar, Shouval et al., 2010Shouval H.Z. Wang S.S.-H. Wittenberg G.M. Spike timing dependent plasticity: a consequence of more fundamental learning rules.Front. Comput. Neurosci. 2010; 4: 19PubMed Google Scholar). In that case, the question emerges as to which biophysical pathways contribute to the results from classical STDP protocols and in which ways they are related to other plasticity protocols. A large number of theories and models have been developed with both phenomenological (Morrison et al., 2008Morrison A. Diesmann M. Gerstner W. Phenomenological models of synaptic plasticity based on spike timing.Biol. Cybern. 2008; 98: 459-478Crossref PubMed Scopus (377) Google Scholar) as well as biophysical (Graupner and Brunel, 2010Graupner M. Brunel N. Mechanisms of induction and maintenance of spike-timing dependent plasticity in biophysical synapse models.Front. Comput. Neurosci. 2010; 4: 136Crossref PubMed Scopus (67) Google Scholar) backgrounds that explore these questions, but only a few have recently proposed a unifying concept of multiple pre- and postsynaptic plasticity pathways (Costa et al., 2015Costa R.P. Froemke R.C. Sjöström P.J. van Rossum M.C.W. Unified pre- and postsynaptic long-term plasticity enables reliable and flexible learning.eLife. 2015; 4: e09457PubMed Google Scholar) in neuron models with extended dendrites (Bono and Clopath, 2017Bono J. Clopath C. Modeling somatic and dendritic spike mediated plasticity at the single neuron and network level.Nat. Commun. 2017; 8: 706Crossref PubMed Scopus (57) Google Scholar, Kastellakis et al., 2016Kastellakis G. Silva A.J. Poirazi P. Linking memories across time via neuronal and dendritic overlaps in model neurons with active dendrites.Cell Rep. 2016; 17: 1491-1504Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, Krieg and Triesch, 2014Krieg D. Triesch J. A unifying theory of synaptic long-term plasticity based on a sparse distribution of synaptic strength.Front. Synaptic Neurosci. 2014; 6: 3Crossref PubMed Scopus (8) Google Scholar, Solinas et al., 2019Solinas S.M.G. Edelmann E. Leßmann V. Migliore M. A kinetic model for Brain-Derived Neurotrophic Factor mediated spike timing-dependent LTP.PLoS Comput. Biol. 2019; 15: e1006975Crossref PubMed Scopus (5) Google Scholar, Urbanczik and Senn, 2014Urbanczik R. Senn W. Learning by the dendritic prediction of somatic spiking.Neuron. 2014; 81: 521-528Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar). Although many biophysical details of excitatory long-term synaptic plasticity are still not fully understood, it is widely accepted that postsynaptic Ca2+ plays a fundamental role. According to some theories and experiments, low levels of Ca2+ lead to no changes in synaptic strength, whereas intermediate levels cause LTD and high levels lead to LTP (Artola and Singer, 1993Artola A. Singer W. Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation.Trends Neurosci. 1993; 16: 480-487Abstract Full Text PDF PubMed Scopus (577) Google Scholar, Artola et al., 1990Artola A. Bröcher S. Singer W. Different voltage-dependent thresholds for inducing long-term depression and long-term potentiation in slices of rat visual cortex.Nature. 1990; 347: 69-72Crossref PubMed Scopus (660) Google Scholar, Graupner and Brunel, 2012Graupner M. Brunel N. Calcium-based plasticity model explains sensitivity of synaptic changes to spike pattern, rate, and dendritic location.Proc. Natl. Acad. Sci. USA. 2012; 109: 3991-3996Crossref PubMed Scopus (206) Google Scholar, Lisman, 1989Lisman J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory.Proc. Natl. Acad. Sci. USA. 1989; 86: 9574-9578Crossref PubMed Scopus (859) Google Scholar, Shouval et al., 2002Shouval H.Z. Bear M.F. Cooper L.N. A unified model of NMDA receptor-dependent bidirectional synaptic plasticity.Proc. Natl. Acad. Sci. USA. 2002; 99: 10831-10836Crossref PubMed Scopus (431) Google Scholar). However, more recent experiments have indicated that the levels of postsynaptic Ca2+ by themselves are not always good predictors for plasticity (Nevian and Sakmann, 2006Nevian T. Sakmann B. Spine Ca2+ signaling in spike-timing-dependent plasticity.J. Neurosci. 2006; 26: 11001-11013Crossref PubMed Scopus (343) Google Scholar), and increasing evidence suggests that multiple partly independent signaling routes that use Ca2+ exist (Bender et al., 2006Bender V.A. Bender K.J. Brasier D.J. Feldman D.E. Two coincidence detectors for spike timing-dependent plasticity in somatosensory cortex.J. Neurosci. 2006; 26: 4166-4177Crossref PubMed Scopus (305) Google Scholar, Jedlicka and Deller, 2017Jedlicka P. Deller T. Understanding the role of synaptopodin and the spine apparatus in Hebbian synaptic plasticity—new perspectives and the need for computational modeling.Neurobiol. Learn. Mem. 2017; 138: 21-30Crossref PubMed Scopus (24) Google Scholar, Oliet et al., 1997Oliet S.H. Malenka R.C. Nicoll R.A. Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells.Neuron. 1997; 18: 969-982Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar, Sjöström et al., 2003Sjöström P.J. Turrigiano G.G. Nelson S.B. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors.Neuron. 2003; 39: 641-654Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar, Sjöström et al., 2007Sjöström P.J. Turrigiano G.G. Nelson S.B. Multiple forms of long-term plasticity at unitary neocortical layer 5 synapses.Neuropharmacology. 2007; 52: 176-184Crossref PubMed Scopus (67) Google Scholar), ultimately leading to a mixture of synaptic changes both expressed at presynaptic and postsynaptic sites (Sjöström et al., 2007Sjöström P.J. Turrigiano G.G. Nelson S.B. Multiple forms of long-term plasticity at unitary neocortical layer 5 synapses.Neuropharmacology. 2007; 52: 176-184Crossref PubMed Scopus (67) Google Scholar). In our phenomenological plasticity model, we incorporated four signaling routes that are loosely related to signaling routes in long-term synaptic plasticity that have been characterized previously. Our plasticity model is based on and extends an existing phenomenological voltage-dependent STDP rule (Clopath and Gerstner, 2010Clopath C. Gerstner W. Voltage and spike timing interact in STDP—a unified model.Front. Synaptic Neurosci. 2010; 2: 25PubMed Google Scholar, Clopath et al., 2010Clopath C. Büsing L. Vasilaki E. Gerstner W. Connectivity reflects coding: a model of voltage-based STDP with homeostasis.Nat. Neurosci. 2010; 13: 344-352Crossref PubMed Scopus (389) Google Scholar). We show in our simulations that a single, dendritic-location-independent plasticity mechanism is able to reconcile many of the differences found in experiments, including plasticity measurements that previous models were not able to account for. We propose, in line with previous suggestions (Feldman, 2012Feldman D.E. The spike-timing dependence of plasticity.Neuron. 2012; 75: 556-571Abstract Full Text Full Text PDF PubMed Scopus (548) Google Scholar, Shouval et al., 2010Shouval H.Z. Wang S.S.-H. Wittenberg G.M. Spike timing dependent plasticity: a consequence of more fundamental learning rules.Front. Comput. Neurosci. 2010; 4: 19PubMed Google Scholar), that concepts such as the Ca2+ level hypothesis mentioned above and classical STDP rules could all be consequences of the same pathways that strongly depend on local interactions at the synapse. In our plasticity model, we introduced four pathways that contributed to changes in both pre- and postsynaptic weight factors. Although implemented as a phenomenological rule, its mechanisms were inspired by well-established biophysical pathways described in a multitude of experimental studies on long-term synaptic plasticity. Briefly, presynaptically expressed LTD (pre-LTD; Figure 1A, left) occurs when metabotropic glutamate receptors (mGluRs) and postsynaptic voltage-gated Ca2+ channels (VGCCs) are activated simultaneously (Heifets and Castillo, 2009Heifets B.D. Castillo P.E. Endocannabinoid signaling and long-term synaptic plasticity.Annu. Rev. Physiol. 2009; 71: 283-306Crossref PubMed Scopus (360) Google Scholar). Phospholipase C (PLC) then integrates these two signals in the process of synthesizing endocannabinoids (eCBs) (Hashimotodani et al., 2005Hashimotodani Y. Ohno-Shosaku T. Tsubokawa H. Ogata H. Emoto K. Maejima T. Araishi K. Shin H.-S. Kano M. Phospholipase Cbeta serves as a coincidence detector through its Ca2+ dependency for triggering retrograde endocannabinoid signal.Neuron. 2005; 45: 257-268Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar), which retrogradely act on presynaptic type 1 cannabinoid receptors (CB1Rs) to reduce transmitter release probability (Heifets and Castillo, 2009Heifets B.D. Castillo P.E. Endocannabinoid signaling and long-term synaptic plasticity.Annu. Rev. Physiol. 2009; 71: 283-306Crossref PubMed Scopus (360) Google Scholar), causing pre-LTD. Presynaptically expressed LTP (pre-LTP) is thought to occur when postsynaptic L-type VGCCs (L-VGCCs) are activated, presumably triggering synthesis of nitric oxide (NO) (Padamsey et al., 2017Padamsey Z. Tong R. Emptage N. Glutamate is required for depression but not potentiation of long-term presynaptic function.eLife. 2017; 6: e29688Crossref PubMed Scopus (23) Google Scholar, Pigott and Garthwaite, 2016Pigott B.M. Garthwaite J. Nitric oxide is required for L-type Ca(2+) channel-dependent long-term potentiation in the hippocampus.Front. Synaptic Neurosci. 2016; 8: 17Crossref PubMed Scopus (35) Google Scholar), possibly by calmodulin (CaM) at nitric oxide synthases (NOSs) (Abu-Soud et al., 1994Abu-Soud H.M. Yoho L.L. Stuehr D.J. Calmodulin controls neuronal nitric-oxide synthase by a dual mechanism. Activation of intra- and interdomain electron transfer.J. Biol. Chem. 1994; 269: 32047-32050Abstract Full Text PDF PubMed Google Scholar). NO retrogradely acts on presynaptic guanylyl cyclase (GC) (Koesling et al., 2004Koesling D. Russwurm M. Mergia E. Mullershausen F. Friebe A. Nitric oxide-sensitive guanylyl cyclase: structure and regulation.Neurochem. Int. 2004; 45: 813-819Crossref PubMed Scopus (131) Google Scholar), triggering a signaling chain that is combined with a presynaptic signal by a presynaptic coincidence detector that has yet to be discovered (Padamsey et al., 2017Padamsey Z. Tong R. Emptage N. Glutamate is required for depression but not potentiation of long-term presynaptic function.eLife. 2017; 6: e29688Crossref PubMed Scopus (23) Google Scholar). Postsynaptically expressed LTD and LTP (post-LTD/-LTP; Figure 1A, right) are described as both being driven by coincident binding of glutamate and depolarization of postsynaptic NMDA receptors (NMDARs) (Lüscher and Malenka, 2012Lüscher C. Malenka R.C. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD).Cold Spring Harb. Perspect. Biol. 2012; 4: 1-16Crossref Scopus (567) Google Scholar). Strong NMDAR-gated Ca2+ influx activates protein kinases, such as Ca2+/CaM-dependent protein kinase II (CaMKII), whereas weak Ca2+ influx activates their counterpart molecules, protein phosphatases such as protein phosphatase 1 and calcineurin (Lisman, 1989Lisman J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory.Proc. Natl. Acad. Sci. USA. 1989; 86: 9574-9578Crossref PubMed Scopus (859) Google Scholar). Kinases increase and phosphatases decrease synaptic efficacy determined by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), essentially forming complementary mechanisms of postsynaptic LTD and LTP induction (Lüscher and Malenka, 2012Lüscher C. Malenka R.C. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD).Cold Spring Harb. Perspect. Biol. 2012; 4: 1-16Crossref Scopus (567) Google Scholar). Studies indicate that CaMKII is able to phosphorylate itself (autophosphorylation) due to its specific subunit structure and that this process is more likely to take effect if pulses of Ca2+ bound to CaM are applied rapidly (De Koninck and Schulman, 1998De Koninck P. Schulman H. Sensitivity of CaM kinase II to the frequency of Ca2+ oscillations.Science. 1998; 279: 227-230Crossref PubMed Scopus (1081) Google Scholar), suggesting that this mechanism could play a role in the frequency dependence of plasticity. In our model, pre-LTD (indicated by the variable E; Figure 1B, left; see also Figure S1) was induced when the low-pass-filtered postsynaptic voltage trace T coincided with the brief presynaptic signal D. Due to the transient nature of D, pre-LTD was only induced if the postsynaptic cell experienced depolarization shortly before the presynaptic signal, e.g., if the stimulation included a post-pre pair (Figure 1C, medium green color in left versus right column). Consequently, this mechanism only detected post-pre timings and was insensitive to pre-post timings, consistent with pre-LTD in experimental studies (Nevian and Sakmann, 2006Nevian T. Sakmann B. Spine Ca2+ signaling in spike-timing-dependent plasticity.J. Neurosci. 2006; 26: 11001-11013Crossref PubMed Scopus (343) Google Scholar, Sjöström et al., 2003Sjöström P.J. Turrigiano G.G. Nelson S.B. Neocortical LTD via coincident activation of presynaptic NMDA and cannabinoid receptors.Neuron. 2003; 39: 641-654Abstract Full Text Full Text PDF PubMed Scopus (477) Google Scholar). Pre-LTP (indicated by the variable X; Figure 1B, left) in our model required that two consecutively filtered traces based on postsynaptic voltage Nα and Nβ coincided to result in a trace N. Owing to Nβ being filtered from Nα, N was sensitive to the frequency of postsynaptic events during postsynaptic activity due to summation (Figure 1C, light violet color). Only if N was sufficiently elevated during the occurrence of the slow presynaptic signal Z, pre-LTP was switched on. Post-LTD (indicated by the variable P; Figure 1B, right) was modeled by calculating the coincidence of the slow presynaptic signal G and a portion of membrane voltage u. The resulting variable C was subjected to an activation function with two thresholds, namely, θC− and θC+ (Figure 1D). This formalism was consistent with Ca2+-level-based rules (Artola and Singer, 1993Artola A. Singer W. Long-term depression of excitatory synaptic transmission and its relationship to long-term potentiation.Trends Neurosci. 1993; 16: 480-487Abstract Full Text PDF PubMed Scopus (577) Google Scholar, Lisman, 1989Lisman J. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory.Proc. Natl. Acad. Sci. USA. 1989; 86: 9574-9578Crossref PubMed Scopus (859) Google Scholar, Shouval et al., 2002Shouval H.Z. Bear M.F. Cooper L.N. A unified model of NMDA receptor-dependent bidirectional synaptic plasticity.Proc. Natl. Acad. Sci. USA. 2002; 99: 10831-10836Crossref PubMed Scopus (431) Google Scholar) that have previously been used for modeling synaptic plasticity (see Discussion). No synaptic weight changes were induced below θC−. Whenever C resided between θC− and θC+, post-LTD was activated (Figure 1C, orange color). To model post-LTP (indicated by the variable K; Figure 1B, right), the portion of C above θC+, named Kα, was used to compute the two slower traces Kβ and Kγ, which were filtered versions of Kα. The variable ρ limited the sum of Kα and Kβ. Post-LTP was only switched on when Kα, Kβ, and Kγ were nonzero. Thus, similarly to pre-LTP, this mechanism was frequency dependent. A pre-post-post protocol, therefore, evoked considerably more post-LTP than a post–pre-post protocol (Figure 1C, turquoise color in right versus left column). The rule’s voltage dependence is demonstrated in Figure 1E. One single presynaptic event was evoked while the postsynaptic cell was clamped to values between −75 mV and −15 mV. Voltages below −60 mV led to no change in weight, whereas voltages between −60 mV and about −28 mV caused LTD and voltages above that caused net LTP. Consistent with experiments on voltage dependence of LTD pathways (Oliet et al., 1997Oliet S.H. Malenka R.C. Nicoll R.A. Two distinct forms of long-term depression coexist in CA1 hippocampal pyramidal cells.Neuron. 1997; 18: 969-982Abstract Full Text Full Text PDF PubMed Scopus (459) Google Scholar), post-LTD more strongly depended on depolarization than pre-LTD. To consider all the effects of realistic firing behavior, active dendrites, and synapse location, we incorporated our plasticity model into a highly detailed cortical layer 5b (L5b) pyramidal cell model (Hay et al., 2011Hay E. Hill S. Schürmann F. Markram H. Segev I. Models of neocortical layer 5b pyramidal cells capturing a wide range of dendritic and perisomatic active properties.PLoS Comput. Biol. 2011; 7: e1002107Crossref PubMed Scopus (178) Google Scholar). In the first stimulation protocol we used, regular bursts of five pre- and five postsynaptic APs were evoked at either pre-post (Δt=+10ms) or post-pre (Δt=−10ms) timings (Figure 2A inset; see STAR Methods). The frequency within the bursts (intra-burst frequency) varied between 0.1 Hz and 50 Hz. Even at 50 Hz, distal dendrites in the neuron model experienced only weak depolarization due to bAP attenuation (Figure 2A). We optimized the plasticity rule’s parameters (Table S1, set 1) to match the experimental data (Sjöström and Häusser, 2006Sjöström P.J. Häusser M. A cooperative switch determines the sign of synaptic plasticity in distal dendrites of neocortical pyramidal neurons.Neuron. 2006; 51: 227-238Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, Sjöström et al., 2001Sjöström P.J. Turrigiano G.G. Nelson S.B. Rate, timing, and cooperativity jointly determine cortical synaptic plasticity.Neuron. 2001; 32: 1149-1164Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar). At proximal locations (90 μm from the soma; Figure 2B, left panel), a pre-post timing at a frequency of 0.1 Hz led to no change in weight, whereas at and above 10 Hz, in accordance with experiments (Sjöström et al., 2001Sjöström P.J. Turrigiano G.G. Nelson S.B. Rate, timing, and cooperativity jointly determine cortical synaptic plasticity.Neuron. 2001; 32: 1149-1164Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar), LTP was induced. In the model, 0.1-Hz bursts were unable to cause any relevant summation of postsynaptic traces in either LTP pathway. In contrast, at 10 Hz and above, such summation was achieved, leading to LTP. A post-pre timing caused LTD below a frequency of about 30 Hz and LTP beyond 30 Hz both in experiments (Sjöström et al., 2001Sjöström P.J. Turrigiano G.G. Nelson S.B. Rate, timing, and cooperativity jointly determine cortical synaptic plasticity.Neuron. 2001; 32: 1149-1164Abstract Full Text Full Text PDF PubMed Scopus (819) Google Scholar) and in the model. Here, mainly pre-LTD was initiated in the model at lower frequencies. However, at higher frequencies, summation in both LTP pathways caused the overall switch. When pre-LTD was blocked in the model, this caused even stronger LTP, whereas blockade of pre-LTP substantially reduced the amount of LTP (Figure S2), which is in line with experimental studies (Sjöström et al., 2007Sjöström P.J. Turrigiano G.G. Nelson S.B. Multiple forms of long-term plasticity at unitary neocortical layer 5 synapses.Neuropharmacology. 2007; 52: 176-184Crossref PubMed Scopus (67) Google Scholar). At distal locations (669 μm from the soma; Figure 2B, right panel), LTP was absent for both timings and across all frequencies, whereas frequencies above 20 Hz resulted in slight LTD. Except for pre-post at 50 Hz (Sjöström and Häusser, 2006Sjöström P.J. Häusser M. A cooperative switch determines the sign of synaptic plasticity in distal dendrites of neocortical pyramidal neurons.Neuron. 2006; 51: 227-238Abstract Full Text Fu" @default.
• W2998668254 created "2020-01-10" @default.
• W2998668254 creator A5022211221 @default.
• W2998668254 creator A5039497694 @default.
• W2998668254 creator A5046801422 @default.
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• W2998668254 date "2019-12-01" @default.
• W2998668254 modified "2023-10-10" @default.
• W2998668254 title "Unifying Long-Term Plasticity Rules for Excitatory Synapses by Modeling Dendrites of Cortical Pyramidal Neurons" @default.
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• W2998668254 doi "https://doi.org/10.1016/j.celrep.2019.11.068" @default.
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