Invertebrate and vertebrate experimental models, each providing unique advantages for addressing specific questions, offer a multifaceted and multiscale view of plasticity. Integration of the obtained knowledge is crucial for understanding general principles and specific mechanisms of synaptic plasticity. However, this process is hindered by field-specific discrepancies in terminology and concepts. A profound case of such discrepancy is heterosynaptic plasticity, which refers to distinct experimental phenomena and mechanisms and serves different functional roles in invertebrate and vertebrate nervous systems. In Aplysia research, heterosynaptic facilitation originally referred to several phenomena and mechanisms of synaptic plasticity that mediate simple forms of learning. In vertebrate research, heterosynaptic plasticity originally referred to changes at synapses that were not activated during the induction of long-term potentiation in the hippocampus. Ironically, most of the difference between the wordings comes from the meaning attributed to their common part, the heterosynaptic. Here, we consider these differences and discuss how the phenomena and concepts behind the field-specific terminologies are related and can be compared.
AbrahamWCGoddardGV. 1983. Asymmetric relationships between homosynaptic long-term potentiation and heterosynaptic long-term depression. Nature. 305:717–719.
2.
AbrahamWCWickensJR.1991. Heterosynaptic long-term depression is facilitated by blockade of inhibition in area CA1 of the hippocampus. Brain Res. 546:336–340.
3.
AbramsTKarlKKandelE.1991. Biochemical studies of stimulus convergence during classical conditioning in Aplysia: dual regulation of adenylate cyclase by Ca2+/calmodulin and transmitter. J Neurosci. 11:2655–2665.
4.
AdesnikHScanzianiM.2010. Lateral competition for cortical space by layer-specific horizontal circuits. Nature. 464:1155–1160.
5.
AntonovIAntonovaIKandelERHawkinsRD. 2003. Activity-dependent presynaptic facilitation and Hebbian LTP are both required and interact during classical conditioning in Aplysia. Neuron. 37:135–147.
6.
AntonovIHaTAntonovaIMorozLLHawkinsRD. 2007. Role of nitric oxide in classical conditioning of siphon withdrawal in Aplysia. J Neurosci. 27:10993–11002.
7.
BaileyCHChenM.1983. Morphological basis of long-term habituation and sensitization in Aplysia. Science. 220:91–93.
8.
BaileyCHGiustettoMHuangYYHawkinsRDKandelER. 2000. Is heterosynaptic modulation essential for stabilizing Hebbian plasticity and memory?Nat Rev Neurosci. 1:11–20.
9.
BannonNMChistiakovaMChenJ-YBazhenovMVolgushevM.2017. Adenosine shifts plasticity regimes between associative and homeostatic by modulating heterosynaptic changes. J Neurosci. 37:1439–1452
10.
BannonNMChistiakovaMVolgushevM.2020. Synaptic plasticity in cortical inhibitory neurons: what mechanisms may help to balance synaptic weight changes?Front Cell Neurosci. 14:204.
11.
BienenstockECooperLMunroP.1982. Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex. J Neurosci. 2:32–48.
12.
BittnerKC, et al. 2015. Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons. Nat Neurosci. 18:1133–1142.
13.
BlissTVPCollingridgeGL. 1993. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 361:31–39.
14.
BlissTVPLømoT. 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 232:331–356
15.
BöhmeGABonCStutzmannJ-MDobleABlanchardJ-C.1991. Possible involvement of nitric oxide in long-term potentiation. Eur J Pharmacol. 199:379–381.
16.
BonhoefferTStaigerVAertsenA.1989. Synaptic plasticity in rat hippocampal slice cultures: local “Hebbian” conjunction of pre- and postsynaptic stimulation leads to distributed synaptic enhancement. Proc Natl Acad Sci U S A. 86:8113–8117.
17.
BorczykMŚliwińskaMACalyABernasTRadwanskaK.2019. Neuronal plasticity affects correlation between the size of dendritic spine and its postsynaptic density. Sci Rep. 9:1693.
18.
BortolottoZABashirZIDaviesCHCollingridgeGL. 1994. A molecular switch activated by metabotropic glutamate receptors regulates induction of long-term potentiation. Nature. 368:740–743.
19.
BradlerJEBarrionuevoG.1990. Heterosynaptic correlates of long-term potentiation induction in hippocampal CA3 neurons. Neuroscience. 35:265–271.
20.
BravarenkoNIGusevP VBalabanPMVoroninLL. 1995. Postsynaptic induction of long-term synaptic facilitation in snail central neurones. Neuroreport. 6:1182–1186.
21.
BrunelliMCastellucciVKandelER. 1976. Synaptic facilitation and behavioral sensitizationin Aplysia : possible role of serotonin and cyclic AMP. Science. 194:1178–1181.
22.
BrzoskoZMierauSBPaulsenO.2019. Neuromodulation of spike-timing-dependent plasticity: past, present, and future. Neuron. 103:563–581.
23.
ByrneJHKandelER. 1996. Presynaptic facilitation revisited: state and time dependence. J Neurosci. 16:425–435.
24.
CaporaleNDanY. 2008. Spike timing-dependent plasticity: a Hebbian learning rule. Annu Rev Neurosci. 31:25–46.
25.
CardinJA. 2018. Inhibitory interneurons regulate temporal precision and correlations in cortical circuits. Trends Neurosci. 41:689–700.
26.
CarewTJHawkinsRDKandelER. 1983. Differential classical conditioning of a defensive withdrawal reflex in Aplysia californica. Science. 219:397–400.
27.
CarewTJWaltersETKandelER. 1981. Classical conditioning in a simple withdrawal reflex in Aplysia californica. J Neurosci. 1:1426–1437.
ChistiakovaMBalabanPEyselUTVolgushevM.1999. NMDA receptor blockade prevents LTD, but not LTP induction by intracellular tetanization. Neuroreport. 10:3869–3874.
33.
ChistiakovaMBannonNMBazhenovMVolgushevM.2014. Heterosynaptic plasticity: multiple mechanisms and multiple roles. Neuroscientist. 20:483–498.
34.
ChistiakovaMBannonNMChenJ-YBazhenovMVolgushevM.2015. Homeostatic role of heterosynaptic plasticity: models and experiments. Front Comput Neurosci. 9:89
35.
ChistiakovaM, et al. 2019. Distinct heterosynaptic plasticity in fast spiking and non-fast-spiking inhibitory neurons in rat visual cortex. J Neurosci. 39:6865–6878
36.
ChistiakovaMVolgushevM.2009. Heterosynaptic plasticity in the neocortex. Exp Brain Res. 199:377–390.
37.
ChitwoodRALiQGlanzmanDL. 2001. Serotonin facilitates AMPA-type responses in isolated siphon motor neurons of Aplysia in culture. J Physiol. 534:501–510.
38.
ChoKAggletonJPBrownMWBashirZI.2001. An experimental test of the role of postsynaptic calcium levels in determining synaptic strength using perirhinal cortex of rat. J Physiol. 532:459–466.
39.
ChristieBRKerrDSAbrahamWC. 1994. Flip side of synaptic plasticity: long-term depression mechanisms in the hippocampus. Hippocampus. 4:127–135.
40.
ChristofiGNowickyAVBolsoverSRBindmanLJ. 1993. The postsynaptic induction of nonassociative long-term depression of excitatory synaptic transmission in rat hippocampal slices. J Neurophysiol. 69:219–229.
41.
El-BoustaniS, et al. 2018. Locally coordinated synaptic plasticity of visual cortex neurons in vivo. Science. 360:1349–1354.
42.
EngertFBonhoefferT.1997. Synapse specificity of long-term potentiation breaks down at short distances. Nature. 388:279–284.
43.
FavorovOVNilaweeraWUMiasnikovAABeloozerovaIN. 2015. Activity of somatosensory-responsive neurons in high subdivisions of SI cortex during locomotion. J Neurosci. 35:7763–7776.
44.
FrémauxNGerstnerW. 2016. Neuromodulated spike-timing-dependent plasticity, and theory of three-factor learning rules. Front Neural Circuits. 9:85.
45.
GallyJAMontaguePRReekeGNEdelmanGM. 1990. The NO hypothesis: possible effects of a short-lived, rapidly diffusible signal in the development and function of the nervous system. Proc Natl Acad Sci. 87:3547–3551.
46.
GerstnerWLehmannMLiakoniVCorneilDBreaJ.2018. Eligibility traces and plasticity on behavioral time scales: experimental support of NeoHebbian three-factor learning rules. Front Neural Circuits. 12:1–16.
47.
GlanzmanDL, et al. 1989. Depletion of serotonin in the nervous system of Aplysia reduces the behavioral enhancement of gill withdrawal as well as the heterosynaptic facilitation produced by tail shock. J Neurosci. 9:4200–4213.
48.
GovindarajanAKelleherRJTonegawaS.2006. A clustered plasticity model of long-term memory engrams. Nat Rev Neurosci. 7:575–583.
HawkinsRDKandelERBaileyCH. 2006. Molecular mechanisms of memory storage in Aplysia. Biol Bull. 210:174–191.
51.
HeK, et al. 2015. Distinct eligibility traces for LTP and LTD in cortical synapses. Neuron. 88:528–538.
52.
HedrickNG, et al. 2016. Rho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity. Nature. 538:104–108.
53.
HedrickNGYasudaR.2017. Regulation of Rho GTPase proteins during spine structural plasticity for the control of local dendritic plasticity. Curr Opin Neurobiol. 45:193–201.
54.
HolthoffKTsayDYusteR.2002. Calcium dynamics of spines depend on their dendritic location. Neuron. 33:425–437.
55.
HuberKMKayserMSBearMF. 2000. Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science. 288:1254–1256.
56.
KandelERKoesterJDMackSHSiegelbaumSA. 2021. Cellular mechanisms of implicit memory storage and the biological basis of individuality. In: KandelERKoesterJDMackSHSiegelbaumSA editors. Principles of neural science (6th ed). McGraw-Hill. Chap 53.
57.
KandelERSchwartzJH. 1982. Molecular biology of learning: modulation of transmitter release. Science. 218:433–443.
58.
KandelERTaucL.1965a. Heterosynaptic facilitation in neurones of the abdominal ganglion of Aplysia depilans. J Physiol. 181:1–27.
59.
KandelERTaucL.1965b. Mechanism of heterosynaptic facilitation in the giant cell of the abdominal ganglion of Aplysia depilans. J Physiol. 181:28–47.
KowalskiJGanJJonasPPernía-AndradeAJ. 2016. Intrinsic membrane properties determine hippocampal differential firing pattern in vivo in anesthetized rats. Hippocampus. 26:668–682.
62.
KrugMMüller-WeldePWagnerMOttTMatthiesH.1985. Functional plasticity in two afferent systems of the granule cells in the rat dentate area: frequency-related changes, long-term potentiation and heterosynaptic depression. Brain Res. 360:264–272.
63.
KuhntUKleschevnikovAMVoroninLL. 1994. Long term enhancement of synaptic transmission in the hippocampus after tetanization of single neurons by short intracellular current pulses. Neurosci Res Commun. 14:115–123.
64.
KurotaniTYamadaKYoshimuraYCrairMCKomatsuY.2008. State-dependent bidirectional modification of somatic inhibition in neocortical pyramidal cells. Neuron. 57:905–916.
65.
LechnerHAByrneJH. 1998. New perspectives on classical conditioning: a synthesis of Hebbian and non-Hebbian mechanisms. Neuron. 20:355–358.
66.
LeeCMStoelzelCChistiakovaMVolgushevM.2012. Heterosynaptic plasticity induced by intracellular tetanization in layer 2/3 pyramidal neurons in rat auditory cortex. J Physiol. 590:2253–2271.
67.
LetellierMLevetFThoumineOGodaY.2019. Differential role of pre-and postsynaptic neurons in the activity-dependent control of synaptic strengths across dendrites. PLoS Biol17.
68.
LismanJ. 1989. A mechanism for the Hebb and the anti-Hebb processes underlying learning and memory. Proc Natl Acad Sci. 86:9574–9578.
69.
LismanJEE. 2001. Three Ca 2+ levels affect plasticity differently: the LTP zone, the LTD zone and no man’s land. J Physiol. 532:285–285.
70.
LourençoJ, et al. 2014. Non-associative potentiation of perisomatic inhibition alters the temporal coding of neocortical layer 5 pyramidal neurons. PLoS Biol. 12:e1001903.
71.
LuJLiCZhaoJ-PPooMZhangX.2007. Spike-timing–dependent plasticity of neocortical excitatory synapses on inhibitory interneurons depends on target cell type. J Neurosci. 27:9711–9720.
72.
LynchGSDunwiddieTGribkoffV.1977. Heterosynaptic depression: a postsynaptic correlate of long-term potentiation. Nature. 266:737–739.
73.
MagóÁWeberJPUjfalussyBBMakaraJK. 2020. Synaptic plasticity depends on the fine-scale input pattern in thin dendrites of CA1 pyramidal neurons. J Neurosci. 40:2593–2605.
74.
MalenkaRCKauerJAZuckerRSNicollRA. 1988. Postsynaptic calcium is sufficient for potentiation of hippocampal synaptic transmission. science. 242:81–84.
75.
MalinowRMalenkaRC. 2002. AMPA receptor trafficking and synaptic plasticity. Annu Rev Neurosci. 25:103–126.
76.
MalyshevABravarenkoNBalabanP.1997. Dependence of synaptic facilitation postsynaptically induced in snail neurones on season and serotonin level. Neuroreport. 8:1179–1182.
77.
MartinKC, et al. 1997. Synapse-specific, long-term facilitation of Aplysia sensory to motor synapses: a function for local protein synthesis in memory storage. Cell. 91:927–938.
78.
MatsuzakiMHonkuraNEllis-DaviesGCRKasaiH.2004. Structural basis of long-term potentiation in single dendritic spines. Nature. 429:761–766.
79.
MillerKD. 1996. Synaptic economics: competition and cooperation in synaptic plasticity. Neuron. 17:371–374.
80.
MillerKDMacKayDJC. 1994. The role of constraints in Hebbian learning. Neural Comput. 6:100–126.
81.
MontaroloPG, et al. 1986. A critical period for macromolecular synthesis in long-term heterosynaptic facilitation in Aplysia. Science. 234:1249–1254.
82.
MontaroloPGKandelERSchacherS.1988. Long-term heterosynaptic inhibition in Aplysia. Nature. 333:171–174.
83.
MurakoshiHWangHYasudaR.2011. Local, persistent activation of Rho GTPases during plasticity of single dendritic spines. Nature. 472:100–104.
84.
MurphyGGGlanzmanDL. 1996. Enhancement of sensorimotor connections by conditioning-related stimulation in Aplysia depends upon postsynaptic Ca2+. Proc Natl Acad Sci. 93:9931–9936.
85.
MurphyGGGlanzmanDL. 1997. Mediation of classical conditioning in Aplysia californica by long-term potentiation of sensorimotor synapses. Science. 278:467–471.
86.
MurphyGGGlanzmanDL. 1999. Cellular analog of differential classical conditioning in Aplysia : disruption by the NMDA receptor antagonistdl-2-amino-5-phosphonovalerate. J Neurosci. 19:10595–10602.
87.
NeveuDZuckerRS. 1996a. Long-lasting potentiation and depression without presynaptic activity. J Neurophysiol. 75:2157–2160.
88.
NeveuDZuckerRS. 1996b. Postsynaptic levels of [Ca2+]i Needed to trigger LTD and LTP. Neuron. 16:619–629.
89.
NevianTSakmannB.2006. Spine Ca2+ signaling in spike-timing-dependent plasticity. J Neurosci. 26:11001–11013.
90.
NishiyamaMHongKMikoshibaKPooMMKatoK.2000. Calcium stores regulate the polarity and input specificity of synaptic modification. Nature. 408:584–588.
O’DellTJAlgerBE. 1991. Single calcium channels in rat and guinea-pig hippocampal neurons. J Physiol. 436:739–767.
93.
OhWCHillTCZitoK.2013. Synapse-specific and size-dependent mechanisms of spine structural plasticity accompanying synaptic weakening. Proc Natl Acad Sci. 110:E305–E312.
94.
OhWCParajuliLKZitoK.2015. Heterosynaptic structural plasticity on local dendritic segments of hippocampal CA1 neurons. Cell Rep. 10:162–169.
95.
OjaE. 1982. Simplified neuron model as a principal component analyzer. J Math Biol. 15:267–273.
96.
OkunoH, et al. 2012. Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKIIβ. Cell. 149:886–898.
97.
OldsJ. 1958. Self-stimulation of the brain. Science. 127:315–324.
98.
OldsJMilnerP.1954. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol. 47:419–427.
99.
PinskerHMHeningWACarewTJKandelER. 1973. Long-term sensitization of a defensive withdrawal reflex in Aplysia. Science. 182:1039–1042.
100.
PolskyAMelBWSchillerJ.2004. Computational subunits in thin dendrites of pyramidal cells. Nat Neurosci. 7:621–627.
101.
RabinowitchISegevI.2008. Two opposing plasticity mechanisms pulling a single synapse. Trends Neurosci. 31:377–383.
102.
ReyesA, et al. 1998. Target-cell-specific facilitation and depression in neocortical circuits. Nat Neurosci. 1:279–285.
103.
RoyerSParéD.2003. Conservation of total synaptic weight through balanced synaptic depression and potentiation. Nature. 422:518–522.
104.
SamadiM, et al. 2023. Mechanisms of mGluR-dependent plasticity in hippocampal area CA2. Hippocampus. 33:730–744.
105.
SchumanEMMadisonDV. 1994. Locally distributed synaptic potentiation in the hippocampus. Science. 263:532–536.
106.
SieberARRMinRNevianT. 2013. Non-Hebbian long-term potentiation of inhibitory synapses in the thalamus. J Neurosci. 33:15675–15685.
107.
SilberbergGGrillnerSLeBeauFENMaexRMarkramH.2005. Synaptic pathways in neural microcircuits. Trends Neurosci. 28:541–551.
108.
SimonovaNAAbonakourAVolgushevMAMalyshevAY. 2024. Non-associative potentiation of proximal excitatory inputs to layer 2/3 pyramidal cells in rat visual cortex. Biochem Biophys Res Commun. 733:150736.
109.
SimonovaNAVolgushevMAMalyshevAY. 2022. Enhanced non-associative long-term potentiation in immature granule cells in the dentate gyrus of adult rats. Front Synaptic Neurosci. 14:889947.
110.
StuartGSchillerJSakmannB.1997a. Action potential initiation and propagation in rat neocortical pyramidal neurons. J Physiol. 505:617–632.
111.
StuartGSprustonNSakmannBHäusserM.1997b. Action potential initiation and backpropagation in neurons of the mammalian CNS. Trends Neurosci. 20:125–131.
112.
StuartGJSakmannB.1994. Active propagation of somatic action potentials into neocortical pyramidal cell dendrites. Nature. 367:69–72.
113.
SvobodaKDenkWKleinfeldDTankDW. 1997. In vivo dendritic calcium dynamics in neocortical pyramidal neurons. Nature. 385:161–165.
114.
TaucLEpsteinR.1967. Heterosynaptic facilitation as a distinct mechanism in Aplysia. Nature. 214:724–725.
115.
TazerartSMitchellDEMiranda-RottmannSArayaR.2020. A spike-timing-dependent plasticity rule for dendritic spines. Nat Commun. 11:4276.
116.
ThomazeauA, et al. 2021. Dissociation of functional and structural plasticity of dendritic spines during NMDAR and mGluR-dependent long-term synaptic depression in wild-type and fragile X model mice. Mol Psychiatry. 26:4652–4669.
117.
TongRChaterTEEmptageNJGodaY.2021. Heterosynaptic cross-talk of pre- and postsynaptic strengths along segments of dendrites. Cell Rep. 34:108693.
118.
VolgushevMBalabanPChistiakovaMEyselUTT. 2000. Retrograde signalling with nitric oxide at neocortical synapses. Eur J Neurosci. 12:4255–4267.
119.
VolgushevM, et al. 2016. Partial breakdown of input specificity of STDP at individual synapses promotes new learning. J Neurosci. 36:8842–8855.
120.
VolgushevMPernbergJEyselUTT. 2003. Gamma-frequency fluctuations of the membrane potential and response selectivity in visual cortical neurons. Eur J Neurosci. 17:1768–1776.
121.
VolgushevMVoroninLLChistiakovaMSingerW.1994. Induction of LTP and LTD in visual cortex neurones by intracellular tetanization. Neuroreport. 5:2069–2072.
122.
VolgushevMVoroninLLChistiakovaMSingerW. 1997. Relations between long-term synaptic modifications and paired-pulse interactions in the rat neocortex. Eur J Neurosci. 9:1656–1665.
123.
von der MalsburgC. 1973. Self-organization of orientation sensitive cells in the striate cortex. Kybernetik. 14:85–100.
124.
VyazovskiyVV, et al. 2009. Cortical firing and sleep homeostasis. Neuron. 63:865–878.
125.
WaltersETByrneJH. 1983. Associative conditioning of single sensory neurons suggests a cellular mechanism for learning. Science. 219:405–408.
126.
WaltersETByrneJH. 1985. Long-term enhancement produced by activity-dependent modulation of Aplysia sensory neurons. J Neurosci. 5:662–672.
127.
WhiteGLevyWBStewardO.1990. Spatial overlap between populations of synapses determines the extent of their associative interaction during the induction of long-term potentiation and depression. J Neurophysiol. 64:1186–1198.
128.
WickensJRAbrahamWC. 1991. The involvement of L-type calcium channels in heterosynaptic long-term depression in the hippocampus. Neurosci Lett. 130:128–132.
129.
WinnubstJLohmannC.2012. Synaptic clustering during development and learning: the why, when, and how. Front Mol Neurosci. 5:70.
130.
YangS-NTangY-GZuckerRS. 1999. Selective induction of LTP and LTD by postsynaptic [Ca2+]i elevation. J Neurophysiol. 81:781–787.
131.
YountsTJChevaleyreVCastilloPE. 2013. CA1 pyramidal cell theta-burst firing triggers endocannabinoid-mediated long-term depression at both somatic and dendritic inhibitory synapses. J Neurosci. 33:13743–13757.
132.
ZalutskyRANicollRA. 1990. Comparison of two forms of long-term potentiation in single hippocampal neurons. Science. 248:1619–1624.
