Input-Timing-Dependent Plasticity in the Hippocampal CA2 Region and Its Potential Role in Social Memory
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Input-timing-dependent plasticity (ITDP) is a circuit-based synaptic learning rule by which paired activation of entorhinal cortical (EC) and Schaffer collateral (SC) inputs to hippocampal CA1 pyramidal neurons (PNs) produces a long-term enhancement of SC excitation. We now find that paired stimulation of EC and SC inputs also induces ITDP of SC excitation of CA2 PNs. However, whereas CA1 ITDP results from long-term depression of feedforward inhibition (iLTD) as a result of activation of CB1 endocannabinoid receptors on cholecystokinin-expressing interneurons, CA2 ITDP results from iLTD through activation of δ-opioid receptors on parvalbumin-expressing interneurons. Furthermore, whereas CA1 ITDP has been previously linked to enhanced specificity of contextual memory, we find that CA2 ITDP is associated with enhanced social memory. Thus, ITDP may provide a general synaptic learning rule for distinct forms of hippocampal-dependent memory mediated by distinct hippocampal regions.
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Modulation of CA2 parvalbumin-positive interneurons is critical for social memory in that they exhibit a heterosynaptic form of input-timing-dependent inhibitory long-term depression, the blockade of which impairs social memory.
“Modulation of CA2 parvalbumin-positive (PV) interneurons is also critical for social memory in that they exhibit a heterosynaptic form of inputtiming-dependent inhibitory LTD, the blockade of which impairs social memory [75,76].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [75]
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Cites
Bliss, T. V. P., & Gardner-Medwin, A. R. (1973) · The Journal of Physiology · doi:10.1113/jphysiol.1973.sp010274 · Cited by 7,460 · see citing works
High-performance genetically targetable optical neural silencing by light-driven proton pumps
Chow, B. Y., Han, X., Dobry, A. S., Qian, X., Chuong, A. S., Li, M., Henninger, M. A., Belfort, G. M., Lin, Y., Monahan, P. E., et al. (2010) · Nature · doi:10.1038/nature08652 · Cited by 1,188 · see citing works
A Developmental Switch in the Response of DRG Neurons to ETS Transcription Factor Signaling
Hippenmeyer, S., Pecho‐Vrieseling, E., Sigrist, M., Portmann, T., Laengle, C., Ladle, D. R., & Arber, S. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030159 · Cited by 1,059 · see citing works
The hippocampal CA2 region is essential for social memory
Hitti, F. L., & Siegelbaum, S. A. (2014) · Nature · doi:10.1038/nature13028 · Cited by 976 · see citing works
Self-citationOscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving rat
Csicsvari, J., Hirase, H., Czurkó, A., Mamiya, A., & Buzsáki, G. (1999) · The Journal of Neuroscience · doi:10.1523/jneurosci.19-01-00274.1999 · Cited by 966 · see citing works
Cerebellar Long-Term Depression: Characterization, Signal Transduction, and Functional Roles
Ito, M. (2001) · Physiological Reviews · doi:10.1152/physrev.2001.81.3.1143 · Cited by 832 · see citing works
Immunohistochemical localization of enkephalin in rat brain and spinal cord
Sar, M., Stumpf, W. E., Miller, R. J., Chang, K., & Cuatrecasas, P. (1978) · The Journal of Comparative Neurology · doi:10.1002/cne.901820103 · Cited by 822 · see citing works
Neuropeptide Transmission in Brain Circuits
van den Pol, A. N. (2012) · Neuron · doi:10.1016/j.neuron.2012.09.014 · Cited by 810 · see citing works
Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning
Donato, F., Rompani, S. B., & Caroni, P. (2013) · Nature · doi:10.1038/nature12866 · Cited by 703 · see citing works
Urban, D. J., & Roth, B. L. (2014) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010814-124803 · Cited by 660 · see citing works
Ventral CA1 neurons store social memory
Okuyama, T., Kitamura, T., Roy, D. S., Itohara, S., & Tonegawa, S. (2016) · Science · doi:10.1126/science.aaf7003 · Cited by 657 · see citing works
Cell type–specific genetic and optogenetic tools reveal hippocampal CA2 circuits
Kohara, K., Pignatelli, M., Rivest, A. J., Jung, H.-Y., Kitamura, T., Suh, J., Frank, D., Kajikawa, K., Mise, N., Obata, Y., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3614 · Cited by 528 · see citing works
A reduction of nonpyramidal cells in sector CA2 of schizophrenics and manic depressives
Benes, F. M., Kwok, E. W., Vincent, S. L., & Todtenkopf, M. S. (1998) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00138-3 · Cited by 470 · see citing works
Alger, B. E., & Teyler, T. J. (1976) · Brain Research · doi:10.1016/0006-8993(76)90858-1 · Cited by 449 · see citing works
Wall, N. R., Wickersham, I. R., Cetin, A. H., Parra, M. D. L., & Callaway, E. M. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1011756107 · Cited by 369 · see citing works
Gall, C. M., Brecha, N. C., Karten, H. J., & Chang, K. (1981) · The Journal of Comparative Neurology · doi:10.1002/cne.901980211 · Cited by 358 · see citing works
Rediscovering area CA2: unique properties and functions
Dudek, S. M., Alexander, G. M., & Farris, S. (2016) · Nature reviews. Neuroscience · doi:10.1038/nrn.2015.22 · Cited by 329 · see citing works
Island Cells Control Temporal Association Memory
北村, 貴., Pignatelli, M., Suh, J., Kohara, K., Yoshiki, A., Abe, K., & Tonegawa, S. (2014) · Science · doi:10.1126/science.1244634 · Cited by 327 · see citing works
Strong CA2 Pyramidal Neuron Synapses Define a Powerful Disynaptic Cortico-Hippocampal Loop
Chevaleyre, V., & Siegelbaum, S. A. (2010) · Neuron · doi:10.1016/j.neuron.2010.04.013 · Cited by 324 · see citing works
Self-citationPathway Interactions and Synaptic Plasticity in the Dendritic Tuft Regions of CA1 Pyramidal Neurons
Takahashi, H., & Magee, J. C. (2009) · Neuron · doi:10.1016/j.neuron.2009.03.007 · Cited by 312 · see citing works
Rabies Virus CVS-N2c ΔG Strain Enhances Retrograde Synaptic Transfer and Neuronal Viability
Reardon, T. R., Murray, A., Turi, G. F., Wirblich, C., Croce, K. R., Schnell, M. J., Jessell, T. M., & Losonczy, A. (2016) · Neuron · doi:10.1016/j.neuron.2016.01.004 · Cited by 311 · see citing works
Endocannabinoid-Mediated Metaplasticity in the Hippocampus
Chevaleyre, V., & Castillo, P. E. (2004) · Neuron · doi:10.1016/j.neuron.2004.08.036 · Cited by 303 · see citing works
Jarsky, T., Roxin, A., Kath, W. L., & Spruston, N. (2005) · Nature Neuroscience · doi:10.1038/nn1599 · Cited by 301 · see citing works
McGinty, J. F., Henriksen, S. J., D, A. G. M., Terenius, L. Y., & Bloom, F. E. (1983) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.80.2.589 · Cited by 290 · see citing works
Yeckel, M. F., & Berger, T. W. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.15.5832 · Cited by 286 · see citing works
Gating of hippocampal activity, plasticity, and memory by entorhinal cortex long-range inhibition
Basu, J., Zaremba, J. D., Cheung, S. K., Hitti, F. L., Zemelman, B. V., Losonczy, A., & Siegelbaum, S. A. (2016) · Science · doi:10.1126/science.aaa5694 · Cited by 274 · see citing works
Self-citationThe Corticohippocampal Circuit, Synaptic Plasticity, and MemoryPreprint
Basu, J., & Siegelbaum, S. A. (2015) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a021733 · Cited by 244 · see citing works
Self-citationTargeted activation of the hippocampal CA2 area strongly enhances social memory
Smith, A. S., Williams Avram, S. K., Cymerblit-Sabba, A., Song, J., & Young, W. S. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.189 · Cited by 236 · see citing works
Lesions to the <scp>CA</scp>2 region of the hippocampus impair social memory in mice
Stevenson, E. L., & Caldwell, H. K. (2014) · European Journal of Neuroscience · doi:10.1111/ejn.12689 · Cited by 222 · see citing works
Ognjanovski, N., Schaeffer, S. M., Wu, J., Mofakham, S., Maruyama, D., Żochowski, M., & Aton, S. J. (2017) · Nature Communications · doi:10.1038/ncomms15039 · Cited by 221 · see citing works
Pagani, J. H., Zhao, M., Cui, Z., Williams Avram, S. K., Caruana, D. A., Dudek, S. M., & Young, W. S. (2015) · Molecular Psychiatry · doi:10.1038/mp.2014.47 · Cited by 204 · see citing works
Frank, L. M., Brown, E. N., & Wilson, M. A. (2001) · Journal of Neurophysiology · doi:10.1152/jn.2001.86.4.2029 · Cited by 195 · see citing works
Dudman, J. T., Tsay, D., & Siegelbaum, S. A. (2007) · Neuron · doi:10.1016/j.neuron.2007.10.020 · Cited by 192 · see citing works
Self-citationPiskorowski, R. A., Nasrallah, K., Diamantopoulou, A., Mukai, J., Hassan, S. I., Siegelbaum, S. A., Gogos, J. A., & Chevaleyre, V. (2016) · Neuron · doi:10.1016/j.neuron.2015.11.036 · Cited by 180 · see citing works
Self-citationEndogenous Opioid Regulation of Hippocampal Function
Simmons, M. L., & Chavkin, C. (1996) · International review of neurobiology · doi:10.1016/s0074-7742(08)60666-2 · Cited by 148 · see citing works
Quantitative analysis of parvalbumin-immunoreactive cells in the human epileptic hippocampus.
Andrioli, A., Alonso-Nanclares, L., Arellano, J. I., & DeFelipe, J. (2007) · Neuroscience · doi:10.1016/j.neuroscience.2007.07.029 · Cited by 147 · see citing works
Bliss, T. V. P., & Lømo, T. (1973) · The Journal of Physiology · doi:10.1113/jphysiol.1973.sp010273 · Cited by 135 · see citing works
Characterization of the prodynorphin and proenkephalin neuropeptide systems in rat hippocampus
Chavkin, C., Shoemaker, W. J., McGinty, J. F., Bayón, A., & Bloom, F. E. (1985) · Journal of Neuroscience · doi:10.1523/jneurosci.05-03-00808.1985 · Cited by 133 · see citing works
A role for CA3 in social recognition memory
Chiang, M.-C., Huang, A. J. Y., Wintzer, M. E., Ohshima, T., & McHugh, T. J. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2018.01.019 · Cited by 129 · see citing works
Basu, J., Srinivas, K. V., Cheung, S. K., Taniguchi, H., Huang, Z. J., & Siegelbaum, S. A. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.001 · Cited by 122 · see citing works
Self-citationCharacterization of Neurons in the CA2 Subfield of the Adult Rat Hippocampus
Mercer, A., Trigg, H. L., & Thomson, A. M. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1829-07.2007 · Cited by 114 · see citing works
CAV-2—why a canine virus is a neurobiologist's best friend
Junyent, F., & Kremer, E. J. (2015) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2015.08.004 · Cited by 111 · see citing works
Timing dependence of the induction of cerebellar LTD
Safo, P. K., & Regehr, W. G. (2007) · Neuropharmacology · doi:10.1016/j.neuropharm.2007.05.029 · Cited by 103 · see citing works
Piskorowski, R. A., & Chevaleyre, V. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.0649-13.2013 · Cited by 94 · see citing works
Svoboda, K. R., Adams, C. E., & Lupica, C. R. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-01-00085.1999 · Cited by 94 · see citing works
Neuronal types expressing μ‐ and δ‐opioid receptor mRNA in the rat hippocampal formation
Stumm, R. K., Zhou, C., Schulz, S., & Höllt, V. (2003) · The Journal of Comparative Neurology · doi:10.1002/cne.10997 · Cited by 93 · see citing works
Terrian, D. M., Johnston, D., Claiborne, B. J., et al. (1988) · Brain Research Bulletin · doi:10.1016/0361-9230(88)90146-3 · Cited by 92 · see citing works
Kowalski, J., Gan, J., Jónás, P., & Pernía‐Andrade, A. J. (2015) · Hippocampus · doi:10.1002/hipo.22550 · Cited by 85 · see citing works
Ribak, C. E., Seress, L., & Léránth, C. (1993) · The Journal of Comparative Neurology · doi:10.1002/cne.903270211 · Cited by 68 · see citing works
Distribution of delta opioid receptor-expressing neurons in the mouse hippocampus
Erbs, E., Faget, L. C., Scherrer, G., Kessler, P., Hentsch, D., Vonesch, J.-L., Matifas, A., Kieffer, B. L., & Massotte, D. (2012) · Neuroscience · doi:10.1016/j.neuroscience.2012.06.023 · Cited by 67 · see citing works
Coactivation of thalamic and cortical pathways induces input timing–dependent plasticity in amygdala
Cho, J.-H., Bayazitov, I. T., Meloni, E. G., Myers, K. M., Carlezon, W. A., Zakharenko, S. S., & Bolshakov, V. Y. (2011) · Nature Neuroscience · doi:10.1038/nn.2993 · Cited by 57 · see citing works
Blasco‐Ibáñez, J. M., Martinez-Guijarro, F. J., & Freund, T. F. (1998) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1998.00190.x · Cited by 56 · see citing works
Duka, T., Wüster, M., Schubert, P., Stoiber, R., & Herz, A. (1981) · Brain Research · doi:10.1016/0006-8993(81)90730-7 · Cited by 55 · see citing works
Fuentealba, P., Tomioka, R., Dalezios, Y., Márton, L. F., Studer, M., Rockland, K. S., Klausberger, T., & Somogyi, P. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2052-08.2008 · Cited by 51 · see citing works
Inhibitory Plasticity Permits the Recruitment of CA2 Pyramidal Neurons by CA3
Nasrallah, K., Piskorowski, R. A., & Chevaleyre, V. (2015) · eNeuro · doi:10.1523/eneuro.0049-15.2015 · Cited by 49 · see citing works
Xu, J., Zhang, J., & Chen, C. (2012) · The Journal of Physiology · doi:10.1113/jphysiol.2011.223511 · Cited by 45 · see citing works
Commons, K. G., & Milner, T. A. (1996) · Brain Research · doi:10.1016/0006-8993(96)00236-3 · Cited by 36 · see citing works
Burstein, S. R., Williams, T. J., Lane, D., Knudsen, M. G., Pickel, V. M., McEwen, B. S., Waters, E. M., & Milner, T. A. (2013) · Brain Research · doi:10.1016/j.brainres.2013.03.051 · Cited by 32 · see citing works
SP–SR interneurones: A novel class of neurones of the CA2 region of the hippocampus
Mercer, A., Botcher, N. A., Eastlake, K., & Thomson, A. M. (2012) · Hippocampus · doi:10.1002/hipo.22010 · Cited by 24 · see citing works
Evidence for dynorphin-A as a neurotransmitter in rat hippocampus
Chavkin, C., Bakhit, C., & Bloom, F. E. (1983) · Life Sciences · doi:10.1016/0024-3205(83)90432-0 · Cited by 18 · see citing works
Bi-directional interplay between proximal and distal inputs to CA2 pyramidal neurons
Nasrallah, K., Piskorowski, R. A., & Chevaleyre, V. (2016) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2016.06.024 · Cited by 14 · see citing works
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- Authors
- Leroy, F., Brann, D. H., Meira, T., & Siegelbaum, S. A.
- Affiliations
- Columbia University Irving Medical Center (US)
- Corresponding author
- Siegelbaum, Steven A.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-08
- Volume
- 95
- Issue
- 5
- Pages
- 1089-1102.e5
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5617141
- OpenAlex
- W2746239521
- Cited by
- 91
- References
- 62
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 8 · 2023: 11 · 2022: 13 · 2021: 12 · 2020: 9 · 2019: 6 · 2018: 20 · 2017: 1
- FWCI
- 5.65
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-04-03)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
- Funders
- NIH (R01-MH104602, R01-MH106629)
- Portuguese Foundation for Science and Technology (PD/BD/113700/2015)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Keywords
- hippocampal CA2, entorhinal cortex, Schaffer collaterals, pyramidal neurons, long-term depression, feedforward inhibition, cholecystokinin interneurons, delta opioid receptor, parvalbumin interneurons, social memory, contextual memory, synaptic learning rules
- MeSH terms
- Animals, Interneurons, Male, Memory, Mice, Transgenic, Neural Inhibition, Neuronal Plasticity, Parvalbumins, Social Behavior, Time Factors, Receptors, Opioid, delta, Pyramidal Cells, Entorhinal Cortex, Long-Term Synaptic Depression, Mice, CA2 Region, Hippocampal
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