Coding of social novelty in the hippocampal CA2 region and its disruption and rescue in a 22q11.2 microdeletion mouse model
Open accessPublished version of a preprint
Abstract
The hippocampal CA2 region is essential for social memory. To determine whether CA2 activity encodes social interactions, we recorded extracellularly from CA2 pyramidal neurons (PNs) in male mice during social behavior. Although CA2 neuronal firing showed only weak spatial selectivity, it accurately encoded contextual changes and distinguished between a novel and a familiar mouse. In the Df(16)A+/- mouse model of the human 22q11.2 microdeletion, which confers a 30-fold increased risk of schizophrenia, CA2 social coding was impaired, consistent with the social memory deficit observed in these mice; in contrast, spatial coding accuracy was greatly enhanced. CA2 PNs were previously found to be hyperpolarized in Df(16)A+/- mice, likely due to upregulation of TREK-1 K+ current. We found that TREK-1 blockade rescued social memory and CA2 social coding in Df(16)A+/- mice, supporting a crucial role for CA2 in the normal encoding of social stimuli and in social behavioral dysfunction in disease.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Systemic administration of a TREK-1 antagonist rescued deficits in social memory and CA2 firing properties in Df(16)A+/- mice.
“systemic administration of a TREK-1 antagonist rescued deficits in social memory and CA2 firing properties [135].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [135]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cortes, C., & Vapnik, V. N. (1995) · Machine Learning · doi:10.1023/a:1022627411411 · Cited by 34,565 · see citing works
The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat
O'Keefe, J., & Dostrovsky, J. (1971) · Brain Research · doi:10.1016/0006-8993(71)90358-1 · Cited by 6,151 · see citing works
No evidence that carotenoid pigments boost either immune or antioxidant defenses in a songbird
Koch, R. E., Kavazis, A. N., Hasselquist, D., Hood, W. R., Zhang, Y., Toomey, M. B., & Hill, G. E. (2018) · Nature Communications · doi:10.1038/s41467-018-02974-x · Cited by 1,924 · see citing works
The importance of mixed selectivity in complex cognitive tasks
Rigotti, M., Barak, O., Warden, M. R., Wang, X.-J., Daw, N. D., Miller, E. K., & Fusi, S. (2013) · Nature · doi:10.1038/nature12160 · Cited by 1,639 · see citing works
Self-citationHippocampal ‘time cells’ bridge the gap in memory for discontiguous events
MacDonald, C. J., Lepage, K. Q., Eden, U. T., & Eichenbaum, H. (2011) · Neuron · doi:10.1016/j.neuron.2011.07.012 · Cited by 1,193 · 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-citationThe Cognitive Neuroscience of Human Memory Since H.M.
Squire, L. R., & Wixted, J. T. (2011) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113720 · Cited by 749 · 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
Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model
Stark, K. L., Xu, B., Bagchi, A., Lai, W.-S., Liu, H., Hsu, R., Wan, X., Pavlidis, P., Mills, A. A., Karayiorgou, M., et al. (2008) · Nature Genetics · doi:10.1038/ng.138 · Cited by 648 · see citing works
Brown, E. N., Frank, L. M., Tang, D., Quirk, M. C., & Wilson, M. A. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-18-07411.1998 · Cited by 575 · see citing works
CNS Distribution of Members of the Two-Pore-Domain (KCNK) Potassium Channel Family
Talley, E. M., Solórzano, G., Lei, Q., Kim, D., & Bayliss, D. A. (2001) · The Journal of Neuroscience · doi:10.1523/jneurosci.21-19-07491.2001 · Cited by 573 · see citing works
Hippocampal “Time Cells”: Time versus Path Integration
Kraus, B. J., Robinson, R. J., White, J. A., Eichenbaum, H., & Hasselmo, M. E. (2013) · Neuron · doi:10.1016/j.neuron.2013.04.015 · Cited by 526 · see citing works
Direct visualization of current-induced spin accumulation in topological insulators
Liu, Y., Besbas, J., Wang, Y., He, P., Chen, M., Zhu, D., Wu, Y., Lee, J. M., Wang, L., Moon, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04939-6 · Cited by 507 · see citing works
22q11.2 microdeletions: linking DNA structural variation to brain dysfunction and schizophrenia
Karayiorgou, M., Simon, T. J., & Gogos, J. A. (2010) · Nature Reviews Neuroscience · doi:10.1038/nrn2841 · Cited by 474 · 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
Zhang, Z. J., & Reynolds, G. P. (2002) · Schizophrenia Research · doi:10.1016/s0920-9964(01)00188-8 · Cited by 460 · see citing works
McKenzie, S., Frank, A. J., Kinsky, N. R., Porter, B., Rivière, P. D., & Eichenbaum, H. (2014) · Neuron · doi:10.1016/j.neuron.2014.05.019 · Cited by 373 · see citing works
Identification of PDGFR as a receptor for AAV-5 transduction
Pasquale, G. D., Davidson, B. L., Stein, C. S., Martins, I., Scudiero, D., Monks, A., & Chiorini, J. A. (2003) · Nature Medicine · doi:10.1038/nm929 · Cited by 355 · see citing works
A hippocampal circuit linking dorsal CA2 to ventral CA1 critical for social memory dynamics
Meira, T., Leroy, F., Buss, E. W., Oliva, A., Park, J., & Siegelbaum, S. A. (2018) · Nature Communications · doi:10.1038/s41467-018-06501-w · Cited by 310 · see citing works
Self-citationHippocampal oxytocin receptors are necessary for discrimination of social stimuli
Raam, T., McAvoy, K. M., Besnard, A., Veenema, A. H., & Sahay, A. (2017) · Nature Communications · doi:10.1038/s41467-017-02173-0 · Cited by 292 · see citing works
Skaggs, W. E., & McNaughton, B. L. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-20-08455.1998 · Cited by 287 · see citing works
Hippocampal CA2 activity patterns change over time to a larger extent than between spatial contexts
Mankin, E. A., Diehl, G. W., Sparks, F. T., Leutgeb, S., & Leutgeb, J. K. (2015) · Neuron · doi:10.1016/j.neuron.2014.12.001 · Cited by 279 · see citing works
Steinvorth, S., Levine, B., & Corkin, S. (2005) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2005.01.001 · Cited by 267 · see citing works
Targeted 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
A hippocampal network for spatial coding during immobility and sleep
Kay, K., Sosa, M., Chung, J. E., Karlsson, M. P., Larkin, M. C., & Frank, L. M. (2016) · Nature · doi:10.1038/nature17144 · Cited by 224 · see citing works
Young, W. S., Li, J., Wersinger, S. R., & Palkovits, M. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.08.040 · Cited by 222 · 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
Hypothalamic and other connections with dorsal CA2 area of the mouse hippocampus
Cui, Z., Gerfen, C. R., & Young, W. S. (2013) · Journal of Comparative Neurology · doi:10.1002/cne.23263 · Cited by 214 · see citing works
The Sparseness of Mixed Selectivity Neurons Controls the Generalization–Discrimination Trade-Off
Barak, O., Rigotti, M., & Fusi, S. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.2753-12.2013 · Cited by 207 · see citing works
Self-citationLife History AND BIOECONOMY OF THE House Mouse
Berry, R. J., & Bronson, F. H. (1992) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/j.1469-185x.1992.tb01192.x · Cited by 202 · see citing works
Social and novel contexts modify hippocampal CA2 representations of space
Alexander, G. M., Farris, S., Pirone, J. R., Zheng, C., Colgin, L. L., & Dudek, S. M. (2016) · Nature Communications · doi:10.1038/ncomms10300 · Cited by 191 · see citing works
Piskorowski, 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-citationSchmitzer-Torbert, N. C., & Redish, A. D. (2004) · Journal of Neurophysiology · doi:10.1152/jn.00687.2003 · Cited by 176 · see citing works
Molecular regulations governing TREK and TRAAK channel functions
Noël, J., Sandoz, G., & Lesage, F. (2011) · Channels · doi:10.4161/chan.5.5.16469 · Cited by 163 · see citing works
Grid Cells Use HCN1 Channels for Spatial Scaling
Giocomo, L. M., Hussaini, S. A., Fan, Z., Kandel, E. R., Moser, M., & Moser, E. I. (2011) · Cell · doi:10.1016/j.cell.2011.08.051 · Cited by 158 · see citing works
A Distributed Neural Code in the Dentate Gyrus and in CA1
Stefanini, F., Kushnir, L., Jimenez, J., Jennings, J. H., Woods, N. I., Stuber, G. D., Kheirbek, M. A., Hen, R., & Fusi, S. (2020) · Neuron · doi:10.1016/j.neuron.2020.05.022 · Cited by 155 · see citing works
Self-citationTopography of Place Maps along the CA3-to-CA2 Axis of the Hippocampus
Lu, L., Igarashi, K. M., Witter, M. P., Moser, E. I., & Moser, M. (2015) · Neuron · doi:10.1016/j.neuron.2015.07.007 · Cited by 149 · see citing works
Xu, B., Hsu, P.-K., Stark, K. L., Karayiorgou, M., & Gogos, J. A. (2013) · Cell · doi:10.1016/j.cell.2012.11.052 · Cited by 145 · see citing works
Place Field Repetition and Purely Local Remapping in a Multicompartment Environment
Spiers, H. J., Hayman, R. M. A., Jovalekic, A., Marozzi, E., & Jeffery, K. J. (2015) · Cerebral Cortex · doi:10.1093/cercor/bht198 · Cited by 138 · 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
Silencing CA3 disrupts temporal coding in the CA1 ensemble
Middleton, S. J., & McHugh, T. J. (2016) · Nature Neuroscience · doi:10.1038/nn.4311 · Cited by 128 · see citing works
Impaired hippocampal place cell dynamics in a mouse model of the 22q11.2 deletion
Zaremba, J. D., Diamantopoulou, A., Danielson, N., Grosmark, A., Kaifosh, P., Bowler, J. C., Liao, Z., Sparks, F. T., Gogos, J. A., & Losonczy, A. (2017) · Nature Neuroscience · doi:10.1038/nn.4634 · Cited by 124 · see citing works
Spatial coding and physiological properties of hippocampal neurons in the Cornu Ammonis subregions
Oliva, A., Fernández‐Ruiz, A., Buzsáki, G., & Berényi, A. (2016) · Hippocampus · doi:10.1002/hipo.22659 · Cited by 113 · see citing works
Meltzer, H. Y. (1996) · Neuropsychopharmacology · doi:10.1016/0893-133x(95)00202-o · Cited by 105 · see citing works
Chronic Loss of CA2 Transmission Leads to Hippocampal Hyperexcitability
Boehringer, R., Polygalov, D., Huang, A. J. Y., Middleton, S. J., Robert, V., Wintzer, M. E., Piskorowski, R. A., Chevaleyre, V., & McHugh, T. J. (2017) · Neuron · doi:10.1016/j.neuron.2017.04.014 · Cited by 105 · see citing works
TREK-1 Is a Novel Molecular Target in Prostate Cancer
Voloshyna, I., Besana, A., Castillo, M., Matos, T., Weinstein, I. B., Mansukhani, M., Robinson, R. B., Cordon-Cardo, C., & Feinmark, S. J. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5163 · Cited by 104 · see citing works
Precise spatial coding is preserved along the longitudinal hippocampal axis
Keinath, A., Wang, M. E., Wann, E. G., Yuan, R. K., Dudman, J. T., & Muzzio, I. A. (2014) · Hippocampus · doi:10.1002/hipo.22333 · Cited by 101 · see citing works
The Hippocampal CA2 Ensemble Is Sensitive to Contextual Change
Wintzer, M. E., Boehringer, R., Polygalov, D., & McHugh, T. J. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.2563-13.2014 · Cited by 98 · see citing works
Neuronal Responses to Conspecifics in the Ventral CA1
Rao, R. P., von Heimendahl, M., Bahr, V., & Brecht, M. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.05.081 · Cited by 85 · see citing works
CA2 neuronal activity controls hippocampal low gamma and ripple oscillations
Alexander, G. M., Brown, L. Y., Farris, S., Lustberg, D. J., Pantazis, C. B., Gloss, B. R., Plummer, N. W., Riddick, N. V., Moy, S. S., Jensen, P., et al. (2018) · eLife · doi:10.7554/elife.38052 · Cited by 73 · see citing works
Talbot, Z. N., Sparks, F. T., Dvořák, D., Curran, B. M., Alarcón, J. M., & Fenton, A. A. (2018) · Neuron · doi:10.1016/j.neuron.2017.12.043 · Cited by 68 · see citing works
Weak and Nondiscriminative Responses to Conspecifics in the Rat Hippocampus
von Heimendahl, M., Rao, R. P., & Brecht, M. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.3812-11.2012 · Cited by 63 · see citing works
Borsotto, M., Veyssière, J., Maati, H. M. O., Devader, C., Mazella, J., & Heurteaux, C. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12953 · Cited by 63 · see citing works
Field repetition and local mapping in the hippocampus and the medial entorhinal cortex
Grieves, R. M., Duvelle, É., Wood, E. R., & Dudchenko, P. A. (2017) · Journal of Neurophysiology · doi:10.1152/jn.00933.2016 · Cited by 21 · see citing works
A distributed neural code in the dentate gyrus and in CA1Preprint
Stefanini, F., Kheirbek, M. A., Kushnir, L., Jimenez, J., Jennings, J. H., Stuber, G. D., Hen, R., & Fusi, S. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/292953 · Cited by 14 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Oxytocin, Neural Plasticity, and Social Behavior
Froemke, R. C., & Young, L. J. (2021) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-102320-102847 · Cited by 487 · see citing works
Hippocampal CA2 sharp-wave ripples reactivate and promote social memory
Oliva, A., Fernández-Ruiz, A., Leroy, F., & Siegelbaum, S. A. (2020) · Nature · doi:10.1038/s41586-020-2758-y · Cited by 268 · see citing works
Self-citationREM sleep-active hypothalamic neurons may contribute to hippocampal social-memory consolidation
Qin, H., Fu, L., Jian, T., Jin, W., Liang, M., Li, J., Chen, Q., Yang, X., Du, H., Liao, X., et al. (2022) · Neuron · doi:10.1016/j.neuron.2022.09.004 · Cited by 78 · see citing works
Neural circuits regulating prosocial behaviors
Walsh, J. J., Christoffel, D. J., & Malenka, R. C. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-022-01348-8 · Cited by 72 · see citing works
- Authors
- Donegan, M. L., Stefanini, F., Meira, T., Gordon, J. A., Fusi, S., & Siegelbaum, S. A.
- Affiliations
- Columbia University (US)
- National Institutes of Health (US)
- Corresponding author
- Siegelbaum, Steven A.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2020-10-19
- Volume
- 23
- Issue
- 11
- Pages
- 1365-1375
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC8861630
- OpenAlex
- W3093008185
- Cited by
- 114
- References
- 56
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 24 · 2023: 18 · 2022: 23 · 2021: 13 · 2020: 3
- FWCI
- 7.65
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Neuroscience (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NSF | Directorate for Biological Sciences (DGE – 1644869)
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH106629)
- 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, social memory, 22q11.2 microdeletion, schizophrenia, pyramidal neurons, TREK-1, potassium currents, spatial coding, contextual memory, neuronal firing patterns
- MeSH terms
- Social Interaction, Action Potentials, Animals, Chromosome Deletion, Chromosomes, Human, Pair 22, Disease Models, Animal, Exploratory Behavior, Male, Mice, Inbred C57BL, Mice, Transgenic, Social Behavior, Pyramidal Cells, CA2 Region, Hippocampal, Spatial Processing
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
