Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The role of inhibitory circuits in hippocampal memory processing

Abstract

GABAergic inhibitory circuits play an essential role in coordinating various hippocampal functions. Several decades of work dedicated to a thorough characterization of hippocampal inhibitory populations have highlighted how specific types of interneuron can contribute to network activity. Recent studies have used genetically targeted recordings and peturbations of activity during memory-related behaviours to determine how interneurons that inhibit distinct subcellular domains of principal cells or specialize in principal cell disinhibition may sculpt hippocampal memory. These studies highlight unique contributions of distinct interneuron types to the temporal binding of hippocampal ensembles, synaptic plasticity and the acquisition of spatial and contextual information. Here, we review the current state of knowledge around hippocampal inhibition and memory by discussing the multifaceted roles of populations of inhibitory cells at different stages of hippocampal mnemonic processing.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Major types of hippocampal CA1 inhibitory interneurons that express PV, SOM and VIP.
Fig. 2: Activity patterns of CA1 inhibitory interneurons during network oscillations.
Fig. 3: Activity-dependent synaptic plasticity in CA1 inhibitory interneurons.
Fig. 4: Role of hippocampal CA1 interneurons in encoding and consolidation of contextual fear memory.

References

  1. Aranzi, G. C. De Humano Foetu Liber Tertio Editus, ac Recognitus. Ejusdem Anatomicarum Observationum Liber ac De Tumoribus Tecundum Locos Affectos Liber Nunc Primum Editi (Apud Jacobum Brechtanum, 1587).

  2. Duff, M. C., Covington, N. V., Hilverman, C. & Cohen, N. J. Semantic memory and the hippocampus: revisiting, reaffirming, and extending the reach of their critical relationship. Front. Hum. Neurosci. 13, 471 (2019).

    PubMed  Article  Google Scholar 

  3. Scoville, W. B. & Milner, B. Loss of recent memory after bilateral hippocampal lesions. J. Neurol. Neurosurg. Psychiatry 20, 11–21 (1957).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. O’Keefe, J. & Dostrovsky, J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Res. 34, 171–175 (1971).

    PubMed  Article  Google Scholar 

  5. Morris, R. G. Elements of a neurobiological theory of hippocampal function: the role of synaptic plasticity, synaptic tagging and schemas. Eur. J. Neurosci. 23, 2829–2846 (2006).

    CAS  PubMed  Article  Google Scholar 

  6. Amaral, D. G. & Witter, M. P. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571–591 (1989).

    CAS  PubMed  Article  Google Scholar 

  7. Buzsaki, G. & Chrobak, J. J. Temporal structure in spatially organized neuronal ensembles: a role for interneuronal networks. Curr. Opin. Neurobiol. 5, 504–510 (1995).

    CAS  PubMed  Article  Google Scholar 

  8. Buzsaki, G. Theta oscillations in the hippocampus. Neuron 33, 325–340 (2002).

    CAS  PubMed  Article  Google Scholar 

  9. Fernandez-Ruiz, A. et al. Entorhinal-CA3 dual-input control of spike timing in the hippocampus by theta–gamma coupling. Neuron 93, 1213–1226.e5 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Boyce, R., Glasgow, S. D., Williams, S. & Adamantidis, A. Causal evidence for the role of REM sleep theta rhythm in contextual memory consolidation. Science 352, 812–816 (2016).

    CAS  PubMed  Article  Google Scholar 

  11. Goutagny, R., Jackson, J. & Williams, S. Self-generated theta oscillations in the hippocampus. Nat. Neurosci. 12, 1491–1493 (2009).

    CAS  PubMed  Article  Google Scholar 

  12. Jackson, J. et al. Reversal of theta rhythm flow through intact hippocampal circuits. Nat. Neurosci. 17, 1362–1370 (2014).

    CAS  PubMed  Article  Google Scholar 

  13. Colgin, L. L. et al. Frequency of gamma oscillations routes flow of information in the hippocampus. Nature 462, 353–357 (2009).

    CAS  PubMed  Article  Google Scholar 

  14. Schomburg, E. W. et al. Theta phase segregation of input-specific gamma patterns in entorhinal–hippocampal networks. Neuron 84, 470–485 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. Colgin, L. L. Theta–gamma coupling in the entorhinal–hippocampal system. Curr. Opin. Neurobiol. 31, 45–50 (2015).

    CAS  PubMed  Article  Google Scholar 

  16. Buzsaki, G., Horvath, Z., Urioste, R., Hetke, J. & Wise, K. High-frequency network oscillation in the hippocampus. Science 256, 1025–1027 (1992).

    CAS  PubMed  Article  Google Scholar 

  17. Buzsaki, G. Hippocampal sharp wave-ripple: a cognitive biomarker for episodic memory and planning. Hippocampus 25, 1073–1188 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  18. Fuchs, E. C. et al. Recruitment of parvalbumin-positive interneurons determines hippocampal function and associated behavior. Neuron 53, 591–604 (2007).

    CAS  PubMed  Article  Google Scholar 

  19. Korotkova, T., Fuchs, E. C., Ponomarenko, A., von Engelhardt, J. & Monyer, H. NMDA receptor ablation on parvalbumin-positive interneurons impairs hippocampal synchrony, spatial representations, and working memory. Neuron 68, 557–569 (2010).

    CAS  PubMed  Article  Google Scholar 

  20. Royer, S. et al. Control of timing, rate and bursts of hippocampal place cells by dendritic and somatic inhibition. Nat. Neurosci. 15, 769–775 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Stark, E. et al. Pyramidal cell–interneuron interactions underlie hippocampal ripple oscillations. Neuron 83, 467–480 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. Amilhon, B. et al. Parvalbumin interneurons of hippocampus tune population activity at theta frequency. Neuron 86, 1277–1289 (2015).

    CAS  PubMed  Article  Google Scholar 

  23. Zarnadze, S. et al. Cell-specific synaptic plasticity induced by network oscillations. eLife https://doi.org/10.7554/eLife.14912 (2016). This study demonstrates that theta-nested gamma oscillations enhance hippocampal SWRs in vivo via induction of cell type-specific plasticity in CA3 interneurons.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Malenka, R. C. & Bear, M. F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004).

    CAS  PubMed  Article  Google Scholar 

  25. Castillo, P. E., Chiu, C. Q. & Carroll, R. C. Long-term plasticity at inhibitory synapses. Curr. Opin. Neurobiol. 21, 328–338 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Honore, E., Khlaifia, A., Bosson, A. & Lacaille, J. C. Hippocampal somatostatin interneurons, long-term synaptic plasticity and memory. Front. Neural Circuits 15, 687558 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. Topolnik, L. Dendritic calcium mechanisms and long-term potentiation in cortical inhibitory interneurons. Eur. J. Neurosci. 35, 496–506 (2012).

    PubMed  Article  Google Scholar 

  28. Sun, X. et al. Functionally distinct neuronal ensembles within the memory engram. Cell 181, 410–423.e17 (2020). This study reports that memory engrams contain functionally different neuronal ensembles that are driven by specifically enhanced excitatory input from the medial entorhinal cortex and inhibitory drive from CCK+ interneurons, which together help to promote fear memory generalization versus discrimination.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Freund, T. F. & Buzsaki, G. Interneurons of the hippocampus. Hippocampus 6, 347–470 (1996).

    CAS  PubMed  Article  Google Scholar 

  30. Pawelzik, H., Hughes, D. I. & Thomson, A. M. Physiological and morphological diversity of immunocytochemically defined parvalbumin- and cholecystokinin-positive interneurones in CA1 of the adult rat hippocampus. J. Comp. Neurol. 443, 346–367 (2002).

    PubMed  Article  Google Scholar 

  31. Que, L., Lukacsovich, D., Luo, W. & Foldy, C. Transcriptional and morphological profiling of parvalbumin interneuron subpopulations in the mouse hippocampus. Nat. Commun. 12, 108 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Baude, A., Bleasdale, C., Dalezios, Y., Somogyi, P. & Klausberger, T. Immunoreactivity for the GABAA receptor α1 subunit, somatostatin and Connexin36 distinguishes axoaxonic, basket, and bistratified interneurons of the rat hippocampus. Cereb. Cortex 17, 2094–2107 (2007).

    PubMed  Article  Google Scholar 

  33. Mikulovic, S., Restrepo, C. E., Hilscher, M. M., Kullander, K. & Leao, R. N. Novel markers for OLM interneurons in the hippocampus. Front. Cell. Neurosci. 9, 201 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  34. Jinno, S. et al. Neuronal diversity in GABAergic long-range projections from the hippocampus. J. Neurosci. 27, 8790–8804 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Acsady, L., Arabadzisz, D. & Freund, T. F. Correlated morphological and neurochemical features identify different subsets of vasoactive intestinal polypeptide-immunoreactive interneurons in rat hippocampus. Neuroscience 73, 299–315 (1996).

    CAS  PubMed  Article  Google Scholar 

  36. Acsady, L., Gorcs, T. J. & Freund, T. F. Different populations of vasoactive intestinal polypeptide-immunoreactive interneurons are specialized to control pyramidal cells or interneurons in the hippocampus. Neuroscience 73, 317–334 (1996).

    CAS  PubMed  Article  Google Scholar 

  37. Csicsvari, J., Hirase, H., Czurko, A., Mamiya, A. & Buzsaki, G. Oscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving rat. J. Neurosci. 19, 274–287 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Klausberger, T. et al. Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo. Nature 421, 844–848 (2003).

    CAS  PubMed  Article  Google Scholar 

  39. Klausberger, T. et al. Spike timing of dendrite-targeting bistratified cells during hippocampal network oscillations in vivo. Nat. Neurosci. 7, 41–47 (2004).

    CAS  PubMed  Article  Google Scholar 

  40. Klausberger, T. et al. Complementary roles of cholecystokinin- and parvalbumin-expressing GABAergic neurons in hippocampal network oscillations. J. Neurosci. 25, 9782–9793 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Francavilla, R. et al. Connectivity and network state-dependent recruitment of long-range VIP-GABAergic neurons in the mouse hippocampus. Nat. Commun. 9, 5043 (2018). This study identifies a novel type of LRP VIP+ GABAergic neuron in the mouse CA1 hippocampal area that exhibits a region-specific target preference and theta-off activity pattern in behaving animals.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. Mikulovic, S. et al. Ventral hippocampal OLM cells control type 2 theta oscillations and response to predator odor. Nat. Commun. 9, 3638 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. Siwani, S. et al. OLMα2 cells bidirectionally modulate learning. Neuron 99, 404–412 e403 (2018).

    CAS  PubMed  Article  Google Scholar 

  44. Arriaga, M. & Han, E. B. Dedicated hippocampal inhibitory networks for locomotion and immobility. J. Neurosci. 37, 9222–9238 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Arriaga, M. & Han, E. B. Structured inhibitory activity dynamics in new virtual environments. eLife https://doi.org/10.7554/eLife.47611 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Turi, G. F. et al. Vasoactive intestinal polypeptide-expressing interneurons in the hippocampus support goal-oriented spatial learning. Neuron 101, 1150–1165.e8 (2019). This study demonstrates that VIP+ interneurons in the hippocampal CA1 area form two functionally distinct populations as defined on the basis of their activity patterns during behavioural states, with disinhibitory VIP/CR-co-expressing cells supporting spatial and goal-oriented learning.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Geiller, T. et al. Large-scale 3D two-photon imaging of molecularly identified CA1 interneuron dynamics in behaving mice. Neuron 108, 968–983 e969 (2020). This tour-de-force study provides simultaneous activity dynamics of hundreds of molecularly defined hippocampal interneurons during distinct behavioural states.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Dudok, B. et al. Alternating sources of perisomatic inhibition during behavior. Neuron 109, 997–1012.e9 (2021). This study reveals the inverse coupling of the activity of hippocampal CA1 PV+ and CCK+ BCs, which results in brain state-specific segregation of perisomatic inhibition of CA1 pyramidal cells during spontaneous behaviour.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Dudok, B. et al. Recruitment and inhibitory action of hippocampal axo-axonic cells during behavior. Neuron https://doi.org/10.1016/j.neuron.2021.09.033 (2021). This study selectively targets hippocampal AACs and reports that in vivo these cells inhibit CA1 pyramidal neurons and may restrain place field formation in behaving mice.

    Article  PubMed  PubMed Central  Google Scholar 

  50. Geiller, T. et al. Local circuit amplification of spatial selectivity in the hippocampus. Nature 601, 105–109 (2022). This study identifies a local circuit mechanism in the hippocampal CA1 area that enables multi-neuronal representations of the environment via functionally recurrent subnetworks and inverse firing selectivity in a subset of interneurons.

    CAS  PubMed  Article  Google Scholar 

  51. Artinian, J. et al. Regulation of hippocampal memory by mTORC1 in somatostatin interneurons. J. Neurosci. 39, 8439–8456 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. Sharma, V. et al. eIF2α controls memory consolidation via excitatory and somatostatin neurons. Nature 586, 412–416 (2020). This study demonstrates the cell type-specific translational control of memory consolidation, with an important role played by eIF2α in excitatory neurons and SOM+ interneurons.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Tukker, J. J., Fuentealba, P., Hartwich, K., Somogyi, P. & Klausberger, T. Cell type-specific tuning of hippocampal interneuron firing during gamma oscillations in vivo. J. Neurosci. 27, 8184–8189 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Lapray, D. et al. Behavior-dependent specialization of identified hippocampal interneurons. Nat. Neurosci. 15, 1265–1271 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Viney, T. J. et al. Network state-dependent inhibition of identified hippocampal CA3 axo-axonic cells in vivo. Nat. Neurosci. 16, 1802–1811 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Katona, L. et al. Sleep and movement differentiates actions of two types of somatostatin-expressing GABAergic interneuron in rat hippocampus. Neuron 82, 872–886 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. Unal, G., Joshi, A., Viney, T. J., Kis, V. & Somogyi, P. Synaptic targets of medial septal projections in the hippocampus and extrahippocampal cortices of the mouse. J. Neurosci. 35, 15812–15826 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Katona, L. et al. Behavior-dependent activity patterns of GABAergic long-range projecting neurons in the rat hippocampus. Hippocampus 27, 359–377 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Armstrong, C. & Soltesz, I. Basket cell dichotomy in microcircuit function. J. Physiol. 590, 683–694 (2012).

    CAS  PubMed  Article  Google Scholar 

  60. Varga, C., Golshani, P. & Soltesz, I. Frequency-invariant temporal ordering of interneuronal discharges during hippocampal oscillations in awake mice. Proc. Natl Acad. Sci. USA 109, E2726–E2734 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Lee, S. H. et al. Parvalbumin-positive basket cells differentiate among hippocampal pyramidal cells. Neuron 82, 1129–1144 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Varga, C. et al. Functional fission of parvalbumin interneuron classes during fast network events. eLife https://doi.org/10.7554/eLife.04006 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Cobb, S. R., Buhl, E. H., Halasy, K., Paulsen, O. & Somogyi, P. Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 378, 75–78 (1995).

    CAS  PubMed  Article  Google Scholar 

  64. Miles, R., Toth, K., Gulyas, A. I., Hajos, N. & Freund, T. F. Differences between somatic and dendritic inhibition in the hippocampus. Neuron 16, 815–823 (1996).

    CAS  PubMed  Article  Google Scholar 

  65. Fricker, D. & Miles, R. EPSP amplification and the precision of spike timing in hippocampal neurons. Neuron 28, 559–569 (2000).

    CAS  PubMed  Article  Google Scholar 

  66. Bartos, M. et al. Fast synaptic inhibition promotes synchronized gamma oscillations in hippocampal interneuron networks. Proc. Natl Acad. Sci. USA 99, 13222–13227 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Glickfeld, L. L. & Scanziani, M. Distinct timing in the activity of cannabinoid-sensitive and cannabinoid-insensitive basket cells. Nat. Neurosci. 9, 807–815 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Somogyi, P., Nunzi, M. G., Gorio, A. & Smith, A. D. A new type of specific interneuron in the monkey hippocampus forming synapses exclusively with the axon initial segments of pyramidal cells. Brain Res. 259, 137–142 (1983).

    CAS  PubMed  Article  Google Scholar 

  69. Li, X. G., Somogyi, P., Tepper, J. M. & Buzsaki, G. Axonal and dendritic arborization of an intracellularly labeled chandelier cell in the CA1 region of rat hippocampus. Exp. Brain Res. 90, 519–525 (1992).

    CAS  PubMed  Article  Google Scholar 

  70. Pouille, F. & Scanziani, M. Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition. Science 293, 1159–1163 (2001).

    CAS  PubMed  Article  Google Scholar 

  71. Pouille, F. & Scanziani, M. Routing of spike series by dynamic circuits in the hippocampus. Nature 429, 717–723 (2004).

    CAS  PubMed  Article  Google Scholar 

  72. Bezaire, M. J. & Soltesz, I. Quantitative assessment of CA1 local circuits: knowledge base for interneuron–pyramidal cell connectivity. Hippocampus 23, 751–785 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  73. Buzsaki, G. & Eidelberg, E. Commissural projection to the dentate gyrus of the rat: evidence for feed-forward inhibition. Brain Res. 230, 346–350 (1981).

    CAS  PubMed  Article  Google Scholar 

  74. Miles, R. Synaptic excitation of inhibitory cells by single CA3 hippocampal pyramidal cells of the guinea-pig in vitro. J. Physiol. 428, 61–77 (1990).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. Geiger, J. R., Lubke, J., Roth, A., Frotscher, M. & Jonas, P. Submillisecond AMPA receptor-mediated signaling at a principal neuron–interneuron synapse. Neuron 18, 1009–1023 (1997).

    CAS  PubMed  Article  Google Scholar 

  76. Ashwood, T. J., Lancaster, B. & Wheal, H. V. In vivo and in vitro studies on putative interneurones in the rat hippocampus: possible mediators of feed-forward inhibition. Brain Res. 293, 279–291 (1984).

    CAS  PubMed  Article  Google Scholar 

  77. Buhl, E. H., Szilagyi, T., Halasy, K. & Somogyi, P. Physiological properties of anatomically identified basket and bistratified cells in the CA1 area of the rat hippocampus in vitro. Hippocampus 6, 294–305 (1996).

    CAS  PubMed  Article  Google Scholar 

  78. Gulyas, A. I., Megias, M., Emri, Z. & Freund, T. F. Total number and ratio of excitatory and inhibitory synapses converging onto single interneurons of different types in the CA1 area of the rat hippocampus. J. Neurosci. 19, 10082–10097 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Ganter, P., Szucs, P., Paulsen, O. & Somogyi, P. Properties of horizontal axo-axonic cells in stratum oriens of the hippocampal CA1 area of rats in vitro. Hippocampus 14, 232–243 (2004).

    PubMed  Article  Google Scholar 

  80. Szabadics, J. et al. Excitatory effect of GABAergic axo-axonic cells in cortical microcircuits. Science 311, 233–235 (2006).

    CAS  PubMed  Article  Google Scholar 

  81. Glickfeld, L. L., Roberts, J. D., Somogyi, P. & Scanziani, M. Interneurons hyperpolarize pyramidal cells along their entire somatodendritic axis. Nat. Neurosci. 12, 21–23 (2009).

    CAS  PubMed  Article  Google Scholar 

  82. Woodruff, A., Xu, Q., Anderson, S. A. & Yuste, R. Depolarizing effect of neocortical chandelier neurons. Front. Neural Circuits 3, 15 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  83. Gallo, N. B., Paul, A. & Van Aelst, L. Shedding light on chandelier cell development, connectivity, and contribution to neural disorders. Trends Neurosci. 43, 565–580 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Karson, M. A., Tang, A. H., Milner, T. A. & Alger, B. E. Synaptic cross talk between perisomatic-targeting interneuron classes expressing cholecystokinin and parvalbumin in hippocampus. J. Neurosci. 29, 4140–4154 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. Lovett-Barron, M. et al. Regulation of neuronal input transformations by tunable dendritic inhibition. Nat. Neurosci. 15, 423–430 (2012).

    CAS  PubMed  Article  Google Scholar 

  86. Galarreta, M. & Hestrin, S. A network of fast-spiking cells in the neocortex connected by electrical synapses. Nature 402, 72–75 (1999).

    CAS  PubMed  Article  Google Scholar 

  87. Bartos, M., Vida, I., Frotscher, M., Geiger, J. R. & Jonas, P. Rapid signaling at inhibitory synapses in a dentate gyrus interneuron network. J. Neurosci. 21, 2687–2698 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. Sik, A., Penttonen, M., Ylinen, A. & Buzsaki, G. Hippocampal CA1 interneurons: an in vivo intracellular labeling study. J. Neurosci. 15, 6651–6665 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. Cobb, S. R. et al. Synaptic effects of identified interneurons innervating both interneurons and pyramidal cells in the rat hippocampus. Neuroscience 79, 629–648 (1997).

    CAS  PubMed  Article  Google Scholar 

  90. Hefft, S. & Jonas, P. Asynchronous GABA release generates long-lasting inhibition at a hippocampal interneuron–principal neuron synapse. Nat. Neurosci. 8, 1319–1328 (2005).

    CAS  PubMed  Article  Google Scholar 

  91. Matyas, F., Freund, T. F. & Gulyas, A. I. Convergence of excitatory and inhibitory inputs onto CCK-containing basket cells in the CA1 area of the rat hippocampus. Eur. J. Neurosci. 19, 1243–1256 (2004).

    PubMed  Article  Google Scholar 

  92. Klausberger, T. & Somogyi, P. Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 321, 53–57 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Bloss, E. B. et al. Structured dendritic inhibition supports branch-selective integration in CA1 pyramidal cells. Neuron 89, 1016–1030 (2016).

    CAS  PubMed  Article  Google Scholar 

  94. Halasy, K., Buhl, E. H., Lorinczi, Z., Tamas, G. & Somogyi, P. Synaptic target selectivity and input of GABAergic basket and bistratified interneurons in the CA1 area of the rat hippocampus. Hippocampus 6, 306–329 (1996).

    CAS  PubMed  Article  Google Scholar 

  95. Lacaille, J. C., Mueller, A. L., Kunkel, D. D. & Schwartzkroin, P. A. Local circuit interactions between oriens/alveus interneurons and CA1 pyramidal cells in hippocampal slices: electrophysiology and morphology. J. Neurosci. 7, 1979–1993 (1987).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. Maccaferri, G., Roberts, J. D., Szucs, P., Cottingham, C. A. & Somogyi, P. Cell surface domain specific postsynaptic currents evoked by identified GABAergic neurones in rat hippocampus in vitro. J. Physiol. 524, 91–116 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Herkenham, M. The connections of the nucleus reuniens thalami: evidence for a direct thalamo-hippocampal pathway in the rat. J. Comp. Neurol. 177, 589–610 (1978).

    CAS  PubMed  Article  Google Scholar 

  98. Pikkarainen, M., Ronkko, S., Savander, V., Insausti, R. & Pitkanen, A. Projections from the lateral, basal, and accessory basal nuclei of the amygdala to the hippocampal formation in rat. J. Comp. Neurol. 403, 229–260 (1999).

    CAS  PubMed  Article  Google Scholar 

  99. Szonyi, A. et al. The ascending median raphe projections are mainly glutamatergic in the mouse forebrain. Brain Struct. Funct. 221, 735–751 (2016).

    CAS  PubMed  Article  Google Scholar 

  100. Martina, M., Vida, I. & Jonas, P. Distal initiation and active propagation of action potentials in interneuron dendrites. Science 287, 295–300 (2000).

    CAS  PubMed  Article  Google Scholar 

  101. Kispersky, T. J., Fernandez, F. R., Economo, M. N. & White, J. A. Spike resonance properties in hippocampal O-LM cells are dependent on refractory dynamics. J. Neurosci. 32, 3637–3651 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Sekulic, V., Chen, T. C., Lawrence, J. J. & Skinner, F. K. Dendritic distributions of I h channels in experimentally-derived multi-compartment models of oriens-lacunosum/moleculare (O-LM) hippocampal interneurons. Front. Synaptic Neurosci. 7, 2 (2015).

    PubMed  PubMed Central  Google Scholar 

  103. Sekulic, V. & Skinner, F. K. Computational models of O-LM cells are recruited by low or high theta frequency inputs depending on h-channel distributions. eLife https://doi.org/10.7554/eLife.22962 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Leao, R. N. et al. OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons. Nat. Neurosci. 15, 1524–1530 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. Elfant, D., Pal, B. Z., Emptage, N. & Capogna, M. Specific inhibitory synapses shift the balance from feedforward to feedback inhibition of hippocampal CA1 pyramidal cells. Eur. J. Neurosci. 27, 104–113 (2008).

    PubMed  Article  Google Scholar 

  106. Gulyas, A. I., Hajos, N. & Freund, T. F. Interneurons containing calretinin are specialized to control other interneurons in the rat hippocampus. J. Neurosci. 16, 3397–3411 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. Tyan, L. et al. Dendritic inhibition provided by interneuron-specific cells controls the firing rate and timing of the hippocampal feedback inhibitory circuitry. J. Neurosci. 34, 4534–4547 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. Guet-McCreight, A., Skinner, F. K. & Topolnik, L. Common principles in functional organization of VIP/calretinin cell-driven disinhibitory circuits across cortical areas. Front. Neural Circuits 14, 32 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Kullander, K. & Topolnik, L. Cortical disinhibitory circuits: cell types, connectivity and function. Trends Neurosci. 44, 643–657 (2021).

    CAS  PubMed  Article  Google Scholar 

  110. Chamberland, S., Salesse, C., Topolnik, D. & Topolnik, L. Synapse-specific inhibitory control of hippocampal feedback inhibitory circuit. Front. Cell. Neurosci. 4, 130 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  111. Luo, X. et al. Synaptic mechanisms underlying the network state-dependent recruitment of VIP-expressing interneurons in the CA1 hippocampus. Cereb. Cortex 30, 3667–3685 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  112. Luo, X. et al. Transcriptomic profile of the subiculum-projecting VIP GABAergic neurons in the mouse CA1 hippocampus. Brain Struct. Funct. 224, 2269–2280 (2019).

    CAS  PubMed  Article  Google Scholar 

  113. Xu, X., Roby, K. D. & Callaway, E. M. Immunochemical characterization of inhibitory mouse cortical neurons: three chemically distinct classes of inhibitory cells. J. Comp. Neurol. 518, 389–404 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  114. Hasselmo, M. E. & Stern, C. E. Theta rhythm and the encoding and retrieval of space and time. Neuroimage 85, 656–666 (2014).

    PubMed  Article  Google Scholar 

  115. Siegle, J. H. & Wilson, M. A. Enhancement of encoding and retrieval functions through theta phase-specific manipulation of hippocampus. eLife 3, e03061 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  116. Wilson, M. A. & McNaughton, B. L. Reactivation of hippocampal ensemble memories during sleep. Science 265, 676–679 (1994).

    CAS  PubMed  Article  Google Scholar 

  117. Ylinen, A. et al. Intracellular correlates of hippocampal theta rhythm in identified pyramidal cells, granule cells, and basket cells. Hippocampus 5, 78–90 (1995).

    CAS  PubMed  Article  Google Scholar 

  118. Fuentealba, P. et al. Ivy cells: a population of nitric-oxide-producing, slow-spiking GABAergic neurons and their involvement in hippocampal network activity. Neuron 57, 917–929 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Katona, L. et al. Synaptic organisation and behaviour-dependent activity of mGluR8a-innervated GABAergic trilaminar cells projecting from the hippocampus to the subiculum. Brain Struct. Funct. 225, 705–734 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Mizuseki, K., Sirota, A., Pastalkova, E. & Buzsaki, G. Theta oscillations provide temporal windows for local circuit computation in the entorhinal-hippocampal loop. Neuron 64, 267–280 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Ali, A. B. & Thomson, A. M. Facilitating pyramid to horizontal oriens–alveus interneurone inputs: dual intracellular recordings in slices of rat hippocampus. J. Physiol. 507, 185–199 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. Toth, K. & McBain, C. J. Afferent-specific innervation of two distinct AMPA receptor subtypes on single hippocampal interneurons. Nat. Neurosci. 1, 572–578 (1998).

    CAS  PubMed  Article  Google Scholar 

  123. Lei, S. & McBain, C. J. Distinct NMDA receptors provide differential modes of transmission at mossy fiber–interneuron synapses. Neuron 33, 921–933 (2002).

    CAS  PubMed  Article  Google Scholar 

  124. Losonczy, A., Zhang, L., Shigemoto, R., Somogyi, P. & Nusser, Z. Cell type dependence and variability in the short-term plasticity of EPSCs in identified mouse hippocampal interneurones. J. Physiol. 542, 193–210 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. Croce, A., Pelletier, J. G., Tartas, M. & Lacaille, J. C. Afferent-specific properties of interneuron synapses underlie selective long-term regulation of feedback inhibitory circuits in CA1 hippocampus. J. Physiol. 588, 2091–2107 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. Matta, J. A. et al. Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity. Nat. Neurosci. 16, 1032–1041 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Kwon, O., Feng, L., Druckmann, S. & Kim, J. Schaffer collateral inputs to CA1 excitatory and inhibitory neurons follow different connectivity rules. J. Neurosci. 38, 5140–5152 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. Buzsaki, G., Czopf, J., Kondakor, I. & Kellenyi, L. Laminar distribution of hippocampal rhythmic slow activity (RSA) in the behaving rat: current-source density analysis, effects of urethane and atropine. Brain Res. 365, 125–137 (1986).

    CAS  PubMed  Article  Google Scholar 

  129. O’Keefe, J. & Recce, M. L. Phase relationship between hippocampal place units and the EEG theta rhythm. Hippocampus 3, 317–330 (1993).

    PubMed  Article  Google Scholar 

  130. Takacs, V. T., Klausberger, T., Somogyi, P., Freund, T. F. & Gulyas, A. I. Extrinsic and local glutamatergic inputs of the rat hippocampal CA1 area differentially innervate pyramidal cells and interneurons. Hippocampus 22, 1379–1391 (2012).

    CAS  PubMed  Article  Google Scholar 

  131. Zemankovics, R., Veres, J. M., Oren, I. & Hajos, N. Feedforward inhibition underlies the propagation of cholinergically induced gamma oscillations from hippocampal CA3 to CA1. J. Neurosci. 33, 12337–12351 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. Lasztoczi, B. & Klausberger, T. Layer-specific GABAergic control of distinct gamma oscillations in the CA1 hippocampus. Neuron 81, 1126–1139 (2014).

    CAS  PubMed  Article  Google Scholar 

  133. Buzsaki, G., Leung, L. W. & Vanderwolf, C. H. Cellular bases of hippocampal EEG in the behaving rat. Brain Res. 287, 139–171 (1983).

    CAS  PubMed  Article  Google Scholar 

  134. Colom, L. V. & Bland, B. H. State-dependent spike train dynamics of hippocampal formation neurons: evidence for theta-on and theta-off cells. Brain Res. 422, 277–286 (1987).

    CAS  PubMed  Article  Google Scholar 

  135. Guet-McCreight, A. & Skinner, F. K. Deciphering how interneuron specific 3 cells control oriens lacunosum-moleculare cells to contribute to circuit function. J. Neurophysiol. https://doi.org/10.1152/jn.00204.2021 (2021).

    Article  PubMed  Google Scholar 

  136. Stark, E. et al. Inhibition-induced theta resonance in cortical circuits. Neuron 80, 1263–1276 (2013).

    CAS  PubMed  Article  Google Scholar 

  137. Huh, C. Y. et al. Excitatory inputs determine phase-locking strength and spike-timing of CA1 stratum oriens/alveus parvalbumin and somatostatin interneurons during intrinsically generated hippocampal theta rhythm. J. Neurosci. 36, 6605–6622 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  138. Bezaire, M. J., Raikov, I., Burk, K., Vyas, D. & Soltesz, I. Interneuronal mechanisms of hippocampal theta oscillations in a full-scale model of the rodent CA1 circuit. eLife https://doi.org/10.7554/eLife.18566 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Ferguson, K. A., Chatzikalymniou, A. P. & Skinner, F. K. Combining theory, model, and experiment to explain how intrinsic theta rhythms are enerated in an in vitro whole hippocampus preparation without oscillatory inputs. eNeuro https://doi.org/10.1523/ENEURO.0131-17.2017 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Chatzikalymniou, A. P. & Skinner, F. K. Deciphering the contribution of oriens-lacunosum/moleculare (OLM) cells to intrinsic theta rhythms using biophysical local field potential (LFP) models. eNeuro https://doi.org/10.1523/ENEURO.0146-18.2018 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Gu, Z. et al. Hippocampal interneuronal α7 nAChRs modulate theta oscillations in freely moving mice. Cell Rep. 31, 107740 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. Foster, D. J. & Wilson, M. A. Reverse replay of behavioural sequences in hippocampal place cells during the awake state. Nature 440, 680–683 (2006).

    CAS  PubMed  Article  Google Scholar 

  143. Diba, K. & Buzsaki, G. Forward and reverse hippocampal place-cell sequences during ripples. Nat. Neurosci. 10, 1241–1242 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. Girardeau, G., Benchenane, K., Wiener, S. I., Buzsaki, G. & Zugaro, M. B. Selective suppression of hippocampal ripples impairs spatial memory. Nat. Neurosci. 12, 1222–1223 (2009).

    CAS  PubMed  Article  Google Scholar 

  145. Ego-Stengel, V. & Wilson, M. A. Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat. Hippocampus 20, 1–10 (2010).

    PubMed  PubMed Central  Google Scholar 

  146. Jadhav, S. P., Kemere, C., German, P. W. & Frank, L. M. Awake hippocampal sharp-wave ripples support spatial memory. Science 336, 1454–1458 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. van de Ven, G. M., Trouche, S., McNamara, C. G., Allen, K. & Dupret, D. Hippocampal offline reactivation consolidates recently formed cell assembly patterns during sharp wave-ripples. Neuron 92, 968–974 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  148. Buzsaki, G. Hippocampal sharp waves: their origin and significance. Brain Res. 398, 242–252 (1986).

    CAS  PubMed  Article  Google Scholar 

  149. Ylinen, A. et al. Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms. J. Neurosci. 15, 30–46 (1995).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. Gan, J., Weng, S. M., Pernia-Andrade, A. J., Csicsvari, J. & Jonas, P. Phase-locked inhibition, but not excitation, underlies hippocampal ripple oscillations in awake mice in vivo. Neuron 93, 308–314 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. Chittajallu, R. et al. Dual origins of functionally distinct O-LM interneurons revealed by differential 5-HT3AR expression. Nat. Neurosci. 16, 1598–1607 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Winterer, J. et al. Single-cell RNA-seq characterization of anatomically identified OLM interneurons in different transgenic mouse lines. Eur. J. Neurosci. 50, 3750–3771 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  153. Asgarian, Z., Magno, L., Ktena, N., Harris, K. D. & Kessaris, N. Hippocampal CA1 somatostatin interneurons originate in the embryonic MGE/POA. Stem Cell Rep. 13, 793–802 (2019).

    CAS  Article  Google Scholar 

  154. Melzer, S. et al. Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex. Science 335, 1506–1510 (2012).

    CAS  PubMed  Article  Google Scholar 

  155. Basu, J. et al. Gating of hippocampal activity, plasticity, and memory by entorhinal cortex long-range inhibition. Science 351, aaa5694 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  156. Freund, T. F. & Antal, M. GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus. Nature 336, 170–173 (1988).

    CAS  PubMed  Article  Google Scholar 

  157. Salib, M. et al. GABAergic medial septal neurons with low-rhythmic firing innervating the dentate gyrus and hippocampal area CA3. J. Neurosci. 39, 4527–4549 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  158. Pavlides, C., Greenstein, Y. J., Grudman, M. & Winson, J. Long-term potentiation in the dentate gyrus is induced preferentially on the positive phase of theta-rhythm. Brain Res. 439, 383–387 (1988).

    CAS  PubMed  Article  Google Scholar 

  159. Holscher, C., Anwyl, R. & Rowan, M. J. Stimulation on the positive phase of hippocampal theta rhythm induces long-term potentiation that can be depotentiated by stimulation on the negative phase in area CA1 in vivo. J. Neurosci. 17, 6470–6477 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. Ranck, J. B. Jr. Studies on single neurons in dorsal hippocampal formation and septum in unrestrained rats. I. Behavioral correlates and firing repertoires. Exp. Neurol. 41, 461–531 (1973).

    PubMed  Article  Google Scholar 

  161. Mehta, M. R., Lee, A. K. & Wilson, M. A. Role of experience and oscillations in transforming a rate code into a temporal code. Nature 417, 741–746 (2002).

    CAS  PubMed  Article  Google Scholar 

  162. Dragoi, G. & Buzsaki, G. Temporal encoding of place sequences by hippocampal cell assemblies. Neuron 50, 145–157 (2006).

    CAS  PubMed  Article  Google Scholar 

  163. Huxter, J. R., Senior, T. J., Allen, K. & Csicsvari, J. Theta phase-specific codes for two-dimensional position, trajectory and heading in the hippocampus. Nat. Neurosci. 11, 587–594 (2008).

    CAS  PubMed  Article  Google Scholar 

  164. Perez, Y., Morin, F. & Lacaille, J. C. A Hebbian form of long-term potentiation dependent on mGluR1a in hippocampal inhibitory interneurons. Proc. Natl Acad. Sci. USA 98, 9401–9406 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  165. Lamsa, K. P., Heeroma, J. H., Somogyi, P., Rusakov, D. A. & Kullmann, D. M. Anti-Hebbian long-term potentiation in the hippocampal feedback inhibitory circuit. Science 315, 1262–1266 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  166. Vasuta, C. et al. Metaplastic regulation of CA1 Schaffer collateral pathway plasticity by Hebbian mGluR1a-mediated plasticity at excitatory synapses onto somatostatin-expressing interneurons. eNeuro https://doi.org/10.1523/ENEURO.0051-15.2015 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  167. Lapointe, V. et al. Synapse-specific mGluR1-dependent long-term potentiation in interneurones regulates mouse hippocampal inhibition. J. Physiol. 555, 125–135 (2004).

    CAS  PubMed  Article  Google Scholar 

  168. Topolnik, L., Congar, P. & Lacaille, J. C. Differential regulation of metabotropic glutamate receptor- and AMPA receptor-mediated dendritic Ca2+ signals by presynaptic and postsynaptic activity in hippocampal interneurons. J. Neurosci. 25, 990–1001 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. Topolnik, L., Azzi, M., Morin, F., Kougioumoutzakis, A. & Lacaille, J. C. mGluR1/5 subtype-specific calcium signalling and induction of long-term potentiation in rat hippocampal oriens/alveus interneurones. J. Physiol. 575, 115–131 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  170. Ran, I. et al. Persistent transcription- and translation-dependent long-term potentiation induced by mGluR1 in hippocampal interneurons. J. Neurosci. 29, 5605–5615 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. Ran, I., Laplante, I. & Lacaille, J. C. CREB-dependent transcriptional control and quantal changes in persistent long-term potentiation in hippocampal interneurons. J. Neurosci. 32, 6335–6350 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  172. Le Roux, N., Cabezas, C., Bohm, U. L. & Poncer, J. C. Input-specific learning rules at excitatory synapses onto hippocampal parvalbumin-expressing interneurons. J. Physiol. 591, 1809–1822 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  173. Szabo, A. et al. Calcium-permeable AMPA receptors provide a common mechanism for LTP in glutamatergic synapses of distinct hippocampal interneuron types. J. Neurosci. 32, 6511–6516 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Camire, O. & Topolnik, L. Dendritic calcium nonlinearities switch the direction of synaptic plasticity in fast-spiking interneurons. J. Neurosci. 34, 3864–3877 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  175. Camire, O., Lazarevich, I., Gilbert, T. & Topolnik, L. Mechanisms of supralinear calcium integration in dendrites of hippocampal CA1 fast-spiking cells. Front. Synaptic Neurosci. 10, 47 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. Peterfi, Z. et al. Endocannabinoid-mediated long-term depression of afferent excitatory synapses in hippocampal pyramidal cells and GABAergic interneurons. J. Neurosci. 32, 14448–14463 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. Lau, P. Y. et al. Long-term plasticity in identified hippocampal GABAergic interneurons in the CA1 area in vivo. Brain Struct. Funct. 222, 1809–1827 (2017).

    CAS  PubMed  Article  Google Scholar 

  178. Dupret, D., O’Neill, J. & Csicsvari, J. Dynamic reconfiguration of hippocampal interneuron circuits during spatial learning. Neuron 78, 166–180 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  179. Chevaleyre, V. & Piskorowski, R. Modulating excitation through plasticity at inhibitory synapses. Front. Cell. Neurosci. 8, 93 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  180. Horn, M. E. & Nicoll, R. A. Somatostatin and parvalbumin inhibitory synapses onto hippocampal pyramidal neurons are regulated by distinct mechanisms. Proc. Natl Acad. Sci. USA 115, 589–594 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  181. Udakis, M., Pedrosa, V., Chamberlain, S. E. L., Clopath, C. & Mellor, J. R. Interneuron-specific plasticity at parvalbumin and somatostatin inhibitory synapses onto CA1 pyramidal neurons shapes hippocampal output. Nat. Commun. 11, 4395 (2020). This study demonstrates that inhibitory synapses formed by PV+ and SOM+ interneurons can undergo LTD and LTP, respectively, that allows coordination of the SC and TA inputs to CA1 PCs and that they may cooperate in creating stable PC representations.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. Glickfeld, L. L., Atallah, B. V. & Scanziani, M. Complementary modulation of somatic inhibition by opioids and cannabinoids. J. Neurosci. 28, 1824–1832 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. Schulz, J. M., Knoflach, F., Hernandez, M. C. & Bischofberger, J. Dendrite-targeting interneurons control synaptic NMDA-receptor activation via nonlinear α5-GABAA receptors. Nat. Commun. 9, 3576 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  184. Chevaleyre, V. & Castillo, P. E. Endocannabinoid-mediated metaplasticity in the hippocampus. Neuron 43, 871–881 (2004).

    CAS  PubMed  Article  Google Scholar 

  185. Basu, J. et al. A cortico-hippocampal learning rule shapes inhibitory microcircuit activity to enhance hippocampal information flow. Neuron 79, 1208–1221 (2013).

    CAS  PubMed  Article  Google Scholar 

  186. Murray, A. J. et al. Parvalbumin-positive CA1 interneurons are required for spatial working but not for reference memory. Nat. Neurosci. 14, 297–299 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  187. Grienberger, C., Milstein, A. D., Bittner, K. C., Romani, S. & Magee, J. C. Inhibitory suppression of heterogeneously tuned excitation enhances spatial coding in CA1 place cells. Nat. Neurosci. 20, 417–426 (2017). This study reports that spatially uniform inhibition suppresses out-of-field excitation of PCs and limits dendritic amplification, thus allowing precise spatio-temporal coding by CA1 PCs.

    CAS  PubMed  Article  Google Scholar 

  188. Chiu, C. Q. et al. Compartmentalization of GABAergic inhibition by dendritic spines. Science 340, 759–762 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  189. Lovett-Barron, M. et al. Dendritic inhibition in the hippocampus supports fear learning. Science 343, 857–863 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  190. Roy, D. S. et al. Distinct neural circuits for the formation and retrieval of episodic memories. Cell 170, 1000–1012.e19 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. Haam, J., Zhou, J., Cui, G. & Yakel, J. L. Septal cholinergic neurons gate hippocampal output to entorhinal cortex via oriens lacunosum moleculare interneurons. Proc. Natl Acad. Sci. USA 115, E1886–E1895 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  192. Losonczy, A., Zemelman, B. V., Vaziri, A. & Magee, J. C. Network mechanisms of theta related neuronal activity in hippocampal CA1 pyramidal neurons. Nat. Neurosci. 13, 967–972 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  193. Magnin, E. et al. Input-specific synaptic location and function of the α5 GABAA receptor subunit in the mouse CA1 hippocampal neurons. J. Neurosci. 39, 788–801 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. Dere, E., Huston, J. P. & De Souza Silva, M. A. Episodic-like memory in mice: simultaneous assessment of object, place and temporal order memory. Brain Res. Brain Res. Protoc. 16, 10–19 (2005).

    PubMed  Article  Google Scholar 

  195. Fellini, L. & Morellini, F. Mice create what–where–when hippocampus-dependent memories of unique experiences. J. Neurosci. 33, 1038–1043 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. Fanselow, M. S. From contextual fear to a dynamic view of memory systems. Trends Cogn. Sci. 14, 7–15 (2010).

    PubMed  Article  Google Scholar 

  197. Fanselow, M. S., DeCola, J. P. & Young, S. L. Mechanisms responsible for reduced contextual conditioning with massed unsignaled unconditional stimuli. J. Exp. Psychol. Anim. Behav. Process. 19, 121–137 (1993).

    CAS  PubMed  Article  Google Scholar 

  198. Ito, H. T. & Schuman, E. M. Functional division of hippocampal area CA1 via modulatory gating of entorhinal cortical inputs. Hippocampus 22, 372–387 (2012).

    CAS  PubMed  Article  Google Scholar 

  199. Marr, D. Simple memory: a theory for archicortex. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 262, 23–81 (1971).

    CAS  Google Scholar 

  200. Buzsaki, G. Two-stage model of memory trace formation: a role for “noisy” brain states. Neuroscience 31, 551–570 (1989).

    CAS  PubMed  Article  Google Scholar 

  201. Ognjanovski, N. et al. Parvalbumin-expressing interneurons coordinate hippocampal network dynamics required for memory consolidation. Nat. Commun. 8, 15039 (2017). This study highlights the role of PV+ interneurons in consolidation of fear memory, whereby, following learning, PV+ cells drive CA1 oscillations to promote network plasticity and long-term memory.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  202. Ognjanovski, N., Broussard, C., Zochowski, M. & Aton, S. J. Hippocampal network oscillations rescue memory consolidation deficits caused by sleep loss. Cereb. Cortex 28, 3711–3723 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  203. Caliskan, G. et al. Identification of parvalbumin interneurons as cellular substrate of fear memory persistence. Cereb. Cortex 26, 2325–2340 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  204. Fernandez-Ruiz, A. et al. Long-duration hippocampal sharp wave ripples improve memory. Science 364, 1082–1086 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. Schwindel, C. D. & McNaughton, B. L. Hippocampal–cortical interactions and the dynamics of memory trace reactivation. Prog. Brain Res. 193, 163–177 (2011).

    PubMed  Article  Google Scholar 

  206. Molle, M., Eschenko, O., Gais, S., Sara, S. J. & Born, J. The influence of learning on sleep slow oscillations and associated spindles and ripples in humans and rats. Eur. J. Neurosci. 29, 1071–1081 (2009).

    PubMed  Article  Google Scholar 

  207. Wierzynski, C. M., Lubenov, E. V., Gu, M. & Siapas, A. G. State-dependent spike-timing relationships between hippocampal and prefrontal circuits during sleep. Neuron 61, 587–596 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  208. Averkin, R. G., Szemenyei, V., Borde, S. & Tamas, G. Identified cellular correlates of neocortical ripple and high-gamma oscillations during spindles of natural sleep. Neuron 92, 916–928 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. Xia, F. et al. Parvalbumin-positive interneurons mediate neocortical–hippocampal interactions that are necessary for memory consolidation. eLife https://doi.org/10.7554/eLife.27868 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Tang, S. J. et al. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. Proc. Natl Acad. Sci. USA 99, 467–472 (2002).

    CAS  PubMed  Article  Google Scholar 

  211. Costa-Mattioli, M., Sossin, W. S., Klann, E. & Sonenberg, N. Translational control of long-lasting synaptic plasticity and memory. Neuron 61, 10–26 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  212. Costa-Mattioli, M. et al. eIF2α phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129, 195–206 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  213. Cope, D. W. et al. Cholecystokinin-immunopositive basket and Schaffer collateral-associated interneurones target different domains of pyramidal cells in the CA1 area of the rat hippocampus. Neuroscience 109, 63–80 (2002).

    CAS  PubMed  Article  Google Scholar 

  214. Whissell, P. D. et al. Selective activation of cholecystokinin-expressing GABA (CCK-GABA) neurons enhances memory and cognition. eNeuro https://doi.org/10.1523/ENEURO.0360-18.2019 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Armstrong, C., Krook-Magnuson, E. & Soltesz, I. Neurogliaform and ivy cells: a major family of nNOS expressing GABAergic neurons. Front. Neural Circuits 6, 23 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  216. Chamberland, S. & Topolnik, L. Inhibitory control of hippocampal inhibitory neurons. Front. Neurosci. 6, 165 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  217. Bittner, K. C. et al. Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons. Nat. Neurosci. 18, 1133–1142 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  218. Bittner, K. C., Milstein, A. D., Grienberger, C., Romani, S. & Magee, J. C. Behavioral time scale synaptic plasticity underlies CA1 place fields. Science 357, 1033–1036 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  219. Harris, K. D. et al. Classes and continua of hippocampal CA1 inhibitory neurons revealed by single-cell transcriptomics. PLoS Biol. 16, e2006387 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  220. Leroy, F. et al. Enkephalin release from VIP interneurons in the hippocampal CA2/3a region mediates heterosynaptic plasticity and social memory. Mol. Psychiatry https://doi.org/10.1038/s41380-021-01124-y (2021).

    Article  PubMed  Google Scholar 

  221. Morrison, D. J. et al. Parvalbumin interneurons constrain the size of the lateral amygdala engram. Neurobiol. Learn. Mem. 135, 91–99 (2016).

    CAS  PubMed  Article  Google Scholar 

  222. Stefanelli, T., Bertollini, C., Luscher, C., Muller, D. & Mendez, P. Hippocampal somatostatin interneurons control the size of neuronal memory ensembles. Neuron 89, 1074–1085 (2016).

    CAS  PubMed  Article  Google Scholar 

  223. Hu, H., Martina, M. & Jonas, P. Dendritic mechanisms underlying rapid synaptic activation of fast-spiking hippocampal interneurons. Science 327, 52–58 (2010).

    CAS  PubMed  Article  Google Scholar 

  224. Salesse, C., Mueller, C. L., Chamberland, S. & Topolnik, L. Age-dependent remodelling of inhibitory synapses onto hippocampal CA1 oriens-lacunosum moleculare interneurons. J. Physiol. 589, 4885–4901 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  225. Topolnik, L., Chamberland, S., Pelletier, J. G., Ran, I. & Lacaille, J. C. Activity-dependent compartmentalized regulation of dendritic Ca2+ signaling in hippocampal interneurons. J. Neurosci. 29, 4658–4663 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  226. Papp, E. C., Hajos, N., Acsady, L. & Freund, T. F. Medial septal and median raphe innervation of vasoactive intestinal polypeptide-containing interneurons in the hippocampus. Neuroscience 90, 369–382 (1999).

    CAS  PubMed  Article  Google Scholar 

  227. Guet-McCreight, A., Camire, O., Topolnik, L. & Skinner, F. K. Using a semi-automated strategy to develop multi-compartment models that predict biophysical properties of interneuron-specific 3 (IS3) cells in hippocampus. eNeuro https://doi.org/10.1523/ENEURO.0087-16.2016 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  228. Denny, C. A. et al. Hippocampal memory traces are differentially modulated by experience, time, and adult neurogenesis. Neuron 83, 189–201 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  229. Josselyn, S. A. & Tonegawa, S. Memory engrams: recalling the past and imagining the future. Science https://doi.org/10.1126/science.aaw4325 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  230. Tayler, K. K., Tanaka, K. Z., Reijmers, L. G. & Wiltgen, B. J. Reactivation of neural ensembles during the retrieval of recent and remote memory. Curr. Biol. 23, 99–106 (2013).

    CAS  PubMed  Article  Google Scholar 

  231. Ramirez, S. et al. Creating a false memory in the hippocampus. Science 341, 387–391 (2013).

    CAS  PubMed  Article  Google Scholar 

  232. Tanaka, K. Z. et al. The hippocampal engram maps experience but not place. Science 361, 392–397 (2018).

    CAS  PubMed  Article  Google Scholar 

  233. Barron, H. C., Vogels, T. P., Behrens, T. E. & Ramaswami, M. Inhibitory engrams in perception and memory. Proc. Natl Acad. Sci. USA 114, 6666–6674 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  234. Francavilla, R. et al. Alterations in intrinsic and synaptic properties of hippocampal CA1 VIP interneurons during aging. Front. Cell Neurosci. 14, 554405 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  235. Das, S. et al. Plasticity of local GABAergic interneurons drives olfactory habituation. Proc. Natl Acad. Sci. USA 108, E646–E654 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  236. Kato, H. K., Gillet, S. N. & Isaacson, J. S. Flexible sensory representations in auditory cortex driven by behavioral relevance. Neuron 88, 1027–1039 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  237. Norimoto, H. et al. Hippocampal ripples down-regulate synapses. Science 359, 1524–1527 (2018).

    CAS  PubMed  Article  Google Scholar 

  238. Frank, L. M., Brown, E. N. & Wilson, M. A. A comparison of the firing properties of putative excitatory and inhibitory neurons from CA1 and the entorhinal cortex. J. Neurophysiol. 86, 2029–2040 (2001).

    CAS  PubMed  Article  Google Scholar 

  239. Ego-Stengel, V. & Wilson, M. A. Spatial selectivity and theta phase precession in CA1 interneurons. Hippocampus 17, 161–174 (2007).

    PubMed  Article  Google Scholar 

  240. Wilent, W. B. & Nitz, D. A. Discrete place fields of hippocampal formation interneurons. J. Neurophysiol. 97, 4152–4161 (2007).

    PubMed  Article  Google Scholar 

  241. Hangya, B., Li, Y., Muller, R. U. & Czurko, A. Complementary spatial firing in place cell–interneuron pairs. J. Physiol. 588, 4165–4175 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The authors’ work was supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada. The authors thank D. Topolnik for preparation of figures.

Author information

Authors and Affiliations

Authors

Contributions

Both authors contributed equally to the preparation of the manuscript.

Corresponding author

Correspondence to Lisa Topolnik.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Neuroscience thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Declarative memory

The capacity to store facts about the world (semantic memory) and episodes of everyday life (episodic memory).

Spatial mapping

The acquisition of information in relation to spatial location and orientation.

Memory encoding

The acquisition of experience-associated information by changes in activity levels, synaptic strengths and connectivity patterns in the neuronal networks that make memory systems.

Context

The static features of an environment that define the place in which an experience occurred.

Memory retrieval

The process that allows recall of experience-related information stored in memory traces using a relevant cue.

Memory consolidation

The transformation of temporary experience-associated memory constructs into long-lasting memory traces.

Phase precession

Progressive advancement in the time of firing of action potentials by individual place cells in relation to the phase of the extracellular theta oscillation.

Spatial remapping

The acquisition of information in response to altered spatial location and orientation.

Spatial working memory

The ability of animals to retain spatial information over a long period of time.

Goal-oriented spatial learning

A behavioural paradigm in which spatial learning is reinforced by a reward or punishment.

Novel object recognition

A paradigm in which an animal is exposed to two identical objects and, after a certain delay, is re-exposed to one novel object and one previously explored (familiar) object. Object memory is evaluated from the animal’s capacity to spend more time exploring a novel object than a familiar one.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Topolnik, L., Tamboli, S. The role of inhibitory circuits in hippocampal memory processing. Nat Rev Neurosci (2022). https://doi.org/10.1038/s41583-022-00599-0

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41583-022-00599-0

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing