Colocalization of neurotransmitters in the hippocampus and afferent systems: possible functional role

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Abstract

In neurophysiology, the transmitter phenotype is considered a sign of neuronal identity. Since the end of the last century, it has become known that a nerve cell can produce and use several different molecules to communicate with other neurons. These can be “classical” transmitters: glutamate or gamma-aminobutyric acid (or acetylcholine, serotonin, norepinephrine), as well as second messengers, mainly neuropeptides released from the same neurons. If classical neurotransmitters are released together from the same nerve cell, this is called cotransmission or coreleasing (release from the same vesicles). In this review article, the term “cotransmission” is used in a broad sense, denoting neurons that can release more than one classical mediator. Since transmitters are often intermediate products of metabolism and are found in many cells, the classification of neurons is currently based on carrier proteins (transporters) that “pack” neurotransmitters synthesized in the cytoplasm into vesicles. Here, we limit the question of colocalization of the main neurotransmitters in mammals to neurons of the hippocampus and those structures that send their pathways to it. The review considers problems affecting the mechanisms of multitransmitter signaling, as well as the probable functional role of mediator colocalization in the work of the hippocampus, which has not yet been clarified. It is suggested that co-expression of different mediator phenotypes is involved in maintaining the balance of excitation and inhibition in different regions of the hippocampus; facilitates rapid selection of information processing methods, induction of long-term potentiation, maintenance of spatial coding by place cells, as well as ensuring flexibility of learning and formation of working memory. However, the functional role of mediator colocalization, as well as the mechanisms of release of “dual” transmitters, have not been fully clarified. The solution of these problems will advance some areas of fundamental neuroscience and help in the treatment of those diseases where a violation of the balance of excitation and inhibition is detected, for example, epilepsy, Alzheimer’s disease and many others.

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V. F. Kitchigina

Institute of Theoretical and Experimental Biophysics Russian Academy of Science

Author for correspondence.
Email: vkitchigina@gmail.com
Russian Federation, 142290 Pushchino, Moscow Region

References

  1. Dale, H. H. (1935) Pharmacology and nerve endings, Proc. R. Soc. Med., 28, 319-332, https://doi.org/10.1136/bmj.2.3859.1161.
  2. Nusbaum, M. P., Blitz, D. M., Swensen, A. M., Wood, D., and Marder, E. (2001) The roles of co-transmission in neural network modulation, Trends Neurosci., 24, 146-154, https://doi.org/10.1016/S0166-2236(00)01723-9.
  3. Vaaga, C. E, Borisovska, M., and Westbrook, G. L. (2014) Dual-transmitter neurons: Functional implications of co-release and co-transmission, Curr. Opin. Neurobiol., 29, 25-32, https://doi.org/10.1016/j.conb.2014.04.010.
  4. Tritsch, N. X., Granger, A. J., and Sabatini, B. L. (2016) Mechanisms and functions of GABA co-release, Nat. Rev. Neurosci., 17, 139-45, https://doi.org/10.1038/nrn.2015.21.
  5. Trudeau, L. E., and El Mestikawy, S. (2018) Glutamate cotransmission in cholinergic, GABAergic and monoamine systems: contrasts and commonalities, Front. Neural. Circuits, 12, 113, https://doi.org/10.3389/fncir.2018.00113.
  6. Takamori, S., Rhee, J. S., Rosenmund, C., and Jahn, R. (2000) Identification of a vesicular glutamate transporter that defines a glutamatergic phenotype in neurons, Nature, 407, 189-194, https://doi.org/10.1038/35025070.
  7. Weston, M. C, Nehring, R. B., Wojcik, S. M., and Rosenmund, C. (2011) Interplay between VGLUT isoforms and endophilin A1 regulates neurotransmitter release and short-term plasticity, Neuron, 69, 1147-1159, https://doi.org/10.1016/j.neuron.2011.02.002.
  8. Preobraschenski, J., Zander, J. F., Suzuki, T., Ahnert-Hilger, G., and Jahn, R. (2014) Vesicular glutamate transporters use flexible anion and cation binding sites for efficient accumulation of neurotransmitter, Neuron, 84, 1287-1301, https://doi.org/10.1016/j.neuron.2014.11.008.
  9. Fremeau, R. T. Jr., Troyer, M. D., Pahner, I., Nygaard, G. O., Tran, C. H., Reimer, R. J., Bellocchio, E. E., Fortin, D., Storm-Mathisen, J., and Edwards, R. H. (2001) The expression of vesicular glutamate transporters defines two classes of excitatory synapse, Neuron, 31, 247-260, https://doi.org/10.1016/s0896-6273(01)00344-0.
  10. Xu, J., Jo, A., DeVries, R. P., Deniz, S., Cherian, S., Sunmola, I., Song, X., Marshall, J. J., Gruner, K. A., Daigle, T. L., et al. (2022) Intersectional mapping of multi-transmitter neurons and other cell types in the brain, Cell Rep., 40, 111036, https://doi.org/10.1016/j.celrep.2022.111036.
  11. Somogyi, J., Baude, A., Omori, Y., Shimizu, H., El Mestikawy, S., Fukaya, M., Shigemoto, R., Watanabe, M., and Somogyi, P. (2004) GABAergic basket cells expressing cholecystokinin contain vesicular glutamate transporter type 3 (VGLUT3) in their synaptic terminals in hippocampus and isocortex of the rat, Eur. J. Neurosci., 19, 552-569, https://doi.org/10.1111/j.0953-816x.2003.03091.x.
  12. Scimemi, A. (2014) Plasticity of GABA transporters: an unconventional route to shape inhibitory synaptic transmission, Front. Cell Neurosci., 8, 128, https://doi.org/10.3389/fncel.2014.00128.
  13. Stensrud, M. J., Chaudhry, F. A., Leergaard, T. B., Bjaalie, J. G., and Gundersen, V. (2013) Vesicular glutamate transporter-3 in the rodent brain: vesicular colocalization with vesicular gamma-aminobutyric acid transporter, J. Comp. Neurol., 521, 3042-3056, https://doi.org/10.1002/cne.23331.
  14. Szonyi, A., Zicho, K., Barth, A. M., Gonczi, R. T., Schlingloff, D., Torok, B., Sipos, E., Major, A., Bardoczi, Z., Sos, K. E., Gulyás, A. I., Varga, V., Zelena, D., Freund, T. F., and Nyiri, G. (2019) Median raphe controls acquisition of negative experience in the mouse, Science, 366, 6469, https://doi.org/10.1126/science.aay8746.
  15. Fremeau, R. T. Jr., Burman, J., Qureshi, T., Tran, C. H., Proctor, J., Johnson, J., Zhang, H., Sulzer, D., Copenhagen, D. R., Storm-Mathisen, J., Reimer, R. J., Chaudhry, F. A., and Edwards, R. H. (2002) The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate, Proc. Natl. Acad. Sci. USA, 99, 14488-14493, https://doi.org/10.1073/pnas.222546799.
  16. Schafer, M. K., Varoqui, H., Defamie, N., Weihe, E., and Erickson, J. D. (2002) Molecular cloning and functional identification of mouse vesicular glutamate transporter 3 and its expression in subsets of novel excitatory neurons, J. Biol. Chem., 277, 50734-50748, https://doi.org/10.1074/jbc.m206738200.
  17. Stensrud, M. J., Sogn, C. J., and Gundersen, V. (2015) Immunogold characteristics of VGLUT3-positive GABAergic nerve terminals suggest corelease of glutamate, J. Comp. Neurol., 523, 2698-2713, https://doi.org/10.1002/cne.23811.
  18. Del Pino, I., Brotons-Mas, J. R., Marques-Smith, A., Marighetto, A., Frick, A., Marin, O., and Rico, B. (2017) Abnormal wiring of CCK+ basket cells disrupts spatial information coding, Nat. Neurosci., 20, 784-792, https://doi.org/10.1038/nn.4544.
  19. Klausberger, T., Marton, L. F., O’Neill, J., Huck, J. H. J., Dalezios, Y., Fuentealba, P., Suen, W. Y., Papp, E., Kaneko, T., Watanabe, M., Csicsvari, J., and Somogyi, P. (2005) Complementary roles of cholecystokinin- and parvalbumin-expressing GABAergic neurons in hippocampal network oscillations, J. Neurosci., 25, 9782-9793, https://doi.org/10.1523/JNEUROSCI.3269-05.2005.
  20. Pelkey, K. A., Calvigioni, D., Fang, C., Vargish, G., Ekins, T., Auville, K., Wester, J. C., Lai, M., Mackenzie-Gray Scott, C., Yuan, X., Hunt, S., Abebe, D., Xu, Q., Dimidschstein, J., Fishell, G., et al. (2020) Paradoxical network excitation by glutamate release from VGluT3+ GABAergic interneurons, Elife, 9, e51996, https://doi.org/10.7554/eLife.51996.
  21. Fasano, C., Rocchetti, J., Pietrajtis, K., Zander, J. F., Manseau, F., Sakae, D. Y., Marcus-Sells, M., Ramet, L., Morel, L. J., Carrel, D., Dumas, S., Bolte, S., Bernard, V., Vigneault, E., Goutagny, R., Ahnert-Hilger, G., Giros, B., Daumas, S., Williams, S, and El Mestikawy, S. (2017) Regulation of the hippocampal network by VGLUT3-positive CCK-GABAergic basket cells, Front. Cell Neurosci., 11, 140, https://doi.org/10.3389/fncel.2017.00140.
  22. Johnson, J. W., and Ascher, P. (1987) Glycine potentiates the NMDA response in cultured mouse brain neurons, Nature, 325, 529-531, https://doi.org/10.1038/325529a0.
  23. Cortese, K., Gagliani, M. C., and Raiteri, L. (2023) Interactions between glycine and glutamate through activation of their transporters in hippocampal nerve terminals, Biomedicines, 11, 3152, https://doi.org/10.3390/biomedicines11123152.
  24. Кичигина В. Ф., Шубина Л. В., Попова И. Ю. (2022) Роль зубчатой извилины в осуществлении функций гиппокампа: здоровый мозг, Журн. высш. нерв. деят. им. И.П. Павлова, 72, 317-342, https://doi.org/10.31857/S0044467722030030.
  25. Ramirez, M., and Gutiérrez, R., (2001) Activity-dependent expression of GAD67 in the granule cells of the rat hippocampus, Brain Res., 917, 139-146, https://doi.org/10.1016/s0006-8993(01)02794-9.
  26. Gutiérrez, R. (2003) The GABAergic phenotype of the ‘‘glutamatergic’’ granule cells of the dentate gyrus, Prog. Neurobiol., 71, 337-358, https://doi.org/10.1016/j.pneurobio.2003.11.004.
  27. Gutiérrez, R. (2005) The dual glutamatergic-GABAergic phenotype of hippocampal granule cells, Trends Neurosci., 28, 297-303, https://doi.org/10.1016/j.tins.2005.04.005.
  28. Safiulina, V. F., Fattorini, G., Conti, F., and Cherubini, E. (2006) GABAergic signaling at mossy fiber synapses in neonatal rat hippocampus, J. Neurosci., 26, 597-608, https://doi.org/10.1523/JNEUROSCI.4493-05.2006.
  29. Beltràn, J. Q., and Gutiérrez, R. (2012) Co-release of glutamate and GABA from single, identified mossy fibre giant boutons, J. Physiol., 590, 4789-4800, https://doi.org/10.1113/jphysiol.2012.236372.
  30. Sloviter, R. S., Dichter, M. A., Rachinsky, T. L., Dean, E., Goodman, J. H., Sollas, A. L., and Martin, D. L. (1996) Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus, J. Comp. Neurol., 373, 593-618, https://doi.org/10.1002/(SICI)1096-9861(19960930)373:4<593::AID-CNE8>3.0.CO;2-X.
  31. Bergersen, L., Ruiz, A., Bjaalie, J. G., Kullmann, D. M., and Gundersen, V. (2003) GABA and GABAA receptors at hippocampal mossy fibre synapses, Eur. J. Neurosci., 18, 931-941, https://doi.org/10.1046/j.1460-9568.2003.02828.x.
  32. Zander, J. F., Munster-Wandowski, A., Brunk, I., Pahner, I., Gomez-Lira, G., Heinemann, U., Gutiérrez, R., Laube, G., and Ahnert-Hilger, G. (2010) Synaptic and vesicular coexistence of VGLUT and VGAT in selected excitatory and inhibitory synapses, J. Neurosci., 30, 7634-7645, https://doi.org/10.1523/JNEUROSCI.0141-10.2010.
  33. Gomez-Lira, G., Lamas, M., Romo-Parra, H., and Gutierrez, R. (2005) Programmed and induced phenotype of the hippocampal granule cells, J. Neurosci., 25, 6939-6946, https://doi.org/10.1523/JNEUROSCI.1674-05.2005.
  34. Chaudhry, F. A., Reimer, R., Bellocchio, E. E., Danbolt, N. C., Osen, K. K., Edwards, R. H., and Storm-Mathisen, J. (1998) The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets ofglycinergic as well as GABAergic neurons, J. Neurosci., 18, 9733-9750, https://doi.org/10.1523/JNEUROSCI.18-23-09733.1998.
  35. Sperk, G., Wieselthaler-Hőlzl, A., Pirker, S., Tasan, R., Strasser, S. S., Drexel, M., Pifl, C., Marschalek, J., Ortler, M., Trinka, E., Heitmair-Wietzorrek, K., Ciofi, P., et al. (2012) Glutamate decarboxylase 67 is expressed in hippocampal mossy fibers of temporal lobe epilepsy patients, Hippocampus, 22, 590-603, https://doi.org/10.1002/hipo.20923.
  36. Galván, E. J., and Gutiérrez, R. (2017) Target-dependent compartmentalization of the corelease of glutamate and GABA from the mossy fibers, J. Neurosci., 37, 701-714, https://doi.org/10.1523/JNEUROSCI.1915-16.2016.
  37. Uchigashima, M., Fukaya, M., Watanabe, M., and Kamiya, H. (2007) Evidence against GABA release from glutamatergic mossy fiber terminals in the developing hippocampus, J. Neurosci., 27, 8088-8100, https://doi.org/10.1523/JNEUROSCI.0702-07.2007.
  38. Xiong, G., Zhang, L., Mojsilovic-Petrovic, J., Arroyo, E., Elkind, J., Kundu, S., Johnson, B., Smith, C. J., Cohen, N. A., Grady, S. M., and Cohen, A. S. (2012) GABA and glutamate are not colocalized in mossy fiber terminals of developing rodent hippocampus, Brain Res., 1474, 40-49, https://doi.org/10.1016/j.brainres.2012.07.042.
  39. Gutiérrez, R. (2016) The plastic neurotransmitter phenotype of the hippocampal granule cells and of the moss in their messy fibers, J. Chem. Neuroanat., 73, 9-20, https://doi.org/10.1016/j.jchemneu.2015.11.007.
  40. Gutiérrez, R. (2000) Seizures induce simultaneous GABAergic and glutamatergic transmission in the dentate gyrus-CA3 system, J. Neurophysiol., 84, 3088-3090, https://doi.org/10.1152/jn.2000.84.6.3088.
  41. Walker, M. C., Ruiz, A., and Kullmann, D. M. (2002) Do mossy fibers release GABA? Epilepsia, 43, 196-202, https://doi.org/10.1046/j.1528-1157.43.s.5.6.x.
  42. Treviño, M., and Gutiérrez, R. (2005) The GABAergic projection of the dentate gyrus to hippocampal area CA3 of the rat: pre- and postsynaptic actions after seizures, J. Physiol., 567, 939-949, https://doi.org/10.1113/jphysiol.2005.092064.
  43. Walker, M. C., Ruiz, A., and Kullmann, D. M. (2001) Monosynaptic GABAergic signaling from dentate to CA3 with a pharmacological and physiological profile typical of mossy fiber synapses, Neuron, 29, 703-715, https://doi.org/10.1016/s0896-6273(01)00245-8.
  44. Romo-Parra, H., Vivar, C., Maqueda, J., Morales, M. A., and Gutiérrez, R. (2003) Activity-dependent induction of multitransmitter signaling onto pyramidal cells and interneurons of hippocampal area CA3, J. Neurophysiol., 89, 3155-3167, https://doi.org/10.1152/jn.00985.2002.
  45. Vinogradova, O. S. (1995) Expression, control, and probable functional significance of the neuronal theta-rhythm, Prog. Neurobiol., 45, 523-583, https://doi.org/10.1016/0301-0082(94)00051-I.
  46. Vinogradova, O. S. (2001) Hippocampus as comparator: role of the two input and two output systems of the hippocampus in selection and registration of information, Hippocampus, 11, 578-598, https://doi.org/10.1002/hipo.1073.
  47. Vinogradova, O. S., Brazhnik, E. S., Kitchigina, V. F., and Stafekhina, V. S. (1993) Acetylcholine, theta-rhythm and activity of the hippocampal neurons in the rabbit. IV. Sensory stimulation, Neuroscience, 53, 993-1007, https://doi.org/10.1016/0306-4522(93)90484-w.
  48. Buzsáki, G. (2002) Theta oscillations in the hippocampus, Neuron, 33, 325-340, https://doi.org/10.1016/s0896-6273(02)00586-x.
  49. Freund, T. F., and Gulyás, A. I. (1997) Inhibitory control of GABAergic interneurons in the hippocampus, Can. J. Physiol. Pharmacol., 75, 479-487, https://doi.org/10.1139/y97-033.
  50. Toth, K., Freund, T. F., and Miles, R. (1997) Disinhibition of rat hippocampal pyramidal cells by GABAergic afferents from the septum, J. Physiol., 500, 463-474, https://doi.org/10.1113/jphysiol.1997.sp022033.
  51. Sotty, M., Danik, F., Manseau, F., Laplante, R., Quirion, S., and Williams, S. (2003) Glutamatergic, cholinergic and GABAergic neurons contribute to the septohippocampal pathway and exhibit distinct electrophysiological properties: novel implications for hippocampal rhythmicity, J. Physiol., 551, 927-943, https://doi.org/10.1113/jphysiol.2003.046847.
  52. Colom, L. V., Castañeda, M. T., Reyna, T., Hernandez, S., and Garrido-Sanabria, E. (2005) Characterization of medial septal glutamatergic neurons and their projection to the hippocampus, Synapse, 58, 151-164, https://doi.org/10.1002/syn.20184.
  53. Tkatch, K., Baranauskas, G., and Surmeier, D. J. (1998) Basal forebrain neurons adjacent to the globus pallidus co-express GABAergic and cholinergic marker mRNAs, Neuroreport, 9, 1935-1939, https://doi.org/10.1097/00001756-199806220-00004.
  54. Puma, C., Danik, M., Quirion, R., Ramon, F., and Williams, S. (2001) The chemokine interleukin-8 acutely reduces Ca2+ currents in identified cholinergic septal neurons expressing CXCR1 and CXCR2 receptor mRNAs, J. Neurochem., 78, 960-971, https://doi.org/10.1046/j.1471-4159.2001.00469.x.
  55. Han, S.-H., McCool, B. A., Murchison, D., Nahm, S.-S., Parrish, A., and Griffith, W. H. (2002) Single-cell RT-PCR detects shifts in mRNA expression profiles of basal forebrain neurons during aging, Mol. Brain Res., 98, 67-80, https://doi.org/10.1016/s0169-328x(01)00322-9.
  56. Huh, C. Y., Danik, M., Manseau, F., Trudeau, L. E., and Williams, S. (2008) Chronic exposure to nerve growth factor increases acetylcholine and glutamate release from cholinergic neurons of the rat medial septum and diagonal band of Broca via mechanisms mediated by p75NTR, J. Neurosci., 6, 1404-1409, https://doi.org/10.1523/JNEUROSCI.4851-07.2008.
  57. Case, D. T., Burton, S. D., Gedeon, J. Y., Williams, S. G., Urban, N. N., and Seal, R. P. (2017) Layer- and cell type-selective co-transmission by a basal forebrain cholinergic projection to the olfactory bulb, Nat. Commun., 8, 652, https://doi.org/10.1038/s41467-017-00765-4.
  58. Hillegaart, V. (1991) Functional topography of brain serotonergic pathways in the rat, Acta Physiol. Scand., 142, 1-54.
  59. Acsady, L., Halasy, K., and Freund, T. D. (1993) Calretinin is present in nonpyramidal cells of the rat hippocampus. III. Their inputs from the medial raphe and medial septal nuclei, Neuroscience, 52, 829-841, https://doi.org/10.1016/0306-4522(93)90532-k.
  60. McQuade, R., and Sharp, T. (1997) Functional mapping of dorsal and median raphe 5-hydroxytryptamine pathways in forebrain of the rat using microdialysis, J. Neurochem., 69, 791-796, https://doi.org/10.1046/j.1471-4159.1997.69020791.x.
  61. Kusljic, S., and van den Buuse, M. (2004) Functional dissociation between serotonergic pathways in dorsal and ventral hippocampus in psychotomimetic drug-induced locomotor hyperactivity and prepulse inhibition in rats, Eur. J. Neurosci., 20, 3424-3432, https://doi.org/10.1111/j.1460-9568.2004.03804.x.
  62. Freund, T. F., Gulyás, A. I., Acsády, L., Görcs, T., and Tóth, K. (1990) Serotonergic control of the hippocampus via local inhibitory interneurons, Proc. Natl. Acad. Sci. USA, 87, 8501, https://doi.org/10.1073/pnas.87.21.8501.
  63. Gras, C., Herzog, E, Bellenchi, G. C., Bernard, V., Ravassard, P., Pohl, M., Gasnier, B., Giros, B., and El Mestikawy, S. (2002) A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons, J. Neurosci., 22, 5442-5451, https://doi.org/10.1523/JNEUROSCI.22-13-05442.2002.
  64. Shutoh, F., Ina, A., Yoshida, S., Konno, J., and Hisano, S. (2008) Two distinct subtypes of serotonergic fibers classified by co-expression with vesicular glutamate transporter 3 in rat forebrain, Neurosci. Lett., 432, 132-136, https://doi.org/10.1016/j.neulet.2007.12.050.
  65. Voisin, A. N., Mnie-Filali, O., Giguere, N., Fortin, G. M., Vigneault, E., El Mestikawy, S., Descarries, L., and Trudeau, L. E. (2016) Axonal segregation and role of the vesicular glutamate transporter VGLUT3 in serotonin neurons, Front. Neuroanat., 10, 39, https://doi.org/10.3389/fnana.2016.00039.
  66. Calizo, L. H., Akanwa, A., Ma, X., Pan, Y. Z., Lemos, J. C., Craige, C., Heemstra, L. A., and Beck, S. G. (2011) Raphe serotonin neurons are not homogenous: Electrophysiological, morphological and neurochemical evidence, Neuropharmacology, 61, 524-543, https://doi.org/10.1016/j.neuropharm.2011.04.008.
  67. Gagnon, D., and Parent, M. (2014) Distribution of VGLUT3 in highly collateralized axons from the rat dorsal raphe nucleus as revealed by single-neuron reconstructions, PLoS One, 9, e87709, https://doi.org/10.1371/journal.pone.0087709.
  68. Belmer, A., Beecher, K., Jacques, A., Patkar, O. L., Sicherre, F., and Bartlett, S. E. (2019) Axonal Non-segregation of the vesicular glutamate transporter VGLUT3 within serotonergic projections in the mouse forebrain, Front. Cell. Neurosci., 13, 193, https://doi.org/10.3389/fncel.2019.00193.
  69. Ren, J., Friedmann, D., Xiong, J., Liu, C. D., Ferguson, B. R., Weerakkody, T., DeLoach, K. E., Ran, C., Pun, A., Sun, Y., Weissbourd, B., Neve, R. L., Huguenard, J., et al. (2018) Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems, Cell, 175, 472-487, e420, https://doi.org/10.1016/j.cell.2018.07.043.
  70. Herzog, E., Gilchrist, J., Gras, C., Muzerelle, A., Ravassard, P., Giros, B., Gaspar, P., and El Mestikawy, S. (2004) Localization of VGLUT3, the vesicular glutamate transporter type 3, in the rat brain, Neuroscience, 123, 983-1002, https://doi.org/10.1016/j.neuroscience.2003.10.039.
  71. Hioki, H., Nakamura, H., Ma, Y. F., Konno, M., Hayakawa, T., Nakamura, K. C., Fujiyama, F., and Kaneko, T. (2010) Vesicular glutamate transporter 3-expressing nonserotonergic projection neurons constitute a subregion in the rat midbrain raphe nuclei, J. Comp. Neurol., 518, 668-686, https://doi.org/10.1002/cne.22237.
  72. Sos, K. E., Mayer, M. I., Cserep, C., Takacs, F. S., Szonyi, A., Freund, T. F., and Nyiri, G. (2017) Cellular architecture and transmitter phenotypes of neurons of the mouse median raphe region, Brain Struct. Funct., 222, 287-299, https://doi.org/10.1007/s00429-016-1217-x.
  73. Zimmermann, J., Herman, M. A., and Rosenmund, C. (2015) Co-release of glutamate and GABA from single vesicles in GABAergic neurons exogenously expressing VGLUT3, Front. Synaptic Neurosci., 7, 16, https://doi.org/10.3389/fnsyn.2015.00016.
  74. Pan, W. X., and McNaughton, N. (2004) The supramammillary area: its organization, functions and relationship to the hippocampus, Prog. Neurobiol., 74, 127-166, https://doi.org/10.1016/j.pneurobio.2004.09.003.
  75. Vertes, R. P., and Kocsis, B. (1997) Brainstem-diencephalo-septohippocampal system controlling the theta rhythm of the hippocampus, Neuroscience, 81, 893-926, https://doi.org/10.1016/s0306-4522(97)00239-x.
  76. Billwiller, F., Castillo, L., Elseedy, H. A.,·Ivanov, A. I., Scapula, J., Ghestem, A.·Carponcy, J., Libourel, P. A., Bras, H., Abdelmeguid, N. E. S., Krook-Magnuson, E., Soltesz, I., Bernard, C., Luppi, P.-H., and Esclapez, M. (2020) GABA-glutamate supramammillary neurons control theta and gamma oscillations in the dentate gyrus during paradoxical (REM) sleep, Brain Struct. Funct., 225, 2643-2668, https://doi.org/10.1007/s00429-020-02146-y.
  77. Boulland, J. L., Jenstad, M., Boekel, A. J., Wouterlood, F. G., Edwards, R. H., Storm-Mathisen, J., and Chaudhry, F. A. (2009) Vesicular glutamate and GABA transporters sort to distinct sets of vesicles in a population of presynaptic terminals, Cereb. Cortex, 19, 241-248, https://doi.org/10.1093/cercor/bhn077.
  78. Soussi, R., Zhang, N., Tahtakran, S., Houser, C. R., and Esclapez, M. (2010) Heterogeneity of the supramammillary-hippocampal pathways: evidence for a unique GABAergic neurotransmitter phenotype and regional differences: GABAergic and glutamatergic supramammillary-hippocampal pathways, Eur. J. Neurosci., 32, 771-785, https://doi.org/10.1111/j.1460-9568.2010.07329.x.
  79. Root, D. H., Zhang, S., Barker, D. J., Miranda-Barrientos, J., Liu, B., Wang, H. L., and Morales, M. (2018) Selective brain distribution and distinctive synaptic architecture of dual glutamatergic–GABAergic neurons, Cell Rep., 23, 3465-3479, https://doi.org/10.1016/j.celrep.2018.05.063.
  80. Pedersen, N. P., Ferrari, L., Venner, A., Wang, J. L., Abbott, S. B. G., Vujovic, N., Arrigoni, E., Saper, C. B., and Fuller, P. M. (2017) Supramammillary glutamate neurons are a key node of the arousal system, Nat. Commun., 8, 1405, https://doi.org/10.1038/s41467-017-01004-6.
  81. Hashimotodani, Y., Karube, F., Yanagawa, Y., Fujiyama, F., and Kano, M. (2018) Supramammillary nucleus afferents to the dentate gyrus co-release glutamate and GABA and potentiate granule cell output, Cell Rep., 25, 2704-2715, https://doi.org/10.1016/j.celrep.2018.11.016.
  82. Kocsis, B., and Vertes, R. P. (1994) Characterization of neurons of the supramammillary nucleus and mammillary body that discharge rhythmically with the hippocampal theta rhythm in the rat, J. Neurosci., 14, 7040-7052, https://doi.org/10.1523/JNEUROSCI.14-11-07040.1994.
  83. Kocsis, B., and Kaminski, M. (2006) Dynamic changes in the direction of the theta rhythmic drive between supramammillary nucleus and the septohippocampal system, Hippocampus, 16, 531-540, https://doi.org/10.1002/hipo.20180.
  84. Pasquier, D. A., and Reinoso-Suarez, F. (1976) Direct projections from hypothalamus to hippocampus in the rat demonstrated by retrograde transport of horseradish peroxidase, Brain Res., 108, 165-169, https://doi.org/10.1016/0006-8993(76)90172-4.
  85. Richmond, M. A., Yee, B. K., Pouzet, B., Veenman, L., Rawlins, J. N., Feldon, J., and Bannerman, D. M. (1999) Dissociating context and space within the hippocampus: effects of complete, dorsal, and ventral excitotoxic hippocampal lesions on conditioned freezing and spatial learning, Behav. Neurosci., 113, 1189-1203, https://doi.org/10.1037/0735-7044.113.6.1189.
  86. Pan, W. X., and McNaughton, N. (2002) The role of the medial supramammillary nucleus in the control of hippocampal theta activity and behaviour in rats, Eur. J. Neurosci., 16, 1797-1809, https://doi.org/10.1046/j.1460-9568.2002.02267.x.
  87. Santin, L. J., Aguirre, J. A., Rubio, S., Begega, A., Miranda, R., and Arias, J. L. (2003) c-Fos expression in supramammillary and medial mammillary nuclei following spatial reference and working memory tasks, Physiol. Behav., 78, 733-739, https://doi.org/10.1016/s0031-9384(03)00060-x.
  88. Shahidi, S., Motamedi, F., and Naghdi, N. (2004) Effect of reversible inactivation of the supramammillary nucleus on spatial learning and memory in rats, Brain Res., 1026, 267-274, https://doi.org/10.1016/j.brainres.2004.08.030.
  89. Gasbarri, A., Verney, C., Innocenzti, R., Campana, E., and Pacitti, C. (1994) Mesolimbic dopaminergic neurons innervating the hippocampal formation in the rat: a combined retrograde tracing and immunohistochemical study, Brain Res., 668, 71-79, https://doi.org/10.1016/0006-8993(94)90512-6.
  90. Samson, Y., Wu, J. J., Friedman, A. H., and Davis, J. N. (1990) Catecholaminergic innervation of the hippocampus in the cynomologus monkey, J. Comp. Neurol., 298, 250-263, https://doi.org/10.1002/cne.902980209.
  91. Sulzer, D., Joyce, M. P., Lin, L., Geldwert, D., Haber, S. N., Hattori, T., and Rayport, S. (1998) Dopamine neurons make glutamatergic synapses in vitro, J. Neurosci., 18, 4588-4602, https://doi.org/10.1523/JNEUROSCI.18-12-04588.1998.
  92. Hnasko, T. S., Chuhma, N., Zhang, H., Goh, G. Y., Sulzer, D., Palmiter, R. D., Rayport, S., and Edwards, R. H. (2010) Vesicular glutamate transport promotes dopamine storage and glutamate corelease in vivo, Neuron, 65, 643-656, https://doi.org/10.1016/j.neuron.2010.02.012.
  93. Chuhma, N., Mingote, S., Moore, H., and Rayport, S. (2014) Dopamine neurons control striatal cholinergic neurons via regionally heterogeneous dopamine and glutamate signaling, Neuron, 81, 901-912, https://doi.org/10.1016/j.neuron.2013.12.027.
  94. Trudeau, L.-E., Hnasko, T. S., Wallén-Mackenzie, A., Morales, M., Rayport, S., and Sulzer, D. (2014) The multilingual nature of dopamine neurons, Prog. Brain Res., 211, 141-164, https://doi.org/10.1016/b978-0-444-63425-2.00006-4.
  95. Nelson, A. B., Bussert, T. G., Kreitzer, A. C., and Seal, R. P. (2014) Striatal cholinergic neurotransmission requires VGLUT3, J. Neurosci., 34, 8772-8777, https://doi.org/10.1523/jneurosci.0901-14.2014.
  96. Frahm, S., Antolin-Fontes, B., Görlich, A., Zander, J.-F., Ahnert-Hilger, G., and Ibañez-Tallon, I. (2015) An essential role of acetylcholine-glutamate synergy at habenular synapses in nicotine dependence, Elife, 4, e11396, https://doi.org/10.7554/elife.11396.
  97. Yamaguchi, T., Sheen, W., and Morales, M. (2007) Glutamatergic neurons are present in the rat ventral tegmental area, Eur. J. Neurosci., 25, 106-118, https://doi.org/10.1111/j.1460-9568.2006.05263.x.
  98. Li, X., Qi, J., Yamaguchi, T., Wang, H.-L., and Morales, M. (2013) Heterogeneous composition of dopamine neurons of the rat A10 region: molecular evidence for diverse signaling properties, Brain Struct. Funct., 218, 1159-1176, https://doi.org/10.1007/s00429-012-0452-z.
  99. Loy, R., Koziell, D. A., Lindsey, J. D., and Moore, R. Y. (1980) Noradrenergic innervation of the adult rat hippocampal formation, J. Comp. Neurol., 189, 699-710, https://doi.org/10.1002/cne.901890406.
  100. Ford, B., Holmes, C. J., Mainville, L., and Jones, B. E. (1995) GABAergic neurons in the rat pontomesencephalic tegmentum: tegmental neurons projecting to the posterior hypothalamus, J. Comp. Neur., 363, 177-196, https://doi.org/10.1002/cne.903630203.
  101. Privitera, M., von Ziegler, L. M., Floriou-Servou, A., Duss, S. N., Zhang, R., Waag, R., Leimbacher, S., Sturman, O., Roessler, F. K., Heylen, A., Vermeiren, Y., Van Dam, D., et al. (2024) Noradrenaline release from the locus coeruleus shapes stress-induced hippocampal gene expression, Elife, 12, RP88559, https://doi.org/10.7554/eLife.88559.
  102. Stornetta, R. L., Rosin, D. L., Simmons, J. R., McQuiston, T. J., Vujovic, N., Weston, M. C., and Guyenet, P. G. (2005) Coexpression of vesicular glutamate transporter-3 and g-aminobutyric acidergic markers in rat rostral medullary raphe and intermediolateral cell column, J. Comp. Neurol., 492, 477-494, https://doi.org/10.1002/cne.20742.
  103. Mather, M., Clewett, D., Sakaki, M., and Harley, C. W. (2016) Norepinephrine ignites local hotspots of neuronal excitation: how arousal amplifies selectivity in perception and memory, Behav. Brain Sci., 39, e200, https://doi.org/10.1017/S0140525X15000667.
  104. Devoto, P. and Flore, G. (2006) On the origin of cortical dopamine: is it a co-transmitter in noradrenergic neurons? Curr. Neuropharmacol., 4, 115-125, https://doi.org/10.2174/157015906776359559.
  105. Smith, C. C., and Greene, R. W. (2012) CNS dopamine transmission mediated by noradrenergic innervation, J. Neurosci., 32, 6072-6080, https://doi.org/10.1523/JNEUROSCI.6486-11.2012.
  106. Hansen, N., and Manahan-Vaughan, D. (2014) Dopamine D1/D5 receptors mediate informational saliency that promotes persistent hippocampal long-term plasticity, Cereb. Cortex, 24, 845-858, https://doi.org/10.1093/cercor/bhs362.
  107. Takeuchi, T., Duszkiewicz, A. J., Sonneborn, A., Spooner, P. A., Yamasaki, M., Watanabe, M., Smith, C. C., Fernández, G., Deisseroth, K., Greene, R. W, and Morris, R. G. M. (2016) Locus coeruleus and dopaminergic consolidation of everyday memory, Nature, 537, 357-362, https://doi.org/10.1038/nature19325.
  108. Sonneborn, A., and Greene, R. W. (2021) Norepinephrine transporter antagonism prevents dopamine-dependent synaptic plasticity in the mouse dorsal hippocampus, Neurosci. Lett., 740, 135450, https://doi.org/10.1016/j.neulet.2020.135450.
  109. Bragin, A. G., Zhadina, S. D., Vinogradova, O. S., and Kozhechkin, S. N. (1977) Topography and some characteristics of the dentate fascia–field CA3 relations investigated in hippocampal slices in vitro, Brain Res., 135, 55-66.
  110. Lehmann, H., Ebert, U., and Loscher, W. (1996) Immunocytochemical localization of GABA immunoreactivity in dentate granule cells of normal and kindled rats, Neurosci. Lett., 212, 41-44, https://doi.org/10.1016/0304-3940(96)12777-4.
  111. Виноградова О. С. (2000) Нейронаука конца второго тысячелетия: смена парадигм. Журн. высш. нерв. деят. им. И.П. Павлова, 50, 743-774.
  112. Kitchigina, V. F. (2010) Theta oscillations and reactivity of hippocampal stratum oriens neurons, Sci. World J., 10, 930-943, https://doi.org/10.1100/tsw.2010.90.
  113. Bartesaghi, R., and Gessi, T. (2003) Activation of perforant path neurons to field CA1 by hippocampal projections, Hippocampus, 13, 235-249, https://doi.org/10.1002/hipo.10074.
  114. Conrad, B., Benecke, R., and Goehmann, M. (1983) Premovement silent period in fast movement initiation, Exp. Brain Res., 51, 310-313, https://doi.org/10.1007/BF00237208.
  115. Чебкасов С. А. (1995) Предстимульное торможение в нейронных модулях зрительной коры мозга морской свинки, Физиол. Журн. Сеченова, 81, 119.
  116. Gemin, O., Serna, P., Zamith, J., Assendorp, N., Fossati M., Rostaing, P., Triller, A., and Charrier, C. (2021) Unique properties of dually innervated dendritic spines in pyramidal neurons of the somatosensory cortex uncovered by 3D correlative light and electron microscopy, PLoS Biol., 19, e3001375, https://doi.org/10.1371/journal.pbio.3001375.
  117. Chiu, C. Q., Martenson, J. S., Yamazaki, M., Natsume, R., Sakimura, K., Tomita, S., Steven, J. T., and Higley, M. J. (2018) Input-specific NMDAR-dependent potentiation of dendritic GABAergic inhibition, Neuron, 97, 368-377.e3, https://doi.org/10.1016/j.neuron.2017.12.032.
  118. Dorman, D. B., Jędrzejewska-Szmek, J., and Blackwell, K. T. (2018) Inhibition enhances spatially-specific calcium encoding of synaptic input patterns in a biologically constrained model, Elife, 7, e38588, https://doi.org/10.7554/eLife.38588.
  119. El Mestikawy, S., Wallén-Mackenzie, Å., Fortin, G. M., Descarries, L., and Trudeau, L. E. (2011) From glutamate co-release to vesicular synergy: vesicular glutamate transporters, Nat. Rev. Neurosci., 12, 204-216, https://doi.org/10.1038/nrn2969.
  120. Ajibola, M. I., Wu, J.-W., Abdulmajeed, W. I., and Lien, C.-C. (2021) Hypothalamic glutamate/GABA cotransmission modulates hippocampal circuits and supports long-term potentiation, J. Neurosci., 41, 8181-8196, https://doi.org/10.1523/JNEUROSCI.0410-21.2021.
  121. Кичигина В. Ф., Гордеева Т. А. (1995) Регуляция септального пейсмекера тета-ритма медианным ядром шва, Журн. высш. нерв. деят. им. И.П. Павлова, 45, 848-859.
  122. Nitz, D. A., and McNaughton, B. L. (1999) Hippocampal EEG and unit activity responses to modulation of serotonergic median raphe neurons in the freely behaving rat, Learn. Mem., 6, 153-167.
  123. Huh, C. Y., Jacobs, B. L., and Azmitia E. C. (1992) Structure and function of the brain serotonin system, Physiol. Rev., 72, 165-229, https://doi.org/10.1152/physrev.1992.72.1.165.
  124. Kandel, E., Scwartz, J. H., and Jessel, T. M. (2000) Principles of Neural Science, McGraw Hill, New York, Edn. 4.
  125. Varga, V., Losonczy, A., Zemelman, B. V., Borhegyi, Z., Nyiri, G., Domonkos, A., Hangya, B., et al. (2009) Fast synaptic subcortical control of hippocampal circuits, Science, 326, 449-453, https://doi.org/10.1126/science.1178307.
  126. Collins, S. A., Stinson, H. E., Himes, A., Nestor-Kalinoski, A., and Ninan, I. (2023) Sex-specific modulation of the medial prefrontal cortex by glutamatergic median raphe neurons, Sci. Adv., 9, eadg4800, https://doi.org/10.1126/sciadv.adg4800.
  127. Gullino, L. S., Fuller, C., Dunn, P., Collins, H. M., El Mestikawy, S., and Sharp, T. (2024) Evidence for a Role of 5-HT-glutamate co-releasing neurons in acute stress mechanisms, ACS Chem Neurosci., 15, 1185-1196, https://doi.org/10.1021/acschemneuro.3c00758.
  128. Hirase, H., Leinekugel, X., Csicsvari, J., Czurkó, A., and Buzsáki, G., (2001) Behavior-dependent states of the hippocampal network affect functional clustering of neurons, J. Neurosci., 21, RC145, https://doi.org/10.1523/JNEUROSCI.21-10-j0003.2001.
  129. Moita, M. A. P., Rosis, S., Zhou, Y., LeDoux, J. E., and Blair, H. T. (2003) Hippocampal place cells acquire location-specific responses to the conditioned stimulus during auditory fear conditioning, Neuron, 37, 485-497, https://doi.org/10.1016/s0896-6273(03)00033-3.
  130. Freund, T. F., and Antal, M. (1988) GABA-containing neurons in the septum control inhibitory interneurons in the hippocampus, Nature, 336, 170-173, https://doi.org/10.1038/336170a0.
  131. Cardin, J. A., Carlén, M., Meletis, K., Knoblich, U., Zhang, F., Deisseroth, K., Tsai, L.-H., and Moore, C. I. (2009) Driving fast-spiking cells induces gamma rhythm and controls sensory responses, Nature, 459, 663, https://doi.org/10.1038/nature08002.
  132. Klausberger, T., and Somogyi, P. (2008) Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations, Science, 321, 53-57, https://doi.org/10.1523/JNEUROSCI.3269-05.2005.
  133. Valero, M., Cid, E., Averkin, R. G., Aguilar, J., Sanchez-Aguilera, A., Viney, T. J., Gomez-Dominguez, D., Bellistri, E., and de la Prida, L. M. (2015) Determinants of different deep and superficial CA1 pyramidal cell dynamics during sharp-wave ripples, Nat. Neurosci., 18, 1281-1290, https://doi.org/10.1038/nn.4074.
  134. Craske, M. G., Kircanski, K., Zelikowsky, M., Mystkowski, J., Chowdhury, N., and Baker, A. (2008) Optimizing inhibitory learning during exposure therapy, Behav. Res. Ther., 46, 5-27, https://doi.org/10.1016/j.brat.2007.10.003
  135. Ballinger, E. C., Ananth, M., Talmage, D. A., and Role, L. W. (2016) Basal forebrain cholinergic circuits and signaling in cognition and cognitive decline, Neuron, 91,1199-1218, https://doi.org/10.1016/j.neuron.2016.09.006.
  136. Baratta, M. V., Kodandaramaiah, S. B., Monahan, P. E., Yao, J., Weber, M. D., Lin P.-A., Gisabella, B., Petrossian, N., Amat, J., Kim, K., Yang, A., Forest, C. R., Boyden, E. S., and Goosens, K. A. (2016) Stress enables reinforcement-elicited serotonergic consolidation of fear memory, Biol. Psychiatry, 79, 814-822, doi: 10.1016/j.biopsych.2015.06.025.
  137. Wilson, M. A., and Fadel, J. R. (2017) Cholinergic regulation of fear learning and extinction, J. Neurosci. Res., 95, 836-852, https://doi.org/10.1002/jnr.23840.
  138. Krabbe, S., Gründemann, J., and Lüthi, A. (2018) Amygdala inhibitory circuits regulate associative fear conditioning, Biol. Psychiatry, 83, 800-809, https://doi.org/10.1016/j.biopsych.2017.10.006.
  139. Amilhon, B., Lepicard, È., Renoir, T., Mongeau, R., Popa, D., Poirel, O., Miot, S., Gras, C., Gardier, A. M., Gallego, J., Hamon, M., et al. (2010) VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety, J. Neurosci., 30, 2198-2210, https://doi.org/10.1523/JNEUROSCI.5196-09.2010.
  140. Omiya, Y., Uchigashima, M., Konno, K., Yamasaki, M., Miyazaki, T., Yoshida, T., Kusumi, I., and Watanabe, M. (2015) VGluT3-expressing CCK-positive basket cells construct invaginating synapses enriched with endocannabinoid signaling proteins in particular cortical and cortex-like amygdaloid regions of mouse brains, J. Neurosci., 35, 4215-4228, https://doi.org/10.1523/JNEUROSCI.4681-14.2015.
  141. Rovira-Esteban, L., Péterfi, Z., Vikór, A., Máté, Z., Szabó, G., and Hájos, N. (2017) Morphological and physiological properties of CCK/CB1 rexpressing interneurons in the basal amygdala, Brain Struct. Funct., 222, 3543-3565, https://doi.org/10.1007/s00429-017-1417-z.
  142. Sengupta, A., and Holmes, A. (2019) A discrete dorsal raphe to basal amygdala 5-HT circuit calibrates aversive memory, Neuron, 103, 489-505.e7, https://doi.org/10.1016/j.neuron.2019.05.029.
  143. Balázsfi, D., Fodor, A., Török, B., Ferenczi, S., Kovács, K. J., Haller, J., and Zelena, D. (2018) Enhanced innate fear and altered stress axis regulation in VGluT3 knockout mice, Stress, 21,151-161, https://doi.org/10.1080/10253890.2017.1423053.
  144. Fazekas, C. L., Balázsi, D., Horvath, H. R., Balogh, Z., Aliczki, M., Puhova, A., Balagova, L., Chmelova, M., Jezova, D., Haller, J., and Zelena, D. (2019) Consequences of VGluT3 deficiency on learning and memory in mice, Physiol. Behav., 212, 112688, https://doi.org/10.1016/j.physbeh.2019.112688.
  145. Dani, A., Huang, B., Bergan, J., Dulac, C., and Zhuang, X. (2010) Superresolution imaging of chemical synapses in the brain, Neuron, 68, 843-856, https://doi.org/10.1016/J.NEURON.2010.11.021.
  146. Chang, J. B., Chen, F., Yoon, Y. G., Jung, E. E., Babcock, H., Kang, J. S., Asano, S., Suk, H. J., Pak, N., Tillberg, P. W., et al. (2017) Iterative expansion microscopy, Nat. Methods, 14, 593-599, https://doi.org/10.1038/nmeth.4261.

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2. Fig. 1. Schematic of the synaptic architecture of “dual” (VGLUT3+ and VGAT+) neurons releasing glutamate and GABA from separate synaptic vesicles at independent asymmetric or symmetric synapses. Adapted from [79], with permission from Elsevier (license #5922371097009, issued December 5, 2024). GABA, gamma-aminobutyric acid; VGLUT3+ vesicles, positive vesicular glutamate transporters; VGAT+ vesicles, positive vesicular GABA transporters.

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3. Fig. 2. Schematic representation of neurons and axons in the CA1 region of the hippocampus and dorsal dentate gyrus revealing colocalization of neurotransmitters

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