Skip to main content

Thank you for visiting 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.

Diversity and function of corticopetal and corticofugal GABAergic projection neurons


It is still widely thought that cortical projections to distant brain areas derive by and large from glutamatergic neurons. However, an increasing number of reports provide evidence that cortical GABAergic neurons comprise a smaller population of ‘projection neurons’ in addition to the well-known and much-studied interneurons. GABAergic long-range axons that derive from, or project to, cortical areas are thought to entrain distant brain areas for efficient information transfer and processing. Research conducted over the past 10 years has revealed that cortical GABAergic projection neurons are highly diverse in terms of molecular marker expression, synaptic targeting (identity of targeted cell types), activity pattern during distinct behavioural states and precise temporal recruitment relative to ongoing neuronal network oscillations. As GABAergic projection neurons connect many cortical areas unidirectionally or bidirectionally, it is safe to assume that they participate in the modulation of a whole series of behavioural and cognitive functions. We expect future research to examine how long-range GABAergic projections fine-tune activity in distinct distant networks and how their recruitment alters the behaviours that are supported by these networks.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: GABAergic projection neurons form classical and atypical synapses.
Fig. 2: Cortical GABAergic projections.
Fig. 3: Oscillatory coupling of rhythmically firing hippocampal and septal GABAergic projection neurons.
Fig. 4: Target specificity of septo–hippocampal GABAergic neurons.


  1. 1.

    Ito, M. & Yoshida, M. The origin of cerebral-induced inhibition of Deiters neurones. I. Monosynaptic initiation of the inhibitory postsynaptic potentials. Exp. Brain Res. 2, 330–349 (1966).

    CAS  PubMed  Google Scholar 

  2. 2.

    Hattori, T., McGeer, P. L., Fibiger, H. C. & McGeer, E. G. On the source of GABA-containing terminals in the substantia nigra. Electron microscopic autoradiographic and biochemical studies. Brain Res. 54, 103–114 (1973).

    CAS  PubMed  Google Scholar 

  3. 3.

    Fonnum, F., Grofová, I., Rinvik, E., Storm-Mathisen, J. & Walberg, F. Origin and distribution of glutamate decarboxylase in substantia nigra of the cat. Brain Res. 71, 77–92 (1974).

    CAS  PubMed  Google Scholar 

  4. 4.

    Chronister, R. B. & DeFrance, J. F. Organization of projection neurons of the hippocampus. Exp. Neurol. 66, 509–523 (1979).

    CAS  PubMed  Google Scholar 

  5. 5.

    Melzer, S. et al. Long-range-projecting GABAergic neurons modulate inhibition in hippocampus and entorhinal cortex. Science 335, 1506–1510 (2012). Taking recourse to AAVs that enabled the identification and characterization of defined GABAergic projections and employing optogenetically induced axonal stimulation, this study is the first to demonstrate inhibitory postsynaptic currents on functionally identified target cells that were all GABAergic interneurons.

    CAS  PubMed  Google Scholar 

  6. 6.

    Caputi, A., Melzer, S., Michael, M. & Monyer, H. The long and short of GABAergic neurons. Curr. Opin. Neurobiol. 23, 179–186 (2013).

    CAS  PubMed  Google Scholar 

  7. 7.

    Jinno, S. & Kosaka, T. Parvalbumin is expressed in glutamatergic and GABAergic corticostriatal pathway in mice. J. Comp. Neurol. 477, 188–201 (2004).

    CAS  PubMed  Google Scholar 

  8. 8.

    Hu, H., Cavendish, J. Z. & Agmon, A. Not all that glitters is gold: off-target recombination in the somatostatin-IRES-Cre mouse line labels a subset of fast-spiking interneurons. Front. Neural Circuits 7, 195 (2013).

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Neske, G. T., Patrick, S. L. & Connors, B. W. Contributions of diverse excitatory and inhibitory neurons to recurrent network activity in cerebral cortex. J. Neurosci. 35, 1089–1105 (2015).

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Tuncdemir, S. N. et al. Early somatostatin interneuron connectivity mediates the maturation of deep layer cortical circuits. Neuron 89, 521–535 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Tritsch, N. X., Ding, J. B. & Sabatini, B. L. Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature 490, 262–266 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Tritsch, N. X., Oh, W.-J., Gu, C. & Sabatini, B. L. Midbrain dopamine neurons sustain inhibitory transmission using plasma membrane uptake of GABA, not synthesis. eLife 3, e01936 (2014).

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Yu, X. et al. Wakefulness is governed by GABA and histamine cotransmission. Neuron 87, 164–178 (2015). This study reveals how GABA and histamine release from hypothalamic neurons projecting to the cortex differentially affect cortical circuits through tonic currents in pyramidal cells and excitation of inhibitory neurons, respectively; histamine and GABA release from these neurons increases and decreases wakefulness, respectively.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Bao, H. et al. Long-range GABAergic inputs regulate neural stem cell quiescence and control adult hippocampal neurogenesis. Cell Stem Cell 21, 604–617.e5 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Freund, T. F. GABAergic septohippocampal neurons contain parvalbumin. Brain Res. 478, 375–381 (1989).

    CAS  PubMed  Google Scholar 

  16. 16.

    Unal, X. G. et al. 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  Google Scholar 

  17. 17.

    Fuchs, E. C. et al. Local and distant input controlling excitation in layer II of the medial entorhinal cortex. Neuron 89, 194–208 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Desikan, S., Koser, D. E., Neitz, A. & Monyer, H. Target selectivity of septal cholinergic neurons in the medial and lateral entorhinal cortex. Proc. Natl Acad. Sci. USA 115, E2644–E2652 (2018).

    CAS  PubMed  Google Scholar 

  19. 19.

    Takács, V. T. et al. Co-transmission of acetylcholine and GABA regulates hippocampal states. Nat. Commun. 9, 2848 (2018). In this study, the authors infer that ACh and GABA are packaged into distinct vesicles at terminals of septo–hippocampal projections and demonstrate that the synaptic release of GABA alone accounts for the suppression of hippocampal SWR and epileptiform activity; ACh and GABA transmission is differentially regulated by N-type and P/Q-type calcium channels, respectively, and both are suppressed by presynaptic muscarinic and GABA B receptors.

    PubMed  PubMed Central  Google Scholar 

  20. 20.

    Smith, M. L., Hale, B. D. & Booze, R. M. Calbindin-D28k immunoreactivity within the cholinergic and GABAergic projection neurons of the basal forebrain. Exp. Neurol. 130, 230–236 (1994).

    CAS  PubMed  Google Scholar 

  21. 21.

    Viney, T. J. et al. Shared rhythmic subcortical GABAergic input to the entorhinal cortex and presubiculum. eLife 7, 34395 (2018).

    Google Scholar 

  22. 22.

    Joshi, A., Salib, M., Viney, T. J., Dupret, D. & Somogyi, P. Behavior-dependent activity and synaptic organization of septo-hippocampal GABAergic neurons selectively targeting the hippocampal CA3 area. Neuron 96, 1342–1357.e5 (2017). In this study, juxtacellular recording and labelling in awake, head-fixed mice enabled the identification of highly rhythmic PV + septo–hippocampal neurons that target selectively distinct GABAergic interneurons in CA3 and likely account for the phase-coupling of pyramidal cells with ongoing hippocampal theta oscillations.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Tamamaki, N. & Tomioka, R. Long-range GABAergic connections distributed throughout the neocortex and their possible function. Front. Neurosci. 4, 202 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Tomioka, R., Sakimura, K. & Yanagawa, Y. Corticofugal GABAergic projection neurons in the mouse frontal cortex. Front. Neuroanat. 9, 133 (2015).

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    Rock, C., Zurita, H., Wilson, C. & Apicella, A. Jr. An inhibitory corticostriatal pathway. eLife 5, e15890 (2016).

    PubMed  PubMed Central  Google Scholar 

  26. 26.

    Melzer, S. et al. Distinct corticostriatal GABAergic neurons modulate striatal output neurons and motor activity. Cell Rep. 19, 1045–1055 (2017). This study demonstrates that PV + and SOM + GABAergic projections from the motor cortex to the striatum differ with respect to their postsynaptic target and the control that they exert on locomotion, thus highlighting the functional diversity of GABAergic projecting neurons.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Lee, A. T., Vogt, D., Rubenstein, J. L. & Sohal, V. S. A class of GABAergic neurons in the prefrontal cortex sends long-range projections to the nucleus accumbens and elicits acute avoidance behavior. J. Neurosci. 34, 11519–11525 (2014). This study characterizes a molecularly heterogeneous GABAergic projection from the prefrontal cortex to the nucleus accumbens and, using optogenetic stimulation, reveals its impact on avoidance behaviour.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Rock, C., Zurita, H., Lebby, S., Wilson, C. J. & Apicella, A. J. Cortical circuits of callosal GABAergic neurons. Cereb. Cortex 28, 1154–1167 (2018).

    PubMed  Google Scholar 

  29. 29.

    McDonald, A. J. & Zaric, V. Extrinsic origins of the somatostatin and neuropeptide Y innervation of the rat basolateral amygdala. Neuroscience 294, 82–100 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Saffari, R. et al. NPY+-, but not PV+- GABAergic neurons mediated long-range inhibition from infra- to prelimbic cortex. Transl. Psychiatry 6, e736 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Unal, G. et al. Spatio-temporal specialization of GABAergic septo-hippocampal neurons for rhythmic network activity. Brain Struct. Funct. 223, 2409–2432 (2018). In this study, the authors investigated the molecular and morphological features as well as the in vivo firing patterns of several septo–hippocampal projecting neurons using juxtacellular labelling and recording in anaesthetized rats; the differential innervation of hippocampal subregions plus differences in the coupling to hippocampal rhythms emphasizes an unexpected GABAergic projecting neuron diversity.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Muñoz, W., Tremblay, R., Levenstein, D. & Rudy, B. Layer-specific modulation of neocortical dendritic inhibition during active wakefulness. Science 355, 954–959 (2017).

    PubMed  Google Scholar 

  33. 33.

    Brown, R. E. & McKenna, J. T. Turning a negative into a positive: ascending GABAergic control of cortical activation and arousal. Front. Neurol. 6, 135 (2015).

    PubMed  PubMed Central  Google Scholar 

  34. 34.

    Chen, K.-S. et al. A hypothalamic switch for REM and non-REM sleep. Neuron 97, 1168–1176 (2018).

    CAS  PubMed  Google Scholar 

  35. 35.

    Zhang, X. & van den Pol, A. N. Rapid binge-like eating and body weight gain driven by zona incerta GABA neuron activation. Science 356, 853–859 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Stewart, M. & Fox, S. E. Do septal neurons pace the hippocampal theta rhythm? Trends Neurosci. 13, 163–169 (1990).

    CAS  PubMed  Google Scholar 

  37. 37.

    Mann, E. O. & Paulsen, O. Role of GABAergic inhibition in hippocampal network oscillations. Trends Neurosci. 30, 343–349 (2007).

    CAS  PubMed  Google Scholar 

  38. 38.

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

    PubMed  Google Scholar 

  39. 39.

    Bonifazi, P. et al. GABAergic hub neurons orchestrate synchrony in developing hippocampal networks. Science 326, 1419–1424 (2009).

    CAS  PubMed  Google Scholar 

  40. 40.

    Pinto, A., Fuentes, C. & Paré, D. Feedforward inhibition regulates perirhinal transmission of neocortical inputs to the entorhinal cortex: ultrastructural study in guinea pigs. J. Comp. Neurol. 495, 722–734 (2006).

    PubMed  PubMed Central  Google Scholar 

  41. 41.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Gartner, U., Hartig, W., Brauer, K., Brückner, G. & Arendt, T. Immunofluorescence and immunoelectron microscopic evidence for differences in myelination of GABAergic and cholinergic septohippocampal fibres. Int. J. Dev. Neurosci. 19, 347–352 (2001).

    CAS  PubMed  Google Scholar 

  43. 43.

    Borhegyi, Z., Varga, V., Szilágyi, N., Fabo, D. & Freund, T. F. Phase segregation of medial septal GABAergic neurons during hippocampal theta activity. J. Neurosci. 24, 8470–8479 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Paul, A. et al. Transcriptional architecture of synaptic communication delineates GABAergic neuron identity. Cell 171, 522–539 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Dragoi, G., Carpi, D., Recce, M., Csicsvari, J. & Buzsáki, G. Interactions between hippocampus and medial septum during sharp waves and theta oscillation in the behaving rat. J. Neurosci. 19, 6191–6199 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Katona, L. et al. Behavior-dependent activity patterns of GABAergic long-range projecting neurons in the rat hippocampus. Hippocampus 27, 359–377 (2017). This study describes the rhythmic activity and phase-coupling of several molecularly and morphologically defined hippocampal GABAergic projecting neurons in freely moving rats and adds to our understanding of the diversity of GABAergic hippocampal projecting neurons.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Vandecasteele, M. et al. Optogenetic activation of septal cholinergic neurons suppresses sharp wave ripples and enhances theta oscillations in the hippocampus. Proc. Natl Acad. Sci. USA 111, 13535–13540 (2014).

    CAS  PubMed  Google Scholar 

  48. 48.

    Gangadharan, G. et al. Medial septal GABAergic projection neurons promote object exploration behavior and type 2 theta rhythm. Proc. Natl Acad. Sci. USA 113, 6550–6555 (2016).

    CAS  PubMed  Google Scholar 

  49. 49.

    Kim, T. et al. Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. Proc. Natl Acad. Sci. USA 112, 3535–3540 (2015).

    CAS  PubMed  Google Scholar 

  50. 50.

    Schaefer, A. T., Angelo, K., Spors, H. & Margrie, T. W. Neuronal oscillations enhance stimulus discrimination by ensuring action potential precision. PLoS Biol. 4, e163 (2006).

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Singer, W. Synchronization of cortical activity and its putative role in information processing and learning. Annu. Rev. Physiol. 55, 349–374 (1993).

    CAS  PubMed  Google Scholar 

  52. 52.

    Uhlhaas, P. J. & Singer, W. Neuronal dynamics and neuropsychiatric disorders: toward a translational paradigm for dysfunctional large-scale networks. Neuron 75, 963–980 (2012).

    CAS  PubMed  Google Scholar 

  53. 53.

    Linkenkaer-Hansen, K. Breakdown of long-range temporal correlations in theta oscillations in patients with major depressive disorder. J. Neurosci. 25, 10131–10137 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Guitart-Masip, M. et al. Synchronization of medial temporal lobe and prefrontal rhythms in human decision making. J. Neurosci. 33, 442–451 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Tamura, M., Spellman, T. J., Rosen, A. M., Gogos, J. A. & Gordon, J. A. Hippocampal-prefrontal theta-gamma coupling during performance of a spatial working memory task. Nat. Commun. 8, 2182 (2017).

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Köhler, C., Chan-Palay, V. & Wu, J. Y. Septal neurons containing glutamic acid decarboxylase immunoreactivity project to the hippocampal region in the rat brain. Anat. Embryol. 169, 41–44 (1984).

    PubMed  Google Scholar 

  57. 57.

    Lewis, P. R. & Shute, C. C. D. The cholinergic limbic system: projections to hippocampal formation, medial cortex, nuclei of the ascending cholinergic reticular system, and the subfornical organ and supra-optic crest. Brain 90, 521–540 (1967).

    CAS  PubMed  Google Scholar 

  58. 58.

    Winson, J. Loss of hippocampal theta rhythm results in spatial memory deficit in the rat. Science 201, 160–163 (1978).

    CAS  PubMed  Google Scholar 

  59. 59.

    Hagan, J. J., Salamone, J. D., Simpson, J., Iversen, S. D. & Morris, R. G. Place navigation in rats is impaired by lesions of medial septum and diagonal band but not nucleus basalis magnocellularis. Behav. Brain Res. 27, 9–20 (1988).

    CAS  PubMed  Google Scholar 

  60. 60.

    Chrobak, J. J., Stackman, R. W. & Walsh, T. J. Intraseptal administration of muscimol produces dose-dependent memory impairments in the rat. Behav. Neural Biol. 52, 357–369 (1989).

    CAS  PubMed  Google Scholar 

  61. 61.

    Colom, L. V. & Bland, B. H. Medial septal cell interactions in relation to hippocampal field activity and the effects of atropine. Hippocampus 1, 15–30 (1991).

    CAS  PubMed  Google Scholar 

  62. 62.

    Givens, B. S. & Olton, D. S. Cholinergic and GABAergic modulation of medial septal area: effect on working memory. Behav. Neurosci. 104, 849–855 (1990).

    CAS  PubMed  Google Scholar 

  63. 63.

    Givens, B. & Olton, D. S. Local modulation of basal forebrain: effects on working and reference memory. J. Neurosci. 14, 3578–3587 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64.

    McNaughton, N., Ruan, M. & Woodnorth, M.-A. Restoring theta-like rhythmicity in rats restores initial learning in the Morris water maze. Hippocampus 16, 1102–1110 (2006).

    PubMed  Google Scholar 

  65. 65.

    Mitchell, S. J., Rawlins, J. N., Steward, O. & Olton, D. S. Medial septal area lesions disrupt theta rhythm and cholinergic staining in medial entorhinal cortex and produce impaired radial arm maze behavior in rats. J. Neurosci. 2, 292–302 (1982).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Dwyer, T. A., Servatius, R. J. & Pang, K. C. H. Noncholinergic lesions of the medial septum impair sequential learning of different spatial locations. J. Neurosci. 27, 299–303 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Pang, K. C. H., Jiao, X., Sinha, S., Beck, K. D. & Servatius, R. J. Damage of GABAergic neurons in the medial septum impairs spatial working memory and extinction of active avoidance: effects on proactive interference. Hippocampus 21, 835–846 (2011).

    CAS  PubMed  Google Scholar 

  68. 68.

    Koenig, J., Linder, A. N., Leutgeb, J. K. & Leutgeb, S. The spatial periodicity of grid cells is not sustained during reduced theta oscillations. Science 332, 592–595 (2011).

    CAS  PubMed  Google Scholar 

  69. 69.

    Brandon, M. P., Koenig, J., Leutgeb, J. K. & Leutgeb, S. New and distinct hippocampal place codes are generated in a new environment during septal inactivation. Neuron 82, 789–796 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Brandon, M. P. et al. Reduction of theta rhythm dissociates grid cell spatial periodicity from directional tuning. Science 332, 595–599 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Toth, K., Freund, T. F. & Miles, R. Disinhibition of rat hippocampal pyramidal cells by GABAergic afferents from the septum. J. Physiol. 500, 463–474 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Germroth, P., Schwerdtfeger, W. K. & Buhl, E. H. Morphology of identified entorhinal neurons projecting to the hippocampus. A light microscopical study combining retrograde tracing and intracellular injection. Neuroscience 30, 683–691 (1989).

    CAS  PubMed  Google Scholar 

  73. 73.

    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  Google Scholar 

  74. 74.

    Kaifosh, P., Lovett-Barron, M., Turi, G. F., Reardon, T. R. & Losonczy, A. Septo-hippocampal GABAergic signaling across multiple modalities in awake mice. Nat. Neurosci. 16, 1182–1184 (2013). These authors investigated the Ca 2+ dynamics in boutons of GABAergic septo–hippocampal projections and reported a high degree of overlap between locomotion-induced and sensory input-induced activity patterns as well as homogeneity between boutons from a common axon targeting an interneuron.

    CAS  PubMed  Google Scholar 

  75. 75.

    Sainsbury, R. S., Harris, J. L. & Rowland, G. L. Sensitization and hippocampal type 2 theta in the rat. Physiol. Behav. 41, 489–493 (1987).

    CAS  PubMed  Google Scholar 

  76. 76.

    Basu, J. et al. Gating of hippocampal activity, plasticity, and memory by entorhinal cortex long-range inhibition. Science 351, aaa5694 (2016). This study characterizes GABAergic projections from the LEC to the hippocampus that, via disinhibition, induce facilitation of glutamatergic inputs to the hippocampus, thereby supporting context and object recognition memory.

    PubMed  PubMed Central  Google Scholar 

  77. 77.

    Hargreaves, E. L., Rao, G., Lee, I. & Knierim, J. J. Major dissociation between medial and lateral entorhinal input to dorsal hippocampus. Science 308, 1792–1794 (2005).

    CAS  PubMed  Google Scholar 

  78. 78.

    Deshmukh, S. S., Johnson, J. L. & Knierim, J. J. Perirhinal cortex represents nonspatial, but not spatial, information in rats foraging in the presence of objects: comparison with lateral entorhinal cortex. Hippocampus 22, 2045–2058 (2012).

    PubMed  Google Scholar 

  79. 79.

    Hafting, T., Fyhn, M., Bonnevie, T., Moser, M.-B. & Moser, E. I. Hippocampus-independent phase precession in entorhinal grid cells. Nature 453, 1248–1252 (2008).

    CAS  PubMed  Google Scholar 

  80. 80.

    Jeffery, K. J., Donnett, J. G. & O’Keefe, J. Medial septal control of theta-correlated unit firing in the entorhinal cortex of awake rats. Neuroreport 6, 2166–2170 (1995).

    CAS  PubMed  Google Scholar 

  81. 81.

    Ye, J., Witter, M. P., Moser, M.-B. & Moser, E. I. Entorhinal fast-spiking speed cells project to the hippocampus. Proc. Natl Acad. Sci. USA 115, E1627–E1636 (2018).

    CAS  PubMed  Google Scholar 

  82. 82.

    Li, J.-Y., Kuo, T. B. J., Hsieh, I.-T. & Yang, C. C. H. Changes in hippocampal theta rhythm and their correlations with speed during different phases of voluntary wheel running in rats. Neuroscience 213, 54–61 (2012).

    CAS  PubMed  Google Scholar 

  83. 83.

    McFarland, W. L., Teitelbaum, H. & Hedges, E. K. Relationship between hippocampal theta activity and running speed in the rat. J. Comp. Physiol. Psychol. 88, 324–328 (1975).

    CAS  PubMed  Google Scholar 

  84. 84.

    Sławińska, U. & Kasicki, S. The frequency of rat’s hippocampal theta rhythm is related to the speed of locomotion. Brain Res. 796, 327–331 (1998).

    PubMed  Google Scholar 

  85. 85.

    Barnes, C. A. et al. LTP saturation and spatial learning disruption: effects of task variables and saturation levels. J. Neurosci. 14, 5793–5806 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Jinno, S. Structural organization of long-range GABAergic projection system of the hippocampus. Front. Neuroanat. 3, 13 (2009).

    PubMed  PubMed Central  Google Scholar 

  87. 87.

    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). In this study, the authors identified defined VIP + hippocampal GABAergic projecting neurons that are distinct from VIP + neurons with local axons and that exhibit increased Ca 2+ dynamics during immobility.

    PubMed  PubMed Central  Google Scholar 

  88. 88.

    Yamawaki, N. et al. Long-range inhibitory intersection of a retrosplenial thalamocortical circuit by apical tuft-targeting CA1 neurons. Nat. Neurosci. 22, 618–626 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Fries, P. Rhythms for cognition: communication through coherence. Neuron 88, 220–235 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Fries, P., Reynolds, J. H., Rorie, A. E. & Desimone, R. Modulation of oscillatory neuronal synchronization by selective visual attention. Science 291, 1560–1563 (2001).

    CAS  PubMed  Google Scholar 

  91. 91.

    Womelsdorf, T., Fries, P., Mitra, P. P. & Desimone, R. Gamma-band synchronization in visual cortex predicts speed of change detection. Nature 439, 733–736 (2006).

    CAS  PubMed  Google Scholar 

  92. 92.

    Siegle, J. H., Pritchett, D. L. & Moore, C. I. Gamma-range synchronization of fast-spiking interneurons can enhance detection of tactile stimuli. Nat. Neurosci. 17, 1371–1379 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Schoffelen, J.-M., Oostenveld, R. & Fries, P. Neuronal coherence as a mechanism of effective corticospinal interaction. Science 308, 111–113 (2005).

    CAS  PubMed  Google Scholar 

  94. 94.

    Gregoriou, G. G., Gotts, S. J., Zhou, H. & Desimone, R. High-frequency, long-range coupling between prefrontal and visual cortex during attention. Science 324, 1207–1210 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Tan, L. L. et al. Gamma oscillations in somatosensory cortex recruit prefrontal and descending serotonergic pathways in aversion and nociception. Nat. Commun. 10, 983 (2019).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Köster, M., Finger, H., Graetz, S., Kater, M. & Gruber, T. Theta-gamma coupling binds visual perceptual features in an associative memory task. Sci. Rep. 8, 17688 (2018).

    PubMed  PubMed Central  Google Scholar 

  97. 97.

    Honkanen, R., Rouhinen, S., Wang, S. H., Palva, J. M. & Palva, S. Gamma oscillations underlie the maintenance of feature-specific information and the contents of visual working memory. Cereb. Cortex 25, 3788–3801 (2015).

    PubMed  Google Scholar 

  98. 98.

    Veit, J., Hakim, R., Jadi, M. P., Sejnowski, T. J. & Adesnik, H. Cortical gamma band synchronization through somatostatin interneurons. Nat. Neurosci. 20, 951–959 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Kuki, T. et al. Contribution of parvalbumin and somatostatin-expressing GABAergic neurons to slow oscillations and the balance in beta-gamma oscillations across cortical layers. Front. Neural Circuits 9, 6 (2015).

    PubMed  PubMed Central  Google Scholar 

  100. 100.

    Chen, G. et al. Distinct inhibitory circuits orchestrate cortical beta and gamma band oscillations. Neuron 96, 1403–1418 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101.

    Christenson Wick, Z., Tetzlaff, M. R. & Krook-Magnuson, E. Novel long-range inhibitory nNOS-expressing hippocampal cells. eLife 8, e46816 (2019). The authors characterized hippocampal nNOS + GABAergic projecting neurons with extensive axon arborization to several distant brain areas and proposed a role in facilitating the coherence of oscillations in local and distant circuits.

    PubMed  PubMed Central  Google Scholar 

  102. 102.

    Szőnyi, A. et al. Brainstem nucleus incertus controls contextual memory formation. Science 364, eaaw0445 (2019).

    PubMed  PubMed Central  Google Scholar 

  103. 103.

    Saunders, A. et al. A direct GABAergic output from the basal ganglia to frontal cortex. Nature 521, 85–89 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104.

    Bertero, A., Feyen, P. L. C., Zurita, H. & Apicella, A. J. A non-canonical cortico-amygdala inhibitory loop. J. Neurosci. 39, 8424–8438 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Hashimotodani, Y., Karube, F., Yanagawa, Y., Fujiyama, F. & Kano, M. Supramammillary nucleus afferents to the dentate gyrus co-release glutamate and GABA and potentiate granule cell output. Cell Rep. 25, 2704–2715 (2018).

    CAS  PubMed  Google Scholar 

  106. 106.

    Le Magueresse, C. & Monyer, H. GABAergic interneurons shape the functional maturation of the cortex. Neuron 77, 388–405 (2013).

    PubMed  Google Scholar 

  107. 107.

    Ben-Ari, Y. The GABA excitatory/inhibitory developmental sequence: a personal journey. Neuroscience 279, 187–219 (2014).

    CAS  PubMed  Google Scholar 

  108. 108.

    Picardo, M. A. et al. Pioneer GABA cells comprise a subpopulation of hub neurons in the developing hippocampus. Neuron 71, 695–709 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109.

    Mohajerani, M. H. & Cherubini, E. Role of giant depolarizing potentials in shaping synaptic currents in the developing hippocampus. Crit. Rev. Neurobiol. 18, 13–23 (2006).

    CAS  PubMed  Google Scholar 

  110. 110.

    Kasyanov, A. M., Safiulina, V. F., Voronin, L. L. & Cherubini, E. GABA-mediated giant depolarizing potentials as coincidence detectors for enhancing synaptic efficacy in the developing hippocampus. Proc. Natl Acad. Sci. USA 101, 3967–3972 (2004).

    CAS  PubMed  Google Scholar 

  111. 111.

    Lin, C. S., Nicolelis, M. A., Schneider, J. S. & Chapin, J. K. A major direct GABAergic pathway from zona incerta to neocortex. Science 248, 1553–1556 (1990).

    CAS  PubMed  Google Scholar 

  112. 112.

    Nicolelis, M. A. L., Chapin, J. K. & Lin, R. C. S. Development of direct GABAergic projections from the zona incerta to the somatosensory cortex of the rat. Neuroscience 65, 609–631 (1995).

    CAS  PubMed  Google Scholar 

  113. 113.

    Chen, J. & Kriegstein, A. R. A GABAergic projection from the zona incerta to cortex promotes cortical neuron development. Science 350, 554–558 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Owens, D. F., Boyce, L. H., Davis, M. B. E. & Kriegstein, A. R. Excitatory GABA responses in embryonic and neonatal cortical slices demonstrated by gramicidin perforated-patch recordings and calcium imaging. J. Neurosci. 16, 6414–6423 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Cherubini, E., Gaiarsa, J. L. & Ben-Ari, Y. GABA: an excitatory transmitter in early postnatal life. Trends Neurosci. 14, 515–519 (1991).

    CAS  PubMed  Google Scholar 

  116. 116.

    Dammerman, R. S., Flint, A. C., Noctor, S. & Kriegstein, A. R. An excitatory GABAergic plexus in developing neocortical layer 1. J. Neurophysiol. 84, 428–434 (2000).

    CAS  PubMed  Google Scholar 

  117. 117.

    Boon, J. et al. Long-range projections from sparse populations of GABAergic neurons in murine subplate. J. Comp. Neurol. 527, 1610–1620 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Gascon, E. et al. GABA regulates dendritic growth by stabilizing lamellipodia in newly generated interneurons of the olfactory bulb. J. Neurosci. 26, 12956–12966 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. 119.

    Pallotto, M. et al. Early formation of GABAergic synapses governs the development of adult-born neurons in the olfactory bulb. J. Neurosci. 32, 9103–9115 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Song, J. et al. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus. Nat. Neurosci. 16, 1728–1730 (2013). In this study, the authors revealed the importance of septo–hippocampal GABAergic projections in regulating neurogenesis in the adult hippocampus through GABA-mediated tonic currents in PV + cells in the DG.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Burnstock, G. Do some nerve cells release more than one transmitter? Neuroscience 1, 239–248 (1976).

    CAS  Google Scholar 

  122. 122.

    Tritsch, N. X., Granger, A. J. & Sabatini, B. L. Mechanisms and functions of GABA co‑release. Nat. Rev. Neurosci. 17, 139–145 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123.

    Tomioka, R. et al. Demonstration of long-range GABAergic connections distributed throughout the mouse neocortex. Eur. J. Neurosci. 21, 1587–1600 (2005).

    PubMed  Google Scholar 

  124. 124.

    Saunders, A., Granger, A. J. & Sabatini, B. L. Corelease of acetylcholine and GABA from cholinergic forebrain neurons. eLife 4, e06412 (2015).

    PubMed Central  Google Scholar 

  125. 125.

    Gu, Z. & Yakel, J. L. Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity. Neuron 71, 155–165 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126.

    Chotard, C. et al. Effects of histamine H3 receptor agonist and antagonist on histamine co-transmitter expression in rat brain. J. Neural Transm. 109, 293–306 (2002).

    CAS  PubMed  Google Scholar 

  127. 127.

    Kukko-Lukjanov, T. K. & Panula, P. Subcellular distribution of histamine, GABA and galanin in tuberomamillary neurons in vitro. J. Chem. Neuroanat. 25, 279–292 (2003).

    CAS  PubMed  Google Scholar 

  128. 128.

    Smith, C. M. et al. Distribution of relaxin-3 and RXFP3 within arousal, stress, affective, and cognitive circuits of mouse brain. J. Comp. Neurol. 518, 4016–4045 (2010).

    CAS  PubMed  Google Scholar 

  129. 129.

    Ma, S. et al. Relaxin-3 in GABA projection neurons of nucleus incertus suggests widespread influence on forebrain circuits via G-protein-coupled receptor-135 in the rat. Neuroscience 144, 165–190 (2007).

    CAS  PubMed  Google Scholar 

  130. 130.

    Haidar, M. et al. Relaxin-3 inputs target hippocampal interneurons and deletion of hilar relaxin-3 receptors in floxed-RXFP3 mice impairs spatial memory. Hippocampus 27, 529–546 (2017).

    CAS  PubMed  Google Scholar 

  131. 131.

    van den Pol, A. N. Neuropeptide transmission in brain circuits. Neuron 76, 98–115 (2012).

    PubMed  PubMed Central  Google Scholar 

  132. 132.

    Joo, H. R. & Frank, L. M. The hippocampal sharp wave-ripple in memory retrieval for immediate use and consolidation. Nat. Rev. Neurosci. 19, 744–757 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. 133.

    Yavorska, I. & Wehr, M. Somatostatin-expressing inhibitory interneurons in cortical circuits. Front. Neural Circuits 10, 76 (2016).

    PubMed  PubMed Central  Google Scholar 

  134. 134.

    Shabel, S. J., Proulx, C. D., Piriz, J. & Malinow, R. Mood regulation. GABA/glutamate co-release controls habenula output and is modified by antidepressant treatment. Science 345, 1494–1498 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. 135.

    Mamad, O., McNamara, H. M., Reilly, R. B. & Tsanov, M. Medial septum regulates the hippocampal spatial representation. Front. Behav. Neurosci. 9, 166 (2015).

    PubMed  PubMed Central  Google Scholar 

  136. 136.

    Otchy, T. M. et al. Acute off-target effects of neural circuit manipulations. Nature 528, 358–363 (2015).

    CAS  PubMed  Google Scholar 

  137. 137.

    Tervo, D. G. R. et al. A designer AAV variant permits efficient retrograde access to projection neurons. Neuron 92, 372–382 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. 138.

    Sun, Y. et al. Cell-type-specific circuit connectivity of hippocampal CA1 revealed through cre-dependent rabies tracing. Cell Rep. 7, 269–280 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. 139.

    Do, J. P. et al. Cell type-specific long-range connections of basal forebrain circuit. eLife 5, e13214 (2016).

    PubMed  PubMed Central  Google Scholar 

  140. 140.

    Ascoli, G. A. et al. Petilla terminology: Nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9, 557–568 (2008).

    CAS  PubMed  Google Scholar 

  141. 141.

    Murata, K. et al. GABAergic neurons in the olfactory cortex projecting to the lateral hypothalamus in mice. Sci. Rep. 9, 7132 (2019).

    PubMed  PubMed Central  Google Scholar 

  142. 142.

    Chen, M. C. et al. Identification of a direct GABAergic pallidocortical pathway in rodents. Eur. J. Neurosci. 41, 748–759 (2015).

    PubMed  PubMed Central  Google Scholar 

  143. 143.

    McDonald, A. J. & Zaric, V. GABAergic somatostatin-immunoreactive neurons in the amygdala project to the entorhinal cortex. Neuroscience 290, 227–242 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Seo, D. O. et al. A GABAergic projection from the centromedial nuclei of the amygdala to ventromedial prefrontal cortex modulates reward behavior. J. Neurosci. 36, 10831–10842 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145.

    Bang, S. J. & Commons, K. G. Forebrain GABAergic projections from the dorsal raphe nucleus identified by using GAD67-GFP knock-in mice. J. Comp. Neurol. 520, 4157–4167 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146.

    Bakst, I., Avendano, C., Morrison, J. H. & Amaral, D. G. An experimental analysis of the origins of somatostatin-like immunoreactivity in the dentate gyrus of the rat. J. Neurosci. 6, 1452–1462 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147.

    Léránth, C. & Frotscher, M. Cholinergic innervation of hippocampal GAD- and somatostatin-immunoreactive commissural neurons. J. Comp. Neurol. 261, 33–47 (1987).

    PubMed  Google Scholar 

  148. 148.

    Deller, T. & Leranth, C. Synaptic connections of neuropeptide Y (NPY) immunoreactive neurons in the hilar area of the rat hippocampus. J. Comp. Neurol. 300, 433–447 (1990).

    CAS  PubMed  Google Scholar 

  149. 149.

    Zappone, C. A. & Sloviter, R. S. Commissurally projecting inhibitory interneurons of the rat hippocampal dentate gyrus: a colocalization study of neuronal markers and the retrograde tracer Fluoro-Gold. J. Comp. Neurol. 441, 324–344 (2001).

    CAS  PubMed  Google Scholar 

  150. 150.

    Acsády, L., Pascual, M., Rocamora, N., Soriano, E. & Freund, T. F. Nerve growth factor but not neurotrophin-3 is synthesized by hippocampal GABAergic neurons that project to the medial septum. Neuroscience 98, 23–31 (2000).

    PubMed  Google Scholar 

  151. 151.

    Jinno, S. & Kosaka, T. Colocalization of parvalbumin and somatostatin-like immunoreactivity in the mouse hippocampus: quantitative analysis with optical disector. J. Comp. Neurol. 428, 377–388 (2000).

    CAS  PubMed  Google Scholar 

  152. 152.

    Jinno, S. & Kosaka, T. Immunocytochemical characterization of hippocamposeptal projecting GABAergic nonprincipal neurons in the mouse brain: a retrograde labeling study. Brain Res. 945, 219–231 (2002).

    CAS  PubMed  Google Scholar 

  153. 153.

    Gulyás, A. I., Hájos, N., Katona, I. & Freund, T. F. Interneurons are the local targets of hippocampal inhibitory cells which project to the medial septum. Eur. J. Neurosci. 17, 1861–1872 (2003).

    PubMed  Google Scholar 

  154. 154.

    Handelmann, G. E., Beinfeld, M. C., O’Donohue, T. L., Nelson, J. B. & Brenneman, D. E. Extra-hippocampal projections of CCK neurons of the hippocampus and subiculum. Peptides 4, 331–334 (1983).

    CAS  PubMed  Google Scholar 

  155. 155.

    Lübkemann, R. et al. Identification and characterization of GABAergic projection neurons from ventral hippocampus to amygdala. Brain Sci. 5, 299–317 (2015).

    PubMed  PubMed Central  Google Scholar 

  156. 156.

    Higo, S., Udaka, N. & Tamamaki, N. Long-range GABAergic projection neurons in the cat neocortex. J. Comp. Neurol. 503, 421–431 (2007).

    PubMed  Google Scholar 

  157. 157.

    Tomioka, R. & Rockland, K. S. Long-distance corticocortical GABAergic neurons in the adult monkey white and gray matter. J. Comp. Neurol. 505, 526–538 (2007).

    PubMed  Google Scholar 

  158. 158.

    Köhler, C., Smialowska, M., Eriksson, L. G., Chanpalay, V. & Davies, S. Origin of the neuropeptide Y innervation of the rat retrohippocampal region. Neurosci. Lett. 65, 287–292 (1986).

    PubMed  Google Scholar 

  159. 159.

    Haglund, L., Swanson, L. W. & Köhler, C. The projection of the supramammillary nucleus to the hippocampal formation: an immunohistochemical and anterograde transport study with the lectin PHA-L in the rat. J. Comp. Neurol. 229, 171–185 (1984).

    CAS  PubMed  Google Scholar 

  160. 160.

    Pedersen, N. P. et al. Supramammillary glutamate neurons are a key node of the arousal system. Nat. Commun. 8, 1405 (2017).

    PubMed  PubMed Central  Google Scholar 

Download references

Author information




The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Hannah Monyer.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

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

Supplementary information



The release of inhibition from a neuron by the inhibition of inhibitory neurons; usually leads to increased excitability of the disinhibited neuron.


This refers here to currents that are relatively long lasting and emerge through the opening of extrasynaptic receptors.

Theta oscillations

Oscillations of extracellularly recorded currents in the hippocampus at frequencies between 5 and 12 Hz; this rhythmic activity is most prominent during exploratory behaviour.

Grid cells

Neurons in the medial entorhinal cortex that are spatially tuned and whose hexagonal firing pattern accounts for the naming of this cell type; they support spatial memory and navigation.

Sharp wave–ripples

(SWRs). SWRs are extracellularly recorded, high frequency (150–250 Hz) synaptic currents that emerge through the highly synchronous firing of neurons in the hippocampus during immobility and slow wave sleep.

Phase coupling

Temporal alignment of the phases of two oscillators such that the first oscillator coincides with a fixed phase of the second oscillator.

Long-term potentiation

(LTP). Long-term potentiation is a form of plasticity reflecting long-lasting increases in synaptic strength.

Progenitor cells

Descendants from stem cells that have the ability to divide and differentiate but with a more limited differentiation potential than stem cells.

Stem cell quiescence

The state of a stem cell in which it does not divide but can be re-activated by external cues.

Long-term depression

Long-term depression is a form of plasticity reflecting long-lasting decreases in synaptic strength.

Schaffer collateral

An excitatory pathway from the CA3 area to the CA1 area of the hippocampus that undergoes plasticity and is thought to underlie certain forms of memory formation in the hippocampus.


A designed variant of recombinant adeno-associated viruses that allows the virus to be efficiently retrogradely transported from the axon terminal to the neuronal cell body.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Melzer, S., Monyer, H. Diversity and function of corticopetal and corticofugal GABAergic projection neurons. Nat Rev Neurosci 21, 499–515 (2020).

Download citation

Further reading


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