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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
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).
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).
Chronister, R. B. & DeFrance, J. F. Organization of projection neurons of the hippocampus. Exp. Neurol. 66, 509–523 (1979).
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.
Caputi, A., Melzer, S., Michael, M. & Monyer, H. The long and short of GABAergic neurons. Curr. Opin. Neurobiol. 23, 179–186 (2013).
Jinno, S. & Kosaka, T. Parvalbumin is expressed in glutamatergic and GABAergic corticostriatal pathway in mice. J. Comp. Neurol. 477, 188–201 (2004).
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).
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).
Tuncdemir, S. N. et al. Early somatostatin interneuron connectivity mediates the maturation of deep layer cortical circuits. Neuron 89, 521–535 (2016).
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).
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).
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.
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).
Freund, T. F. GABAergic septohippocampal neurons contain parvalbumin. Brain Res. 478, 375–381 (1989).
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).
Fuchs, E. C. et al. Local and distant input controlling excitation in layer II of the medial entorhinal cortex. Neuron 89, 194–208 (2016).
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).
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.
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).
Viney, T. J. et al. Shared rhythmic subcortical GABAergic input to the entorhinal cortex and presubiculum. eLife 7, 34395 (2018).
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.
Tamamaki, N. & Tomioka, R. Long-range GABAergic connections distributed throughout the neocortex and their possible function. Front. Neurosci. 4, 202 (2010).
Tomioka, R., Sakimura, K. & Yanagawa, Y. Corticofugal GABAergic projection neurons in the mouse frontal cortex. Front. Neuroanat. 9, 133 (2015).
Rock, C., Zurita, H., Wilson, C. & Apicella, A. Jr. An inhibitory corticostriatal pathway. eLife 5, e15890 (2016).
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.
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.
Rock, C., Zurita, H., Lebby, S., Wilson, C. J. & Apicella, A. J. Cortical circuits of callosal GABAergic neurons. Cereb. Cortex 28, 1154–1167 (2018).
McDonald, A. J. & Zaric, V. Extrinsic origins of the somatostatin and neuropeptide Y innervation of the rat basolateral amygdala. Neuroscience 294, 82–100 (2015).
Saffari, R. et al. NPY+-, but not PV+- GABAergic neurons mediated long-range inhibition from infra- to prelimbic cortex. Transl. Psychiatry 6, e736 (2016).
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.
Muñoz, W., Tremblay, R., Levenstein, D. & Rudy, B. Layer-specific modulation of neocortical dendritic inhibition during active wakefulness. Science 355, 954–959 (2017).
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).
Chen, K.-S. et al. A hypothalamic switch for REM and non-REM sleep. Neuron 97, 1168–1176 (2018).
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).
Stewart, M. & Fox, S. E. Do septal neurons pace the hippocampal theta rhythm? Trends Neurosci. 13, 163–169 (1990).
Mann, E. O. & Paulsen, O. Role of GABAergic inhibition in hippocampal network oscillations. Trends Neurosci. 30, 343–349 (2007).
Buzsáki, G. & Chrobak, J. J. Temporal structure in spatially organized neuronal ensembles: a role for interneuronal networks. Curr. Opin. Neurobiol. 5, 504–510 (1995).
Bonifazi, P. et al. GABAergic hub neurons orchestrate synchrony in developing hippocampal networks. Science 326, 1419–1424 (2009).
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).
Jinno, S. et al. Neuronal diversity in GABAergic long-range projections from the hippocampus. J. Neurosci. 27, 8790–8804 (2007).
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).
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).
Paul, A. et al. Transcriptional architecture of synaptic communication delineates GABAergic neuron identity. Cell 171, 522–539 (2017).
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).
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.
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).
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).
Kim, T. et al. Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. Proc. Natl Acad. Sci. USA 112, 3535–3540 (2015).
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).
Singer, W. Synchronization of cortical activity and its putative role in information processing and learning. Annu. Rev. Physiol. 55, 349–374 (1993).
Uhlhaas, P. J. & Singer, W. Neuronal dynamics and neuropsychiatric disorders: toward a translational paradigm for dysfunctional large-scale networks. Neuron 75, 963–980 (2012).
Linkenkaer-Hansen, K. Breakdown of long-range temporal correlations in theta oscillations in patients with major depressive disorder. J. Neurosci. 25, 10131–10137 (2005).
Guitart-Masip, M. et al. Synchronization of medial temporal lobe and prefrontal rhythms in human decision making. J. Neurosci. 33, 442–451 (2013).
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).
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).
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).
Winson, J. Loss of hippocampal theta rhythm results in spatial memory deficit in the rat. Science 201, 160–163 (1978).
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).
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).
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).
Givens, B. S. & Olton, D. S. Cholinergic and GABAergic modulation of medial septal area: effect on working memory. Behav. Neurosci. 104, 849–855 (1990).
Givens, B. & Olton, D. S. Local modulation of basal forebrain: effects on working and reference memory. J. Neurosci. 14, 3578–3587 (1994).
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).
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).
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).
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).
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).
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).
Brandon, M. P. et al. Reduction of theta rhythm dissociates grid cell spatial periodicity from directional tuning. Science 332, 595–599 (2011).
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).
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).
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).
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.
Sainsbury, R. S., Harris, J. L. & Rowland, G. L. Sensitization and hippocampal type 2 theta in the rat. Physiol. Behav. 41, 489–493 (1987).
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.
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).
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).
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).
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).
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).
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).
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).
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).
Barnes, C. A. et al. LTP saturation and spatial learning disruption: effects of task variables and saturation levels. J. Neurosci. 14, 5793–5806 (1994).
Jinno, S. Structural organization of long-range GABAergic projection system of the hippocampus. Front. Neuroanat. 3, 13 (2009).
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.
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).
Fries, P. Rhythms for cognition: communication through coherence. Neuron 88, 220–235 (2015).
Fries, P., Reynolds, J. H., Rorie, A. E. & Desimone, R. Modulation of oscillatory neuronal synchronization by selective visual attention. Science 291, 1560–1563 (2001).
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).
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).
Schoffelen, J.-M., Oostenveld, R. & Fries, P. Neuronal coherence as a mechanism of effective corticospinal interaction. Science 308, 111–113 (2005).
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).
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).
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).
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).
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).
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).
Chen, G. et al. Distinct inhibitory circuits orchestrate cortical beta and gamma band oscillations. Neuron 96, 1403–1418 (2017).
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.
Szőnyi, A. et al. Brainstem nucleus incertus controls contextual memory formation. Science 364, eaaw0445 (2019).
Saunders, A. et al. A direct GABAergic output from the basal ganglia to frontal cortex. Nature 521, 85–89 (2015).
Bertero, A., Feyen, P. L. C., Zurita, H. & Apicella, A. J. A non-canonical cortico-amygdala inhibitory loop. J. Neurosci. 39, 8424–8438 (2019).
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).
Le Magueresse, C. & Monyer, H. GABAergic interneurons shape the functional maturation of the cortex. Neuron 77, 388–405 (2013).
Ben-Ari, Y. The GABA excitatory/inhibitory developmental sequence: a personal journey. Neuroscience 279, 187–219 (2014).
Picardo, M. A. et al. Pioneer GABA cells comprise a subpopulation of hub neurons in the developing hippocampus. Neuron 71, 695–709 (2011).
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).
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).
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).
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).
Chen, J. & Kriegstein, A. R. A GABAergic projection from the zona incerta to cortex promotes cortical neuron development. Science 350, 554–558 (2015).
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).
Cherubini, E., Gaiarsa, J. L. & Ben-Ari, Y. GABA: an excitatory transmitter in early postnatal life. Trends Neurosci. 14, 515–519 (1991).
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).
Boon, J. et al. Long-range projections from sparse populations of GABAergic neurons in murine subplate. J. Comp. Neurol. 527, 1610–1620 (2019).
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).
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).
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.
Burnstock, G. Do some nerve cells release more than one transmitter? Neuroscience 1, 239–248 (1976).
Tritsch, N. X., Granger, A. J. & Sabatini, B. L. Mechanisms and functions of GABA co‑release. Nat. Rev. Neurosci. 17, 139–145 (2016).
Tomioka, R. et al. Demonstration of long-range GABAergic connections distributed throughout the mouse neocortex. Eur. J. Neurosci. 21, 1587–1600 (2005).
Saunders, A., Granger, A. J. & Sabatini, B. L. Corelease of acetylcholine and GABA from cholinergic forebrain neurons. eLife 4, e06412 (2015).
Gu, Z. & Yakel, J. L. Timing-dependent septal cholinergic induction of dynamic hippocampal synaptic plasticity. Neuron 71, 155–165 (2011).
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).
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).
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).
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).
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).
van den Pol, A. N. Neuropeptide transmission in brain circuits. Neuron 76, 98–115 (2012).
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).
Yavorska, I. & Wehr, M. Somatostatin-expressing inhibitory interneurons in cortical circuits. Front. Neural Circuits 10, 76 (2016).
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).
Mamad, O., McNamara, H. M., Reilly, R. B. & Tsanov, M. Medial septum regulates the hippocampal spatial representation. Front. Behav. Neurosci. 9, 166 (2015).
Otchy, T. M. et al. Acute off-target effects of neural circuit manipulations. Nature 528, 358–363 (2015).
Tervo, D. G. R. et al. A designer AAV variant permits efficient retrograde access to projection neurons. Neuron 92, 372–382 (2016).
Sun, Y. et al. Cell-type-specific circuit connectivity of hippocampal CA1 revealed through cre-dependent rabies tracing. Cell Rep. 7, 269–280 (2014).
Do, J. P. et al. Cell type-specific long-range connections of basal forebrain circuit. eLife 5, e13214 (2016).
Ascoli, G. A. et al. Petilla terminology: Nomenclature of features of GABAergic interneurons of the cerebral cortex. Nat. Rev. Neurosci. 9, 557–568 (2008).
Murata, K. et al. GABAergic neurons in the olfactory cortex projecting to the lateral hypothalamus in mice. Sci. Rep. 9, 7132 (2019).
Chen, M. C. et al. Identification of a direct GABAergic pallidocortical pathway in rodents. Eur. J. Neurosci. 41, 748–759 (2015).
McDonald, A. J. & Zaric, V. GABAergic somatostatin-immunoreactive neurons in the amygdala project to the entorhinal cortex. Neuroscience 290, 227–242 (2015).
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).
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).
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).
Léránth, C. & Frotscher, M. Cholinergic innervation of hippocampal GAD- and somatostatin-immunoreactive commissural neurons. J. Comp. Neurol. 261, 33–47 (1987).
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).
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).
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).
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).
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).
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).
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).
Lübkemann, R. et al. Identification and characterization of GABAergic projection neurons from ventral hippocampus to amygdala. Brain Sci. 5, 299–317 (2015).
Higo, S., Udaka, N. & Tamamaki, N. Long-range GABAergic projection neurons in the cat neocortex. J. Comp. Neurol. 503, 421–431 (2007).
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).
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).
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).
Pedersen, N. P. et al. Supramammillary glutamate neurons are a key node of the arousal system. Nat. Commun. 8, 1405 (2017).
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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.
About this article
Cite this article
Melzer, S., Monyer, H. Diversity and function of corticopetal and corticofugal GABAergic projection neurons. Nat Rev Neurosci 21, 499–515 (2020). https://doi.org/10.1038/s41583-020-0344-9
Frontiers in Neuroanatomy (2021)
Current Opinion in Neurobiology (2021)