Key Points
-
Neurogliaform cells are a novel subtype of hippocampal and cortical local-circuit GABAergic inhibitory interneuron that primarily reside within the superficial layers of the cortex and hippocampal formations.
-
This comparatively small cell type has both dendrites and axons that remain relatively local to the cell body forming a dense plexus that is highly interconnected with other neurogliaform cells through both chemical and electrical synapses.
-
Anatomical and electrophysiological studies indicate that the axons of these cells have an unusually high presynaptic bouton density and are spatially located at larger than usual distances from their postsynaptic targets. This arrangement suggests that they communicate via a hybrid form of inhibitory synaptic transmission intermediate between phasic and tonic forms of inhibition that lacks target cell specificity
-
NGF cells contain numerous neuroactive petides and compounds such as neuropeptide Y, reelin neuronal nitric oxide synthase and insulin that may all serve important functional roles in regulating the neuronal circuits in which they are embedded.
-
Local circuit GABAergic interneurons have numerous roles in regulating neuronal oscillatory activity. The low-frequency firing of neurogliaform (NGF) cells provide temporally slow GABAergic inputs onto specific pyramidal cell domains suggesting that they contribute to theta rhythms as well as theta-frequency modulation of gamma oscillations
-
The early appearance of NGF cells in the developing cortex makes NGF cells attractive candidates for providing trophic GABA signalling cues to both developing and adult-born glutamatergic principal cells.
Abstract
Recent research into local-circuit GABAergic inhibitory interneurons of the mammalian central nervous system has provided unprecedented insight into the mechanics of neuronal circuitry and its dysfunction. Inhibitory interneurons consist of a broad array of anatomically and neurochemically diverse cell types, and this suggests that each occupies an equally diverse functional role. Although neurogliaform cells were observed by Cajal over a century ago, our understanding of the functional role of this class of interneurons is in its infancy. However, it is rapidly becoming clear that this cell type operates under a distinct repertoire of rules to provide novel forms of inhibitory control of numerous afferent pathways.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Klausberger, T. & Somogyi, P. Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science 321, 53–57 (2008).
McBain, C. J. & Fisahn, A. Interneurons unbound. Nat. Rev. Neurosci. 2, 11–23 (2001).
Bezaire, M. J. & Soltesz, I. Quantitative assessment of CA1 local circuits: knowledge base for interneuron–pyramidal cell connectivity. Hippocampus 23, 751–785 (2013). A comprehensive review providing quantification of interneuron cell types and their connectivity within cortical circuits.
Roux, L. & Buzsaki, G. Tasks for inhibitory interneurons in intact brain circuits. Neuropharmacology 88, 10–23 (2014).
Hu, H., Gan, J. & Jonas, P. Interneurons. Fast-spiking, parvalbumin+ GABAergic interneurons: from cellular design to microcircuit function. Science 345, 1255263 (2014).
Ramón y Cajal, S. Histology of the Nervous System of Man and Vertebrates (Oxford University Press, 1995).
Lacaille, J. C. & Schwartzkroin, P. A. Stratum lacunosum-moleculare interneurons of hippocampal CA1 region. II. Intrasomatic and intradendritic recordings of local circuit synaptic interactions. J. Neurosci. 8, 1411–1424 (1988). An image in this paper may be the first of a filled NGF cell recorded in the CA1 stratum lacunosum moleculare.
Price, C. J. et al. Neurogliaform neurons form a novel inhibitory network in the hippocampal CA1 area. J. Neurosci. 25, 6775–6786 (2005).
Khazipov, R., Congar, P. & Ben-Ari, Y. Hippocampal CA1 lacunosum-moleculare interneurons: modulation of monosynaptic GABAergic IPSCs by presynaptic GABAB receptors. J. Neurophysiol. 74, 2126–2137 (1995).
Vida, I., Halasy, K., Szinyei, C., Somogyi, P. & Buhl, E. H. Unitary IPSPs evoked by interneurons at the stratum radiatum–stratum lacunosum-moleculare border in the CA1 area of the rat hippocampus in vitro. J. Physiol. 506, 755–773 (1998).
Miyoshi, G. et al. Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons. J. Neurosci. 30, 1582–1594 (2010).
Fuentealba, P. et al. Ivy cells: a population of nitric-oxide-producing, slow-spiking GABAergic neurons and their involvement in hippocampal network activity. Neuron 57, 917–929 (2008).
Tricoire, L. et al. Common origins of hippocampal ivy and nitric oxide synthase expressing neurogliaform cells. J. Neurosci. 30, 2165–2176 (2010). This study shows that unlike cortical NGF cells which originate within the caudal ganglionic eminence, hippocampal NGF have their origins in both the medial and caudal ganglionic eminences.
Tricoire, L. et al. A blueprint for the spatiotemporal origins of mouse hippocampal interneuron diversity. J. Neurosci. 31, 10948–10970 (2011).
Somogyi, J., Szabo, A., Somogyi, P. & Lamsa, K. Molecular analysis of ivy cells of the hippocampal CA1 stratum radiatum using spectral identification of immunofluorophores. Front. Neural Circuits 6, 35 (2012).
Jiang, X., Wang, G., Lee, A. J., Stornetta, R. L. & Zhu, J. J. The organization of two new cortical interneuronal circuits. Nat. Neurosci. 16, 210–218 (2013).
Munoz-Manchado, A. B. et al. Novel striatal GABAergic interneuron populations labeled in the 5HT3aEGFP mouse. Cereb. Cortex http://dx.doi.org/10.1093/cercor/bhu179 (2014).
Armstrong, C., Szabadics, J., Tamas, G. & Soltesz, I. Neurogliaform cells in the molecular layer of the dentate gyrus as feed-forward gamma-aminobutyric acidergic modulators of entorhinal–hippocampal interplay. J. Comp. Neurol. 519, 1476–1491 (2011).
Armstrong, C., Krook-Magnuson, E. & Soltesz, I. Neurogliaform and ivy cells: a major family of nNOS expressing GABAergic neurons. Front. Neural Circuits 6, 23 (2012).
Fuentealba, P. et al. Expression of COUP-TFII nuclear receptor in restricted GABAergic neuronal populations in the adult rat hippocampus. J. Neurosci. 30, 1595–1609 (2010).
Sik, A., Penttonen, M., Ylinen, A. & Buzsaki, G. Hippocampal CA1 interneurons: an in vivo intracellular labeling study. J. Neurosci. 15, 6651–6665 (1995).
De Marco Garcia, N. V., Karayannis, T. & Fishell, G. Neuronal activity is required for the development of specific cortical interneuron subtypes. Nature 472, 351–355 (2011).
De Marco Garcia, N. V., Priya, R., Tuncdemir, S. N., Fishell, G. & Karayannis, T. Sensory inputs control the integration of neurogliaform interneurons into cortical circuits. Nat. Neurosci. 18, 393–401 (2015).
Olah, S. et al. Regulation of cortical microcircuits by unitary GABA-mediated volume transmission. Nature 461, 1278–1281 (2009). This study provides anatomical and physiological evidence that NGF cells release GABA into the extracellular space to provide a mode of inhibition that lacks spatial selectivity.
Quattrocolo, G. & Maccaferri, G. Novel GABAergic circuits mediating excitation/inhibition of Cajal-Retzius cells in the developing hippocampus. J. Neurosci. 33, 5486–5498 (2013).
Capogna, M. & Pearce, R. A. GABAA,slow: causes and consequences. Trends Neurosci. 34, 101–112 (2011).
Kawaguchi, Y. Physiological subgroups of nonpyramidal cells with specific morphological characteristics in layer II/III of rat frontal cortex. J. Neurosci. 15, 2638–2655 (1995).
Chikwendu, A. & McBain, C. J. Two temporally overlapping “delayed-rectifiers” determine the voltage-dependent potassium current phenotype in cultured hippocampal interneurons. J. Neurophysiol. 76, 1477–1490 (1996).
Zhang, L. & McBain, C. J. Potassium conductances underlying repolarization and after-hyperpolarization in rat CA1 hippocampal interneurones. J. Physiol. 488, 661–672 (1995).
Zhang, L. & McBain, C. J. Voltage-gated potassium currents in stratum oriens-alveus inhibitory neurones of the rat CA1 hippocampus. J. Physiol. 488, 647–660 (1995).
Morin, F., Haufler, D., Skinner, F. K. & Lacaille, J. C. Characterization of voltage-gated K+ currents contributing to subthreshold membrane potential oscillations in hippocampal CA1 interneurons. J. Neurophysiol. 103, 3472–3489 (2010).
Atzori, M. et al. H2 histamine receptor-phosphorylation of Kv3.2 modulates interneuron fast spiking. Nat. Neurosci. 3, 791–798 (2000).
Weiser, M. et al. Differential expression of Shaw-related K+ channels in the rat central nervous system. J. Neurosci. 14, 949–972 (1994).
Sheffield, M. E., Best, T. K., Mensh, B. D., Kath, W. L. & Spruston, N. Slow integration leads to persistent action potential firing in distal axons of coupled interneurons. Nat. Neurosci. 14, 200–207 (2011).
Sheffield, M. E. et al. Mechanisms of retroaxonal barrage firing in hippocampal interneurons. J. Physiol. 591, 4793–4805 (2013).
Krook-Magnuson, E., Luu, L., Lee, S. H., Varga, C. & Soltesz, I. Ivy and neurogliaform interneurons are a major target of μ-opioid receptor modulation. J. Neurosci. 31, 14861–14870 (2011).
Suzuki, N., Tang, C. S. & Bekkers, J. M. Persistent barrage firing in cortical interneurons can be induced in vivo and may be important for the suppression of epileptiform activity. Front. Cell Neurosci. 8, 76 (2014).
Takacs, V. T., Klausberger, T., Somogyi, P., Freund, T. F. & Gulyas, A. I. Extrinsic and local glutamatergic inputs of the rat hippocampal CA1 area differentially innervate pyramidal cells and interneurons. Hippocampus 22, 1379–1391 (2012).
Matta, J. A. et al. Developmental origin dictates interneuron AMPA and NMDA receptor subunit composition and plasticity. Nat. Neurosci. 16, 1032–1041 (2013).
Quattrocolo, G. & Maccaferri, G. Optogenetic activation of Cajal-Retzius cells reveals their glutamatergic output and a novel feedforward circuit in the developing mouse hippocampus. J. Neurosci. 34, 13018–13032 (2014). This study shows a novel monosynaptic connection between reelin-positive Cajal–Retzius cells and NGF cells within the CA1 hippocampus.
Williams, S., Samulack, D. D., Beaulieu, C. & LaCaille, J. C. Membrane properties and synaptic responses of interneurons located near the stratum lacunosum-moleculare/radiatum border of area CA1 in whole-cell recordings from rat hippocampal slices. J. Neurophysiol. 71, 2217–2235 (1994).
Olah, S. et al. Output of neurogliaform cells to various neuron types in the human and rat cerebral cortex. Front. Neural Circuits 1, 4 (2007).
Karayannis, T. et al. Slow GABA transient and receptor desensitization shape synaptic responses evoked by hippocampal neurogliaform cells. J. Neurosci. 30, 9898–9909 (2010). This study quantifies the low and prolonged GABA concentration profile produced by NGF cells in the hippocampus.
Overstreet, L. S., Jones, M. V. & Westbrook, G. L. Slow desensitization regulates the availability of synaptic GABAA receptors. J. Neurosci. 20, 7914–7921 (2000).
Tamas, G., Lorincz, A., Simon, A. & Szabadics, J. Identified sources and targets of slow inhibition in the neocortex. Science 299, 1902–1905 (2003).
Szabadics, J., Tamas, G. & Soltesz, I. Different transmitter transients underlie presynaptic cell type specificity of GABAA,slow and GABAA,fast . Proc. Natl Acad. Sci. USA 104, 14831–14836 (2007). This study shows that slow IPSCs generated by NGF cells in the cortex have characteristics of spillover-mediated transmission.
Markwardt, S. J., Dieni, C. V., Wadiche, J. I. & Overstreet-Wadiche, L. Ivy/neurogliaform interneurons coordinate activity in the neurogenic niche. Nat. Neurosci. 14, 1407–1409 (2011). This study shows that newly generated adult-born neurons respond to GABA released by single NGF cells.
Isaacson, J. S., Solis, J. M. & Nicoll, R. A. Local and diffuse synaptic actions of GABA in the hippocampus. Neuron 10, 165–175 (1993).
Scanziani, M. GABA spillover activates postsynaptic GABAB receptors to control rhythmic hippocampal activity. Neuron 25, 673–681 (2000).
Price, C. J., Scott, R., Rusakov, D. A. & Capogna, M. GABAB receptor modulation of feedforward inhibition through hippocampal neurogliaform cells. J. Neurosci. 28, 6974–6982 (2008).
Chittajallu, R., Pelkey, K. A. & McBain, C. J. Neurogliaform cells dynamically regulate somatosensory integration via synapse-specific modulation. Nat. Neurosci. 16, 13–15 (2013). This study provides the exception to the rule that all NGF cells lack specificity in their innervation of postsynaptic targets.
Cauli, B. et al. Cortical GABA interneurons in neurovascular coupling: relays for subcortical vasoactive pathways. J. Neurosci. 24, 8940–8949 (2004).
Li, G., Stewart, R., Canepari, M. & Capogna, M. Firing of hippocampal neurogliaform cells induces suppression of synaptic inhibition. J. Neurosci. 34, 1280–1292 (2014).
Molnar, G. et al. GABAergic neurogliaform cells represent local sources of insulin in the cerebral cortex. J. Neurosci. 34, 1133–1137 (2014).
Jarsky, T., Roxin, A., Kath, W. L. & Spruston, N. Conditional dendritic spike propagation following distal synaptic activation of hippocampal CA1 pyramidal neurons. Nat. Neurosci. 8, 1667–1676 (2005).
Colbert, C. M. & Levy, W. B. Electrophysiological and pharmacological characterization of perforant path synapses in CA1: mediation by glutamate receptors. J. Neurophysiol. 68, 1–8 (1992).
Rudy, B., Fishell, G., Lee, S. & Hjerling-Leffler, J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev. Neurobiol. 71, 45–61 (2011).
Lee, S., Hjerling-Leffler, J., Zagha, E., Fishell, G. & Rudy, B. The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. J. Neurosci. 30, 16796–16808 (2010).
Varga, V. et al. Fast synaptic subcortical control of hippocampal circuits. Science 326, 449–453 (2009).
Wozny, C. & Williams, S. R. Specificity of synaptic connectivity between layer 1 inhibitory interneurons and layer 2/3 pyramidal neurons in the rat neocortex. Cereb. Cortex 21, 1818–1826 (2011).
Brombas, A., Fletcher, L. N. & Williams, S. R. Activity-dependent modulation of layer 1 inhibitory neocortical circuits by acetylcholine. J. Neurosci. 34, 1932–1941 (2014).
Simon, A., Olah, S., Molnar, G., Szabadics, J. & Tamas, G. Gap-junctional coupling between neurogliaform cells and various interneuron types in the neocortex. J. Neurosci. 25, 6278–6285 (2005).
Zsiros, V. & Maccaferri, G. Electrical coupling between interneurons with different excitable properties in the stratum lacunosum-moleculare of the juvenile CA1 rat hippocampus. J. Neurosci. 25, 8686–8695 (2005).
Zsiros, V., Aradi, I. & Maccaferri, G. Propagation of postsynaptic currents and potentials via gap junctions in GABAergic networks of the rat hippocampus. J. Physiol. 578, 527–544 (2007).
Banks, M. I., White, J. A. & Pearce, R. A. Interactions between distinct GABAA circuits in hippocampus. Neuron 25, 449–457 (2000).
White, J. A., Banks, M. I., Pearce, R. A. & Kopell, N. J. Networks of interneurons with fast and slow γ-aminobutyric acid type A (GABAA) kinetics provide substrate for mixed gamma–theta rhythm. Proc. Natl Acad. Sci. USA 97, 8128–8133 (2000).
Bartos, M., Vida, I. & Jonas, P. Synaptic mechanisms of synchronized gamma oscillations in inhibitory interneuron networks. Nat. Rev. Neurosci. 8, 45–56 (2007).
Pernia-Andrade, A. J. & Jonas, P. Theta–gamma-modulated synaptic currents in hippocampal granule cells in vivo define a mechanism for network oscillations. Neuron 81, 140–152 (2014).
Wulff, P. et al. Hippocampal theta rhythm and its coupling with gamma oscillations require fast inhibition onto parvalbumin-positive interneurons. Proc. Natl Acad. Sci. USA 106, 3561–3566 (2009).
Cutsuridis, V. & Hasselmo, M. GABAergic contributions to gating, timing, and phase precession of hippocampal neuronal activity during theta oscillations. Hippocampus 22, 1597–1621 (2012).
Lapray, D. et al. Behavior-dependent specialization of identified hippocampal interneurons. Nat. Neurosci. 15, 1265–1271 (2012).
Ewell, L. A. & Jones, M. V. Frequency-tuned distribution of inhibition in the dentate gyrus. J. Neurosci. 30, 12597–12607 (2010).
Sambandan, S., Sauer, J. F., Vida, I. & Bartos, M. Associative plasticity at excitatory synapses facilitates recruitment of fast-spiking interneurons in the dentate gyrus. J. Neurosci. 30, 11826–11837 (2010).
Ben-Ari, Y., Gaiarsa, J. L., Tyzio, R. & Khazipov, R. GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol. Rev. 87, 1215–1284 (2007).
Dieni, C. V., Chancey, J. H. & Overstreet-Wadiche, L. S. Dynamic functions of GABA signaling during granule cell maturation. Front. Neural Circuits 6, 113 (2012).
Ge, S. et al. GABA regulates synaptic integration of newly generated neurons in the adult brain. Nature 439, 589–593 (2006).
Jagasia, R. et al. GABA–cAMP response element-binding protein signaling regulates maturation and survival of newly generated neurons in the adult hippocampus. J. Neurosci. 29, 7966–7977 (2009).
Esposito, M. S. et al. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J. Neurosci. 25, 10074–10086 (2005).
Overstreet Wadiche, L., Bromberg, D. A., Bensen, A. L. & Westbrook, G. L. GABAergic signaling to newborn neurons in dentate gyrus. J. Neurophysiol. 94, 4528–4532 (2005).
Markwardt, S. J., Wadiche, J. I. & Overstreet-Wadiche, L. S. Input-specific GABAergic signaling to newborn neurons in adult dentate gyrus. J. Neurosci. 29, 15063–15072 (2009). This study shows that GABA A receptor-mediated synaptic signaling to adult-born neurons has characteristics of spillover-mediated transmission.
Gaiarsa, J. L. & Porcher, C. Emerging neurotrophic role of GABAB receptors in neuronal circuit development. Front. Cell Neurosci. 7, 206 (2013).
Overstreet, L. S. & Westbrook, G. L. Synapse density regulates independence at unitary inhibitory synapses. J. Neurosci. 23, 2618–2626 (2003).
Song, J. et al. Parvalbumin interneurons mediate neuronal circuitry–neurogenesis coupling in the adult hippocampus. Nat. Neurosci. 16, 1728–1730 (2013).
Chancey, J. H. et al. GABA depolarization is required for experience-dependent synapse unsilencing in adult-born neurons. J. Neurosci. 33, 6614–6622 (2013). This study shows that slow synaptic GABA signalling to adult born neurons provides depolarization needed for AMPA-receptor incorporation at silent synapses.
Chancey, J. H., Poulsen, D. J., Wadiche, J. I. & Overstreet-Wadiche, L. Hilar mossy cells provide the first glutamatergic synapses to adult-born dentate granule cells. J. Neurosci. 34, 2349–2354 (2014).
Wonders, C. P. & Anderson, S. A. The origin and specification of cortical interneurons. Nat. Rev. Neurosci. 7, 687–696 (2006).
Batista-Brito, R. & Fishell, G. The developmental integration of cortical interneurons into a functional network. Curr. Top. Dev. Biol. 87, 81–118 (2009).
Gelman, D. M. & Marin, O. Generation of interneuron diversity in the mouse cerebral cortex. Eur. J. Neurosci. 31, 2136–2141 (2010).
Chittajallu, R. et al. Dual origins of functionally distinct O-LM interneurons revealed by differential 5-HT3AR expression. Nat. Neurosci. 16, 1598–1607 (2013).
Kepecs, A. & Fishell, G. Interneuron cell types are fit to function. Nature 505, 318–326 (2014).
Tricoire, L. & Vitalis, T. Neuronal nitric oxide synthase expressing neurons: a journey from birth to neuronal circuits. Front. Neural Circuits 6, 82 (2012).
Rancillac, A. et al. Glutamatergic control of microvascular tone by distinct GABA neurons in the cerebellum. J. Neurosci. 26, 6997–7006 (2006).
Craig, M. T. & McBain, C. J. Navigating the circuitry of the brain's GPS system: future challenges for neurophysiologists. Hippocampus http://dx.doi.org/10.1002/hipo.22456 (2015).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Glossary
- Subfield
-
Divisions within the hippocampus largely based on anatomical or cellular properties.
- Stratum radiatum
-
A region of the hippocampus representing the primary termination zone of the Schaffer collateral axons of CA3 pyramidal cells.
- Stratum lacunosum moleculare
-
A region of the hippocampus that primary receives inputs from the entorhinal cortex and thalamus as well as other subcortical afferents.
- Arborization
-
The tree-like termination pattern of a neuronal axon.
- Slow integration
-
The processing of excitatory (or inhibitory) inputs onto a cell across a time domain of seconds to minutes.
- Temporoammonic pathway
-
An afferent projection primarily arising from pyramidal cells of the layer III entorhinal cortex and terminating in the CA1, CA2 and subiculum of the hippocampus.
Rights and permissions
About this article
Cite this article
Overstreet-Wadiche, L., McBain, C. Neurogliaform cells in cortical circuits. Nat Rev Neurosci 16, 458–468 (2015). https://doi.org/10.1038/nrn3969
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrn3969
This article is cited by
-
Afferent convergence to a shared population of interneuron AMPA receptors
Nature Communications (2023)
-
MUW researcher of the month
Wiener klinische Wochenschrift (2023)
-
Diverse Roles of Serotonergic Projections to the Basolateral Amygdala
Neuroscience Bulletin (2023)
-
Neurobiology of ARID1B haploinsufficiency related to neurodevelopmental and psychiatric disorders
Molecular Psychiatry (2022)
-
Sleep down state-active ID2/Nkx2.1 interneurons in the neocortex
Nature Neuroscience (2021)