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Interneurons of the neocortical inhibitory system

Key Points

  • The cortical microcircuit seems to be a stereotyped unit that has been replicated and adapted to serve specific computational functions in different regions of the neocortex. An important element of this microcircuit is the wide variety of interneurons, most of which are inhibitory. Interneurons share several common features, but also show considerable diversity.

  • Morphologically, interneurons can be divided into several groups: basket cells (large, small or nest basket cells); chandelier cells; Martinotti cells; bipolar cells; double bouquet cells; bitufted cells; neurogliaform cells; and layer I interneurons. However, the morphology of an interneuron does not define it; within a given morphological type, interneurons can show widely varying electrical or molecular properties.

  • Interneurons can also be divided according to their steady-state or initial responses to stimuli. The main divisions are accommodating, non-accommodating, stuttering, irregular spiking and bursting, and each of these types is subdivided into three classes depending on the characteristics of the initial firing pattern (delayed, bursting or classical). These response types are useful markers, regardless of whether they define discrete classes (as opposed to a continuum).

  • This electrical diversity arises from active properties (ion-channel combinations) and passive properties (the morphology of the neuron). The ion-channel genes that are expressed by an interneuron correlate with its electrophysiological properties. Ion-channel expression seems to fall into three clusters, which map around the three calcium-binding proteins (parvalbumin, calbindin and calretinin) that are expressed in separate populations of interneuron.

  • Other markers that can be used to define interneurons include neuropeptides. Although no one neuropeptide defines a specific interneuron type, some interneuron types tend to express specific combinations of neuropeptides.

  • Excitatory synapses formed by pyramidal neurons onto inhibitory interneurons differ from those formed onto excitatory neurons in terms of receptor subtypes and facilitation. In return, interneurons make inhibitory synapses onto pyramidal neurons that are targeted to specific cellular domains (the dendrites, cell body or axon). Interneurons also receive inhibitory synapses from other interneurons. However, such connections seem to be sparse.

  • The diversity of interneurons might be required to achieve a balance between inhibition and excitation in the neocortex. It is not yet clear whether this diversity represents a continuum or distinct classes of interneuron, although anatomical classes seem to be clear. Gene-expression studies should help to clarify this issue.

Abstract

Mammals adapt to a rapidly changing world because of the sophisticated cognitive functions that are supported by the neocortex. The neocortex, which forms almost 80% of the human brain, seems to have arisen from repeated duplication of a stereotypical microcircuit template with subtle specializations for different brain regions and species. The quest to unravel the blueprint of this template started more than a century ago and has revealed an immensely intricate design. The largest obstacle is the daunting variety of inhibitory interneurons that are found in the circuit. This review focuses on the organizing principles that govern the diversity of inhibitory interneurons and their circuits.

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Figure 1: Anatomical diversity of neocortical neurons.
Figure 2: Different types of interneuron in the layers of somatosensory cortex of juvenile rats.
Figure 3: Expression of calcium-binding proteins (CBPs) and neuropeptides in interneurons.
Figure 4: Contact numbers of interneurons onto and from pyramidal cells.
Figure 5: Different electrophysiological classes of inhibitory interneurons.
Figure 6: Anatomical–electrophysiological diversity of neocortical inhibitory neurons.
Figure 7: Correlation map relating the different ion-channel genes with specific electrical parameters.
Figure 8: Mapping of synaptic dynamics.

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References

  1. DeFelipe, J. & Farinas, I. The pyramidal neuron of the cerebral cortex: morphological and chemical characteristics of the synaptic inputs. Prog. Neurobiol. 39, 563–607 (1992).

    Article  CAS  PubMed  Google Scholar 

  2. Jones, E. G. in Cellular Components of the Cerebral Cortex (eds Peters, A. & Jones, E. G.) 521–554 (Plenum, New York, 1984).

    Book  Google Scholar 

  3. White, E. L. Cortical Circuits. Synaptic Organization of the Cerebral Cortex (Birkhauser, Boston, 1989).

    Google Scholar 

  4. Ren, J. Q., Aika, Y., Heizmann, C. W. & Kosaka, T. Quantitative analysis of neurons and glial cells in the rat somatosensory cortex, with special reference to GABAergic neurons and parvalbumin-containing neurons. Exp. Brain Res. 92, 1–14 (1992). Careful estimates of neuron and synapse numbers.

    Article  CAS  PubMed  Google Scholar 

  5. Beaulieu, C. Numerical data on neocortical neurons in adult rat, with special reference to the GABA population. Brain Res. 609, 284–292 (1993).

    Article  CAS  PubMed  Google Scholar 

  6. Peters, A. & Jones, E. G. (eds) Cellular Components of the Cerebral Cortex (Plenum, New York, 1984).

    Google Scholar 

  7. Peters, A. & Sethares, C. Organization of pyramidal neurons in area 17 of monkey visual cortex. J. Comp. Neurol. 306, 1–23 (1991).

    Article  CAS  PubMed  Google Scholar 

  8. Toledo-Rodriguez, M., Gupta, A., Wang, Y., Wu, C. Z. & Markram, H. in The Handbook of Brain Theory and Neural Networks. (ed. Arbib, M. A.) 719–725 (MIT Press, Cambridge, Massachusetts., 2003).

    Google Scholar 

  9. Cauli, B. et al. Molecular and physiological diversity of cortical non pyramidal cells. J. Neurosci. 17, 3894–3906 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. DeFelipe, J. Neocortical neuronal diversity: chemical heterogeneity revealed by co-localization studies of classic neurotransmitters, neuropeptides, calcium-binding proteins, and cell surface molecules. Cereb. Cortex 3, 273–289 (1993). A key review that reveals different chemical subpopulations of neocortical neurons.

    Article  CAS  PubMed  Google Scholar 

  11. Kawaguchi, Y. & Kubota, Y. GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb. Cortex 7, 476–486 (1997). A multi-dimensional study that emphasizes characteristic physiological, morphological and immunohistochemical features of some non-pyramidal cells, also in combination with synaptic innervation properties. It also shows that vasoactive intestinal peptide, parvalbumin and somatostatin are expressed by distinct subpopulations of interneurons.

    Article  CAS  PubMed  Google Scholar 

  12. DeFelipe, J. Cortical interneurons: from Cajal to 2001. Prog. Brain Res. 136, 215–238 (2002). An excellent review on the history of discovery of different cortical neurons.

    Article  PubMed  Google Scholar 

  13. Houser, C. R., Vaughn, J. E., Hendry, S. H., Jones, E. G. & Peters, A. in Cerebral Cortex: Functional Properties of Cortical Cells (eds Jones, E. G. & Peters, A.) 63–90 (Plenum, New York, 1984).

    Book  Google Scholar 

  14. Somogyi, P., Tamas, G., Lujan, R. & Buhl, E. H. Salient features of synaptic organisation in the cerebral cortex. Brain Res. Brain Res. Rev. 26, 113–135 (1998).

    Article  CAS  PubMed  Google Scholar 

  15. Gupta, A., Wang, Y. & Markram, H. Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. Science 287, 273–278 (2000). The first study to report three distinct types of GABA synapse and several principles that determine which type of synapse is deployed by different anatomical and electrophysiological types of interneuron when inhibitory connections are formed.

    Article  CAS  PubMed  Google Scholar 

  16. Thomson, A. M. & Deuchars, J. Temporal and spatial properties of local circuits in neocortex. Trends Neurosci. 17, 119–126 (1994).

    Article  CAS  PubMed  Google Scholar 

  17. Douglas, R. & Martin, K. A. in The Synaptic Organization of the Brain 459–511 (Oxford Univ. Press, New York, 1998).

    Google Scholar 

  18. Peters, A. in Synaptic Functions (eds Edelman, G. M., Gall, W. E. & Cowan, W. M.) 373–397 (Wiley, New York, 1987).

    Google Scholar 

  19. Fairen, A., DeFelipe, J. & Regidor, J. in Cellular Components of the Cerebral Cortex (eds Peters, A. & Jones, E. G.) 206–241 (Plenum, New York, 1984).

    Google Scholar 

  20. Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. DeFelipe, J. Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbindin-D28K, parvalbumin and calretinin in the neocortex. J. Chem. Neuroanat. 14, 1–19 (1997).

    Article  CAS  PubMed  Google Scholar 

  22. Lund, J. S. Organization of neurons in the visual cortex, area 17, of the monkey (Macaca mulatta). J. Comp. Neurol. 147, 455–496 (1973).

    Article  CAS  PubMed  Google Scholar 

  23. LeVay, S. Synaptic patterns in the visual cortex of the cat and monkey. Electron microscopy of Golgi preparations. J. Comp. Neurol. 150, 53–85 (1973).

    Article  CAS  PubMed  Google Scholar 

  24. Feldmeyer, D., Lubke, J., Silver, R. A. & Sakmann, B. Synaptic connections between layer 4 spiny neuron-layer 2/3 pyramidal cell pairs in juvenile rat barrel cortex: physiology and anatomy of interlaminar signalling within a cortical column. J. Physiol. (Lond.) 538, 803–822 (2002). The first study to reveal a unidirectional pathway from spiny stellate cells in layer IV to layer II/III pyramidal neurons.

    Article  CAS  Google Scholar 

  25. Thomson, A. M. Activity-dependent properties of synaptic transmission at two classes of connections made by rat neocortical pyramidal axons in vitro. J. Physiol. (Lond.) 502, 131–147 (1997).

    Article  CAS  Google Scholar 

  26. Thomson, A. M., West, D. C., Wang, Y. & Bannister, A. P. Synaptic connections and small circuits involving excitatory and inhibitory neurons in layers 2–5 of adult rat and cat neocortex: triple intracellular recordings and biocytin labelling in vitro. Cereb. Cortex 12, 936–953 (2002).

    Article  PubMed  Google Scholar 

  27. Lund, J. S. in Cellular Components of the Cerebral Cortex (eds Peters, A. & Jones, E. G.) 255–308 (Plenum, New York, 1984).

    Google Scholar 

  28. Cajal, S. R. Histology Due Systeme Nerveux de Homme et des Vertebrates (Maloine, Paris, 1909).

    Google Scholar 

  29. Callaway, E. M. Local circuits in primary visual cortex of the macaque monkey. Annu. Rev. Neurosci. 21, 47–74 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Jones, E. G. Varieties and distribution of non-pyramidal cells in the somatic sensory cortex of the squirrel monkey. J. Comp. Neurol. 160, 205–267 (1975).

    Article  CAS  PubMed  Google Scholar 

  31. Gilbert, C. D. Circuitry, architecture, and functional dynamics of visual cortex. Cereb. Cortex 3, 373–386 (1993).

    Article  CAS  PubMed  Google Scholar 

  32. Keller, A. Intrinsic synaptic organization of the motor cortex. Cereb. Cortex 3, 430–441 (1993).

    Article  CAS  PubMed  Google Scholar 

  33. Lund, J. S. Anatomical organization of macaque monkey striate visual cortex. Annu. Rev. Neurosci. 11, 253–288 (1988).

    Article  CAS  PubMed  Google Scholar 

  34. Valverde, F. Intrinsic neocortical organization: some comparative aspects. Neuroscience 18, 1–23 (1986).

    Article  CAS  PubMed  Google Scholar 

  35. Feldman, M. L. & Peters, A. The forms of non-pyramidal neurons in the visual cortex of the rat. J. Comp. Neurol. 179, 761–793 (1978).

    Article  CAS  PubMed  Google Scholar 

  36. Martin, K. A. & Whitteridge, D. Form, function and intracortical projections of spiny neurons in the striate visual cortex of the cat. J. Physiol. (Lond.) 353, 463–504 (1984).

    Article  CAS  Google Scholar 

  37. Peters, A. & Fairen, A. Smooth and sparsely-spined stellate cells in the visual cortex of the rat: a study using a combined Golgi-electron microscopic technique. J. Comp. Neurol. 181, 129–171 (1978).

    Article  CAS  PubMed  Google Scholar 

  38. Wang, Y., Gupta, A., Toledo-Rodriguez, M., Wu, C. Z. & Markram, H. Anatomical, physiological, molecular and circuit properties of nest basket cells in the developing somatosensory cortex. Cereb. Cortex 12, 395–410 (2002). The first study to define the nest basket cell as a distinct subclass of basket cell.

    Article  PubMed  Google Scholar 

  39. Somogyi, P. in Neuronal Mechanisms of Visual Perception, Proc. Retina Res. Found. Symp. 2 (eds Lamm, D. K. & Gilbert, C. D.) 35–62 (Portfolio, Woodlands, Texas, 1989).

    Google Scholar 

  40. Marin-Padilla, M. Origin of the pericellular baskets of the pyramidal cells of the human motor cortex: a Golgi study. Brain Res. 14, 633–646 (1969).

    Article  CAS  PubMed  Google Scholar 

  41. Kisvarday, Z. F. & Eysel, U. T. Cellular organization of reciprocal patchy networks in layer III of cat visual cortex (area 17). Neuroscience 46, 275–286 (1992).

    Article  CAS  PubMed  Google Scholar 

  42. Szentagothai, J. in Central Processing of Visual Information, B. Visual Centers in the Brain (ed. Jung, R.) 269–324 (Springer, Berlin, 1973).

    Google Scholar 

  43. Kisvarday, Z. F., Martin, K. A., Whitteridge, D. & Somogyi, P. Synaptic connections of intracellularly filled clutch cells: a type of small basket cell in the visual cortex of the cat. J. Comp. Neurol. 241, 111–137 (1985).

    Article  CAS  PubMed  Google Scholar 

  44. DeFelipe, J. & Fairen, A. A type of basket cell in superficial layers of the cat visual cortex. A Golgi-electron microscope study. Brain Res. 244, 9–16 (1982).

    Article  CAS  PubMed  Google Scholar 

  45. Peters, A. & Jones, E. G. in Cellular Components of the Cerebral Cortex (eds Peters, A. & Jones, E. G.) 107–122 (Plenum, New York, 1984).

    Google Scholar 

  46. Lund, J. S. & Lewis, D. A. Local circuit neurons of developing and mature macaque prefrontal cortex: Golgi and immunocytochemical characteristics. J. Comp. Neurol. 328, 282–312 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. Somogyi, P. A specific 'axo-axonal' interneuron in the visual cortex of the rat. Brain Res. 136, 345–350 (1977). This paper describes the seminal discovery of the axon-targeting interneurons.

    Article  CAS  PubMed  Google Scholar 

  48. Fairen, A. & Valverde, F. A specialized type of neuron in the visual cortex of cat: a Golgi and electron microscope study of chandelier cells. J. Comp. Neurol. 194, 761–779 (1980).

    Article  CAS  PubMed  Google Scholar 

  49. Buhl, E. H., Halasy, K. & Somogyi, P. Diverse sources of hippocampal unitary inhibitory postsynaptic potentials and the number of synaptic release sites. Nature 368, 823–828 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Miles, R., Toth, K., Gulyas, A. I., Hajos, N. & Freund, T. F. Differences between somatic and dendritic inhibition in the hippocampus. Neuron 16, 815–823 (1996). Important differences in the functional impact of somatic- and dendritic-targeting interneurons were revealed by this study.

    Article  CAS  PubMed  Google Scholar 

  51. Zhu, Y., Stornetta, R. L. & Zhu, J. J. Chandelier cells control excessive cortical excitation: characteristics of whisker-evoked synaptic responses of layer 2/3 nonpyramidal and pyramidal neurons. J. Neurosci. 24, 5101–5108 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Somogyi, P., Freund, T. F. & Cowey, A. The axo-axonic interneuron in the cerebral cortex of the rat, cat and monkey. Neuroscience 7, 2577–2607 (1982).

    Article  CAS  PubMed  Google Scholar 

  53. DeFelipe, J. Chandelier cells and epilepsy. Brain 122, 1807–1822 (1999).

    Article  PubMed  Google Scholar 

  54. DeFelipe, J., Hendry, S. H. & Jones, E. G. Visualization of chandelier cell axons by parvalbumin immunoreactivity in monkey cerebral cortex. Proc. Natl Acad. Sci. USA 86, 2093–2097 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  Google Scholar 

  56. Wang, Y. et al. Anatomical, physiological and molecular properties of Martinotti cells in the somatosensory cortex of the juvenile rat. J. Physiol. (Lond.) 26 Aug 2004 [epub ahead of print].

  57. Braitenberg, V. & Schüz, A. Cortex: Statistics and Geometry of Neural Connectivity (Springer, Heidelberg, 1998).

    Book  Google Scholar 

  58. Peters, A. in Cellular Components of the Cerebral Cortex (eds Peters, A. & Jones, E. G.) 381–408 (Plenum, New York, 1984).

    Google Scholar 

  59. Peters, A. & Harriman, K. M. Enigmatic bipolar cell of rat visual cortex. J. Comp. Neurol. 267, 409–432 (1988).

    Article  CAS  PubMed  Google Scholar 

  60. Peters, A. The axon terminals of vasoactive intestinal polypeptide (VIP)-containing bipolar cells in rat visual cortex. J. Neurocytol. 19, 672–685 (1990).

    Article  CAS  PubMed  Google Scholar 

  61. Somogyi, P. & Cowey, A. Combined Golgi and electron microscopic study on the synapses formed by double bouquet cells in the visual cortex of the cat and monkey. J. Comp. Neurol. 195, 547–166 (1981).

    Article  CAS  PubMed  Google Scholar 

  62. Somogyi, P. & Cowey, A. in Cellular Components of the Cerebral Cortex (eds Peters, A. & Jones, E. G.) 337–360 (Plenum, New York, 1984).

    Google Scholar 

  63. DeFelipe, J., Hendry, S. H., Hashikawa, T., Molinari, M. & Jones, E. G. A microcolumnar structure of monkey cerebral cortex revealed by immunocytochemical studies of double bouquet cell axons. Neuroscience 37, 655–673 (1990).

    Article  CAS  PubMed  Google Scholar 

  64. Jones, E. G. in Cellular Components of the Cerebral Cortex (eds Peters, A. & Jones, E. G.) 409–418 (Plenum, New York, 1984).

    Book  Google Scholar 

  65. Marin-Padilla, M. in Cellular Components of the Cerebral Cortex (eds Peters, A. & Jones, E. G.) 447–478 (Plenum, New York, 1984).

    Google Scholar 

  66. Hestrin, S. & Armstrong, W. E. Morphology and physiology of cortical neurons in layer I. J. Neurosci. 16, 5290–5300 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Anderson, J. C., Martin, K. A. & Picanco-Diniz, C. W. The neurons in layer 1 of cat visual cortex. Proc. R. Soc. Lond. B 248, 27–33 (1992).

    Article  CAS  Google Scholar 

  68. Zhou, F. M. & Hablitz, J. J. Morphological properties of intracellularly labeled layer I neurons in rat neocortex. J. Comp. Neurol. 376, 198–213 (1996).

    Article  CAS  PubMed  Google Scholar 

  69. McCormick, D. A., Connors, B. W., Lighthall, J. W. & Prince, D. A. Comparative electrophysiology of pyramidal and sparsely spiny stellate neurons of the neocortex. J. Neurophysiol. 54, 782–806 (1985). The pioneering study that revealed basic differences in discharge between pyramidal neurons and interneurons.

    Article  CAS  PubMed  Google Scholar 

  70. Gutnick, M. J. & Crill, W. E. in The Cortical Neuron (eds Gutnick, M. J. & Mody, I.) 33–51 (Oxford Univ. Press, New York, 1995).

    Book  Google Scholar 

  71. Connors, B. W. & Gutnick, M. J. Intrinsic firing patterns of diverse neocortical neurons. Trends Neurosci. 13, 99–104 (1990).

    Article  CAS  PubMed  Google Scholar 

  72. Amitai, Y. & Connors, B. W. in Cerebral Cortex (eds Jones, E. G. & Diamond, I. T.) 299–331 (Plenum, New York, 1995).

    Google Scholar 

  73. Kawaguchi, Y. Groupings of nonpyramidal and pyramidal cells with specific physiological and morphological characteristics in rat frontal cortex. J. Neurophysiol. 69, 416–431 (1993).

    Article  CAS  PubMed  Google Scholar 

  74. Kawaguchi, Y. & Kubota, Y. Correlation of physiological subgroupings of nonpyramidal cells with parvalbumin- and calbindinD28k-immunoreactive neurons in layer V of rat frontal cortex. J. Neurophysiol. 70, 387–396 (1993).

    Article  CAS  PubMed  Google Scholar 

  75. Kawaguchi, Y. & Kubota, Y. Physiological and morphological identification of somatostatin- or vasoactive intestinal polypeptide-containing cells among GABAergic cell subtypes in rat frontal cortex. J. Neurosci. 16, 2701–2715 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kawaguchi, Y. & Kubota, Y. Neurochemical features and synaptic connections of large physiologically-identified GABAergic cells in the rat frontal cortex. Neuroscience 85, 677–701 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Porter, J. T. et al. Properties of bipolar VIPergic interneurons and their excitation by pyramidal neurons in the rat neocortex. Eur. J. Neurosci. 10, 3617–3628 (1998).

    Article  CAS  PubMed  Google Scholar 

  78. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Steriade, M. Corticothalamic resonance, states of vigilance and mentation. Neuroscience 101, 243–276 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Llinas, R. The intrinsic electrophysiological properties of mammalian neurons: insights into central nervous system function. Science 242, 1654–1664 (1988).

    Article  CAS  PubMed  Google Scholar 

  81. Mainen, Z. F. & Sejnowski, T. J. Influence of dendritic structure on firing pattern in model neocortical neurons. Nature 382, 363–366 (1996).

    Article  CAS  PubMed  Google Scholar 

  82. Rudy, B. & McBain, C. J. Kv3 channels: voltage-gated K+ channels designed for high-frequency repetitive firing. Trends Neurosci. 24, 517–526 (2001).

    Article  CAS  PubMed  Google Scholar 

  83. Martina, M., Schultz, J. H., Ehmke, H., Monyer, H. & Jonas, P . Functional and molecular differences between voltage-gated K+ channels of fast-spiking interneurons and pyramidal neurons of rat hippocampus. J. Neurosci. 18, 8111–8125 (1998). The first combined patch-clamp reverse transcription PCR study, showing differences in ion channels in pyramidal neurons and interneurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Erisir, A., Lau, D., Rudy, B. & Leonard, C. S. Function of specific K+ channels in sustained high-frequency firing of fast-spiking neocortical interneurons. J. Neurophysiol. 82, 2476–2489 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Toledo-Rodriguez, M. et al. Correlation maps allow neuronal electrical properties to be predicted from single-cell gene expression profiles in rat neocortex. Cereb. Cortex 10 June 2004 [epub ahead of print]. The first study to reveal profiles of ion-channel and calcium-binding protein genes expressed in neocortical neurons and to use expression profiles to predict electrical behaviour.

  86. Vergara, C., Latorre, R., Marrion, N. V. & Adelman, J. P. Calcium-activated potassium channels. Curr. Opin. Neurobiol. 8, 321–329 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Ertel, S. & Ertel, E. Low-voltage-activated T-type Ca2+ channels. Trends Pharmacol. Sci. 18, 37–42 (1997).

    Article  CAS  PubMed  Google Scholar 

  88. Chow, A. et al. K+ channel expression distinguishes subpopulations of parvalbumin- and somatostatin-containing neocortical interneurons. J. Neurosci. 19, 9332–9345 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kubota, Y., Hattori, R. & Yui, Y. Three distinct subpopulations of GABAergic neurons in rat frontal agranular cortex. Brain Res. 649, 159–173 (1994). A seminal study showing that three distinct subpopulations of interneurons express parvalbumin, calretinin or somatostatin.

    Article  CAS  PubMed  Google Scholar 

  90. Demeulemeester, H., Vandesande, F., Orban, G. A., Heizmann, C. W. & Pochet, R. Calbindin D-28K and parvalbumin immunoreactivity is confined to two separate neuronal subpopulations in the cat visual cortex, whereas partial coexistence is shown in the dorsal lateral geniculate nucleus. Neurosci. Lett. 99, 6–11 (1989).

    Article  CAS  PubMed  Google Scholar 

  91. Rogers, J. H. & Resibois, A. Calretinin and calbindin-D28k in rat brain: patterns of partial co-localization. Neuroscience 51, 843–865 (1992). References 90 and 91 revealed the differential expression of calcium-binding proteins in GABA neurons.

    Article  CAS  PubMed  Google Scholar 

  92. Cauli, B. et al. Classification of fusiform neocortical interneurons based on unsupervised clustering. Proc. Natl Acad. Sci. USA 97, 6144–6149 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Hendry, S. H., Jones, E. G. & Emson, P. C. Morphology, distribution, and synaptic relations of somatostatin- and neuropeptide Y-immunoreactive neurons in rat and monkey neocortex. J. Neurosci. 4, 2497–2517 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rogers, J. H. Immunohistochemical markers in rat cortex: co-localization of calretinin and calbindin-D28k with neuropeptides and GABA. Brain Res. 587, 147–157 (1992).

    Article  CAS  PubMed  Google Scholar 

  95. Demeulemeester, H., Vandesande, F., Orban, G. A., Brandon, C. & Vanderhaeghen, J. J. Heterogeneity of GABAergic cells in cat visual cortex. J. Neurosci. 8, 988–1000 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Morrison, J. H., Magistretti, P. J., Benoit, R. & Bloom, F. E. The distribution and morphological characteristics of the intracortical VIP-positive cell: an immunohistochemical analysis. Brain Res. 292, 269–282 (1984).

    Article  CAS  PubMed  Google Scholar 

  97. Jones, E. G. & Hendry, S. H. Peptide-containing neurons of the primate cerebral cortex. Res. Publ. Assoc. Res. Nerv. Ment. Dis. 64, 163–178 (1986).

    CAS  PubMed  Google Scholar 

  98. Somogyi, P. et al. Different populations of GABAergic neurons in the visual cortex and hippocampus of cat contain somatostatin- or cholecystokinin-immunoreactive material. J. Neurosci. 4, 2590–2603 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hendry, S. H. et al. Neuropeptide-containing neurons of the cerebral cortex are also GABAergic. Proc. Natl Acad. Sci. USA 81, 6526–6530 (1984). References 98 and 99 reported the differential expression of intestinal peptides in GABA neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wahle, P. Differential regulation of substance P and somatostatin in Martinotti cells of the developing cat visual cortex. J. Comp. Neurol. 329, 519–538 (1993).

    Article  CAS  PubMed  Google Scholar 

  101. Meinecke, D. L. & Peters, A. Somatostatin immunoreactive neurons in rat visual cortex: a light and electron microscopic study. J. Neurocytol. 15, 121–136 (1986).

    Article  CAS  PubMed  Google Scholar 

  102. Kubota, Y. & Kawaguchi, Y. Two distinct subgroups of cholecystokinin-immunoreactive cortical interneurons. Brain Res. 752, 175–183 (1997).

    Article  CAS  PubMed  Google Scholar 

  103. Jonas, P., Racca, C., Sakmann, B., Seeburg, P. H. & Monyer, H. Differences in Ca2+ permeability of AMPA-type glutamate receptor channels in neocortical neurons caused by differential GluR-B subunit expression. Neuron 12, 1281–1289 (1994).

    Article  CAS  PubMed  Google Scholar 

  104. Stewart, A. E., Yan, Z., Surmeier, D. J. & Foehring, R. C. Muscarine modulates Ca2+ channel currents in rat sensorimotor pyramidal cells via two distinct pathways. J. Neurophysiol. 81, 72–84 (1999).

    Article  CAS  PubMed  Google Scholar 

  105. Angulo, M. C., Lambolez, B., Audinat, E., Hestrin, S. & Rossier, J. Subunit composition, kinetic, and permeation properties of AMPA receptors in single neocortical nonpyramidal cells. J. Neurosci. 17, 6685–6696 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Flint, A. C., Maisch, U. S., Weishaupt, J. H., Kriegstein, A. R. & Monyer, H. NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex. J. Neurosci. 17, 2469–2476 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Monyer, H. & Markram, H. Interneuron diversity series: molecular and genetic tools to study GABAergic interneuron diversity and function. Trends Neurosci. 27, 90–97 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Thomson, A. M., Girdlestone, D. & West, D. C. Voltage-dependent currents prolong single-axon postsynaptic potentials in layer III pyramidal neurons in rat neocortical slices. J. Neurophysiol. 60, 1896–1907 (1988). This paper reported the first dual recordings of synaptically connected neurons in the neocortex.

    Article  CAS  PubMed  Google Scholar 

  109. Lubke, J., Markram, H., Frotscher, M. & Sakmann, B. Frequency and dendritic distribution of autapses established by layer 5 pyramidal neurons in the developing rat neocortex: comparison with synaptic innervation of adjacent neurons of the same class. J. Neurosci. 16, 3209–3218 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Markram, H., Lubke, J., Frotscher, M., Roth, A. & Sakmann, B. Physiology and anatomy of synaptic connections between thick tufted pyramidal neurons in the developing rat neocortex. J. Physiol. (Lond.) 500, 409–440 (1997).

    Article  CAS  Google Scholar 

  111. Silver, R. A., Lubke, J., Sakmann, B. & Feldmeyer, D. High-probability uniquantal transmission at excitatory synapses in barrel cortex. Science 302, 1981–1984 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Tamas, G., Buhl, E. H. & Somogyi, P. Fast IPSPs elicited via multiple synaptic release sites by different types of GABAergic neuron in the cat visual cortex. J. Physiol. (Lond.) 500, 715–738 (1997).

    Article  CAS  Google Scholar 

  113. Tamas, G., Somogyi, P. & Buhl, E. H. Differentially interconnected networks of GABAergic interneurons in the visual cortex of the cat. J. Neurosci. 18, 4255–4270 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Buhl, E. H. et al. Effect, number and location of synapses made by single pyramidal cells onto aspiny interneurons of cat visual cortex. J. Physiol. (Lond.) 500, 689–713 (1997). An elegant multi-dimensional study of a key glutamatergic pathway.

    Article  CAS  Google Scholar 

  115. Ahmed, B., Anderson, J. C., Martin, K. A. & Nelson, J. C. Map of the synapses onto layer 4 basket cells of the primary visual cortex of the cat. J. Comp. Neurol. 380, 230–242 (1997).

    Article  CAS  PubMed  Google Scholar 

  116. Peters, A., Palay, S. L. & Webster, H. D. The Fine Structure of the Nervous System (Oxford Univ. Press, New York, 1991).

    Google Scholar 

  117. Deuchars, J. & Thomson, A. M. Innervation of burst firing spiny interneurons by pyramidal cells in deep layers of rat somatomotor cortex: paired intracellular recordings with biocytin filling. Neuroscience 69, 739–755 (1995).

    Article  CAS  PubMed  Google Scholar 

  118. Krimer, L. S. & Goldman-Rakic, P. S. Prefrontal microcircuits: membrane properties and excitatory input of local, medium, and wide arbor interneurons. J. Neurosci. 21, 3788–3796 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Hestrin, S. Different glutamate receptor channels mediate fast excitatory synaptic currents in inhibitory and excitatory cortical neurons. Neuron 11, 1083–1091 (1993).

    Article  CAS  PubMed  Google Scholar 

  120. Thomson, A. M., Deuchars, J. & West, D. C. Neocortical local synaptic circuitry revealed with dual intracellular recordings and biocytin-filling. J. Physiol. (Paris) 90, 211–215 (1996).

    Article  CAS  Google Scholar 

  121. Thomson, A. M., West, D. C. & Deuchars, J. Properties of single axon excitatory postsynaptic potentials elicited in spiny interneurons by action potentials in pyramidal neurons in slices of rat neocortex. Neuroscience 69, 727–738 (1995).

    Article  CAS  PubMed  Google Scholar 

  122. Thomson, A. M., Deuchars, J. & West, D. C. Single axon excitatory postsynaptic potentials in neocortical interneurons exhibit pronounced paired pulse facilitation. Neuroscience 54, 347–360 (1993). The first demonstration of strongly facilitating glutamatergic synapses.

    Article  CAS  PubMed  Google Scholar 

  123. Thomson, A. M. & Deuchars, J. Synaptic interactions in neocortical local circuits: dual intracellular recordings in vitro. Cereb. Cortex 7, 510–522 (1997).

    Article  CAS  PubMed  Google Scholar 

  124. Thomson, A. M. Neuroscience. More than just frequency detectors? Science 275, 179–180 (1997).

    Article  CAS  PubMed  Google Scholar 

  125. Markram, H., Wang, Y. & Tsodyks, M. Differential signaling via the same axon of neocortical pyramidal neurons. Proc. Natl Acad. Sci. USA 95, 5323–5328 (1998). The first direct demonstration that the same axon from a neocortical neuron can form both depressing and facilitating synapses.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wang, Y., Gupta, A. & Markram, H. Anatomical and functional differentiation of glutamatergic synaptic innervation in the neocortex. J. Physiol. (Paris) 93, 305–317 (1999).

    Article  CAS  Google Scholar 

  127. Reyes, A. et al. Target-cell-specific facilitation and depression in neocortical circuits. Nature Neurosci. 1, 279–285 (1998).

    Article  CAS  PubMed  Google Scholar 

  128. Rozov, A., Jerecic, J., Sakmann, B. & Burnashev, N. AMPA receptor channels with long-lasting desensitization in bipolar interneurons contribute to synaptic depression in a novel feedback circuit in layer 2/3 of rat neocortex. J. Neurosci. 21, 8062–8071 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Galarreta, M. & Hestrin, S. Frequency-dependent synaptic depression and the balance of excitation and inhibition in the neocortex. Nature Neurosci. 1, 587–594 (1998).

    Article  CAS  PubMed  Google Scholar 

  130. Rozov, A., Burnashev, N., Sakmann, B. & Neher, E. Transmitter release modulation by intracellular Ca2+ buffers in facilitating and depressing nerve terminals of pyramidal cells in layer 2/3 of the rat neocortex indicates a target cell-specific difference in presynaptic calcium dynamics. J. Physiol.(Lond). 531, 807–826 (2001).

    Article  CAS  Google Scholar 

  131. Buhl, E. H., Cobb, S. R., Halasy, K. & Somogyi, P. Properties of unitary IPSPs evoked by anatomically identified basket cells in the rat hippocampus. Eur. J. Neurosci. 7, 1989–2004 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  133. Cobb, S. R., Buhl, E. H., Halasy, K., Paulsen, O. & Somogyi, P. Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 378, 75–78 (1995). An excellent paper that revealed the functional impact of different types of interneuron.

    Article  CAS  PubMed  Google Scholar 

  134. Tarczy-Hornoch, K., Martin, K. A., Jack, J. J. & Stratford, K. J. Synaptic interactions between smooth and spiny neurons in layer 4 of cat visual cortex in vitro. J. Physiol. (Lond.) 508 351–363 (1998).

    Article  CAS  Google Scholar 

  135. Segev, I. & Burke, R. in Methods in Neuronal Modeling (eds Koch, C. & Segev, I.) 93–136 (MIT Press, Cambridge, Massachusetts, 1998).

    Google Scholar 

  136. Segev, I. & London, M. in Dendrites (eds Stuart, G., Spruston, N. & Hausser, M.) (Oxford Univ. Press, 1999).

    Google Scholar 

  137. Magee, J. C. & Johnston, D. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275, 209–213 (1997).

    Article  CAS  PubMed  Google Scholar 

  138. Larkum, M. E., Kaiser, K. M. & Sakmann, B. Calcium electrogenesis in distal apical dendrites of layer 5 pyramidal cells at a critical frequency of back-propagating action potentials. Proc. Natl Acad. Sci. USA 96, 14600–14604 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Traub, R. D. Model of synchronized population bursts in electrically coupled interneurons containing active dendritic conductances. J. Comput. Neurosci. 2, 283–289 (1995).

    Article  CAS  PubMed  Google Scholar 

  140. Tamas, G., Lorincz, A., Simon, A. & Szabadics, J. Identified sources and targets of slow inhibition in the neocortex. Science 299, 1902–1905 (2003).

    Article  CAS  PubMed  Google Scholar 

  141. Thomson, A. M. & Destexhe, A. Dual intracellular recordings and computational models of slow inhibitory postsynaptic potentials in rat neocortical and hippocampal slices. Neuroscience 92, 1193–1215 (1999).

    Article  CAS  PubMed  Google Scholar 

  142. Benardo, L. S. Separate activation of fast and slow inhibitory postsynaptic potentials in rat neocortex in vitro. J. Physiol. (Lond.) 476, 203–215 (1994).

    Article  CAS  Google Scholar 

  143. Hughes, D. I., Bannister, A. P., Pawelzik, H. & Thomson, A. M. Double immunofluorescence, peroxidase labelling and ultrastructural analysis of interneurons following prolonged electrophysiological recording in vitro. J. Neurosci. Meth. 101, 107–116 (2000).

    Article  CAS  Google Scholar 

  144. Kisvarday, Z. F., Beaulieu, C. & Eysel, U. T. Network of GABAergic large basket cells in cat visual cortex (area 18): implication for lateral disinhibition. J. Comp. Neurol. 327, 398–415 (1993).

    Article  CAS  PubMed  Google Scholar 

  145. Fukuda, T. & Kosaka, T. Gap junctions linking the dendritic network of GABAergic interneurons in the hippocampus. J. Neurosci. 20, 1519–1528 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Tamas, G., Buhl, E. H., Lorincz, A. & Somogyi, P. Proximally targeted GABAergic synapses and gap junctions synchronize cortical interneurons. Nature Neurosci. 3, 366–371 (2000).

    Article  CAS  PubMed  Google Scholar 

  147. Peinado, A., Yuste, R. & Katz, L. C. Extensive dye coupling between rat neocortical neurons during the period of circuit formation. Neuron 10, 103–114 (1993).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  149. Gibson, J. R., Beierlein, M. & Connors, B. W. Two networks of electrically coupled inhibitory neurons in neocortex. Nature 402, 75–79 (1999).

    Article  CAS  PubMed  Google Scholar 

  150. Kisvarday, Z. F. & Eysel, U. T. Functional and structural topography of horizontal inhibitory connections in cat visual cortex. Eur. J. Neurosci. 5, 1558–1572 (1993).

    Article  CAS  PubMed  Google Scholar 

  151. Borg-Graham, L. J., Monier, C. & Fregnac, Y. Visual input evokes transient and strong shunting inhibition in visual cortical neurons. Nature 393, 369–373 (1998).

    Article  CAS  PubMed  Google Scholar 

  152. Monier, C., Chavane, F., Baudot, P., Graham, L. J. & Fregnac, Y. Orientation and direction selectivity of synaptic inputs in visual cortical neurons: a diversity of combinations produces spike tuning. Neuron 37, 663–680 (2003).

    Article  CAS  PubMed  Google Scholar 

  153. Wehr, M. & Zador, A. M. Balanced inhibition underlies tuning and sharpens spike timing in auditory cortex. Nature 426, 442–446 (2003).

    Article  CAS  PubMed  Google Scholar 

  154. McBain, C. J. & Fisahn, A. Interneurons unbound. Nature Rev. Neurosci. 2, 11–23 (2001).

    Article  CAS  Google Scholar 

  155. Hirsch, J. A., Alonso, J. M., Reid, R. C. & Martinez, L. M. Synaptic integration in striate cortical simple cells. J. Neurosci. 18, 9517–9528 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Anderson, J. S., Carandini, M. & Ferster, D. Orientation tuning of input conductance, excitation, and inhibition in cat primary visual cortex. J. Neurophysiol. 84, 909–926 (2000).

    Article  CAS  PubMed  Google Scholar 

  157. Tan, A. Y., Zhang, L. I., Merzenich, M. M. & Schreiner, C. E. Tone-evoked excitatory and inhibitory synaptic conductances of primary auditory cortex neurons. J. Neurophysiol. 92, 630–643 (2004).

    Article  PubMed  Google Scholar 

  158. Silberberg, G., Wu, C. & Markram, H. Synaptic dynamics control the timing of neuronal excitation in the activated neocortical microcircuit. J. Physiol. (Lond.) 556, 19–27 (2004). The first study to show that subthreshold voltage cross-correlations correspond to the form of synaptic dynamics.

    Article  CAS  Google Scholar 

  159. Galarreta, M. & Hestrin, S. Properties of GABAA receptors underlying inhibitory synaptic currents in neocortical pyramidal neurons. J. Neurosci. 17, 7220–7227 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Varela, J. A., Song, S., Turrigiano, G. G. & Nelson, S. B. Differential depression at excitatory and inhibitory synapses in visual cortex. J. Neurosci. 19, 4293–4304 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Bernander, O., Douglas, R. J., Martin, K. A. & Koch, C. Synaptic background activity influences spatiotemporal integration in single pyramidal cells. Proc. Natl Acad. Sci. USA 88, 11569–11573 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Konig, P., Engel, A. K. & Singer, W. Integrator or coincidence detector? The role of the cortical neuron revisited. Trends Neurosci. 19, 130–137 (1996).

    Article  CAS  PubMed  Google Scholar 

  163. Mainen, Z. F. & Sejnowski, T. J. Reability of spike timing in neocortical neurons. Science 268, 1503–1506 (1995).

    Article  CAS  PubMed  Google Scholar 

  164. Azouz, R. & Gray, C. M. Cellular mechanisms contributing to response variability of cortical neurons in vivo. J. Neurosci. 19, 2209–2223 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Silberberg, G., Bethge, M., Markram, H., Pawelzik, K. & Tsodyks, M. Dynamics of population rate codes in ensembles of neocortical neurons. J. Neurophysiol. 91, 704–709 (2004).

    Article  CAS  PubMed  Google Scholar 

  166. Silberberg, G., Gupta, A. & Markram, H. Stereotypy in neocortical microcircuits. Trends Neurosci. 25, 227–230 (2002).

    Article  CAS  PubMed  Google Scholar 

  167. Toledo-Rodriguez, M., Gupta, A., Wang, Y., Wu, C. & Markram, H. in The Handbook of Brain Theory and Neural Networks (ed. Arbib, M.) 719–725 (MIT Press, Boston, Massachusetts, 2002).

    Google Scholar 

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Acknowledgements

We would like to acknowledge M. Segal, A. Grinvald and T. McKenna for their long-term support of the work on the microcircuit. The studies were supported by a number of grants, including the Office of Naval Research; Minerva Foundation; Human Frontiers Science Program; German–Israel Science Foundation; Binational Science Foundation; Israel Science Foundation; European Union Fifth Framework; National Alliance for Autism Research; and, more recently, by the the Swiss Federal Institute for Technology and the Swiss Science Foundation.

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DATABASES

Entrez

Caα1G

Caα1I

CB

CCK

CR

HCN1

HCN2

HCN3

HCN4

Kv1.1

Kv1.2

Kv1.4

Kv1.6

Kv2.2

Kv3.1

Kv3.2

Kv3.3

Kv3.4

NPY

PV

SK2

SOM

VIP

FURTHER INFORMATION

The Brain Mind Institute

Glossary

PARVALBUMIN

(PV). A calcium-binding protein that can act as an endogenous buffer in certain neurons.

CALBINDIN

(CB). A calcium-binding protein that might function as a calcium buffer.

CALRETININ

(CR). A calcium-binding protein that can be used as a marker of preplate neurons.

BINOMIAL ESTIMATES

The number of functional release sites is referred to as binomial n because it is estimated in a quantal analysis using binomial statistics.

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Markram, H., Toledo-Rodriguez, M., Wang, Y. et al. Interneurons of the neocortical inhibitory system. Nat Rev Neurosci 5, 793–807 (2004). https://doi.org/10.1038/nrn1519

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