Journal of Neurocytology

, Volume 31, Issue 3–5, pp 277–287 | Cite as

Parvalbumin, somatostatin and cholecystokinin as chemical markers for specific GABAergic interneuron types in the rat frontal cortex

  • Yasuo Kawaguchi
  • Satoru Kondo


It remains to be clarified how many classes of GABAergic nonpyramidal cells exist in the cortical circuit. We have divided GABA cells in the rat frontal cortex into 3 groups, based on their firing characteristics: fast-spiking (FS) cells, late-spiking (LS) cells, and non-FS cells. Expression of calcium-binding proteins and peptides could be shown in separate groups of GABA cells in layers II/III and V of the frontal cortex: (1) parvalbumin cells, (2) somatostatin cells, (3) calretinin and/or vasoactive intestinal polypeptide (VIP) cells [partially positive for cholecystokinin (CCK)] and (4) large CCK cells (almost negative for VIP/calretinin). Combining the physiological and chemical properties of morphologically diverse nonpyramidal cells allows division into several groups, including FS basket cells containing parvalbumin, non-FS somatostatin Martinotti cells with ascending axonal arbors, and non-FS large basket cells positive for CCK. These subtypes show characteristic spatial distributions of axon collaterals and the innervation tendency of postsynaptic elements. With synchronized activity induced by cortical excitatory or inhibitory circuits, firing patterns were also found to differ. Subtype-selective occurrence of electrical coupling, finding for potassium channel Kv3.1 proteins, and cholinergic and serotonergic modulation supports our tentative classification. To clarify the functional architecture in the frontal cortex, it is important to reveal the connectional characteristics of GABA cell subtypes and determine whether they are similar to those in other cortical regions.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Beierlein, M., Gibson, J. R. &; Connors, B. W. (2000) A network of electrically coupled interneurons drives synchronized inhibition in neocortex. Nature Neuroscience 3, 904–910.PubMedGoogle Scholar
  2. Buhl, E. H., TamÁs, G. &; Fisahn, A. (1998) Cholinergic activation and tonic excitation induce persistent gamma oscillations in mouse somatosensory cortex in vitro. Journal of Physiology (London) 513, 117–126.Google Scholar
  3. Buhl, E. H., TamÁs, G., Szilagyi, T., Stricker, C., Paulsen, O. &; Somogyi, P. (1997) Effect, number and location of synapses made by single pyramidal cells onto aspiny interneurons of cat visual cortex. Journal of Physiology (London) 500, 689–713.Google Scholar
  4. Cape, E. G., Manns, I. D., Alonso, A., Beaudet, A. &; Jones, B. E. (2000) Neurotensin-induced bursting of cholinergic basal forebrain neurons promotes γ and θ cortical activity together with waking and paradoxical sleep. Journal of Neuroscience 20, 8452–8461.PubMedGoogle Scholar
  5. Castro-Alamancos, M. A. &; Rigas, P. (2002) Synchronized oscillations caused by disinhibition in rodent neocortex are generated by recurrent synaptic activity mediated by AMPA receptors. Journal of Physiology (London) 542, 567–581.Google Scholar
  6. Cauli, B., Audinat, E., Lambolez, B., Angulo, M. C., Ropert, N., Tsuzuki, K., Hestrin, S. &; Rossier, J. (1997) Molecular and physiological diversity of cortical nonpyramidal cells. Journal of Neuroscience 17, 3894–3906.PubMedGoogle Scholar
  7. Cauli, B., Porter, J. T., Tsuzuki, K., Lambolez, B., Rossier, J., Quenet, B. &; Audinat, E. (2000) Classification of fusiform neocortical interneurons based on unsupervised clustering. Proceedings of the National Academy of Sciences USA 97, 6144–6149.Google Scholar
  8. Chow, A., Erisir, A., Farb, C., Nadal, M. S., Ozaita, A., Lau, D., Welker, E. &; Rudy, B. (1999) K+ channel expression distinguishes subpopulations of parvalbumin-and somatostatin-containing neocortical interneurons. Journal of Neuroscience 19, 9332–9345.PubMedGoogle Scholar
  9. Connors, B. W. &; Gutnick, M. J. (1990) Intrinsic firing patterns of diverse neocortical neurons. Trends in Neurosciences 13, 99–104.PubMedGoogle Scholar
  10. Cowan, R. L. &; Wilson, C. J. (1994) Spontaneous firing patterns and axonal projections of single corticostriatal neurons in the rat medial agranular cortex. Journal of Neurophysiology 71, 17–32.PubMedGoogle Scholar
  11. deFelipe, J. (1997) Types of neurons, synaptic connections and chemical characteristics of cells immunoreactive for calbindin-D28K, parvalbumin and calretinin in the neocortex. Journal of Chemical Neuroanatomy 14, 1–19.PubMedGoogle Scholar
  12. deFelipe, J. &; FariÑas, I. (1992) The pyramidal neuron of the cerebral cortex: Morphological and chemical characteristics of the synaptic inputs. Progress in Neurobiology 39, 563–607.PubMedGoogle Scholar
  13. Deuchars, J. &; Thomson, A. M. (1995) Single axon fast inhibitory postsynaptic potentials elicited by a sparsely spiny interneuron in rat neocortex. Neuroscience 65, 935–942.PubMedGoogle Scholar
  14. Erisir, A., Lau, D., Rudy, B. &; Leonard, C. S. (1999) Function of specificK+ channels in sustained highfrequency firing of fast-spiking neocortical interneurons. Journal of Neurophysiology 82, 2476–2489.PubMedGoogle Scholar
  15. FairÉn, A., deFelipe, J. &; Regidor, J. (1984) Nonpyramidal neurons: General account. In Cerebral Cortex, Vol. 1, Cellular Components of the Cerebral Cortex (edited by Peters, A. &; Jones, E. G.) pp. 201–253. New York: Plenum.Google Scholar
  16. Feldman, M. L. &; Peters, A. (1978) The forms of nonpyramidal neurons in the visual cortex of the rat. Journal of Comparative Neurology 179, 761–793.PubMedGoogle Scholar
  17. FÉrÉzou, I., Cauli, B., Hill, E. L., Rossier, J., Hamel, E. &; Lambolez, B. (2002) 5-HT3 receptors mediate serotonergic fast synaptic excitation of neocortical vasoactive intestinal peptide/cholecystokinin interneurons. Journal of Neuroscience 22, 7389–7397.PubMedGoogle Scholar
  18. Galarreta, M. &; Hestrin, S. (1998) Frequencydependent synaptic depression and the balance of excitation and inhibition in the neocortex. Nature Neuroscience 1, 587–594.PubMedGoogle Scholar
  19. Galarreta, M. &; Hestrin, S. (1999) A network of fast-spiking cells in the neocortex connected by electrical synapses. Nature 402, 72–75.PubMedGoogle Scholar
  20. Gibson, J. R., Beierlein, M. &; Connors, B. W. (1999) Two networks of electrically coupled inhibitory neurons in neocortex. Nature 402, 75–79.PubMedGoogle Scholar
  21. Gonchar, Y. &; Burkhalter, A. (1997) Three distinct families of GABAergic neurons in rat visual cortex. Cerebral Cortex 7, 347–358.PubMedGoogle Scholar
  22. Gupta, A., Wang, Y. &; Markram, H. (2000) Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. Science 287, 273–278.PubMedGoogle Scholar
  23. Hendry, S. H. C., Jones, E. G., deFelipe, J., Schmechel, D., Brandon, C. &; Emson, P. C. (1984) Neuropeptide containing neurons of the cerebral cortex are also GABAergic. Proceedings of the National Academy of Sciences USA 81, 6526–6530.Google Scholar
  24. Hendry, S. H. C., Jones, E. G., Emson, P. C., Lawson, D. E. M., Heizmann, C. W. &; Streit, P. (1989) Two classes of cortical GABA neurons defined by differential calcium binding protein immunoreactivities. Experimental Brain Research 76, 467–472.Google Scholar
  25. Houser, C. R., Hendry, S. H. C., Jones, E. G. &; Vaughn, V. E. (1983) Morphological diversity of immuno-cytochemically identified GABA neurons in monkey sensory-motor cortex. Journal of Neurocytology 12, 617–638.PubMedGoogle Scholar
  26. Jefferys, J. G. R., Traub, R. D. &; Whittington, M. A. (1996) Neuronal networks for induced' 40 Hz'rhythm. Trends in Neurosciences 19, 202–208.PubMedGoogle Scholar
  27. Jones, E. G. (1975) Varieties and distribution of nonpyramidal cells in the somatic sensory cortex of the squirrel monkey. Journal of Comparative Neurology 160, 205–268.PubMedGoogle Scholar
  28. Jones, E. G. (2000) Microcolumns in the cerebral cortex. Proceedings of the National Academy of Sciences USA 97, 5019–5021.Google Scholar
  29. Kawaguchi, Y. (1997) Selective cholinergic modulation of cortical GABAergic cell subtypes. Journal of Neurophysiology 78, 1743–1747.PubMedGoogle Scholar
  30. Kawaguchi, Y. (2001) Distinct firing patterns of neuronal subtypes in cortical synchronized activities. Journal of Neuroscience 21, 7261–7272.PubMedGoogle Scholar
  31. Kawaguchi, Y. &; Kubota, Y. (1993) Correlation of physiological subgroupings of nonpyramidal cells with parvalbumin-and calbindin D28k-immunoreactive neurons in layer V of rat frontal cortex. Journal of Neurophysiology 70, 387–396.PubMedGoogle Scholar
  32. Kawaguchi, Y. &; Kubota, Y. (1997) GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cerebral Cortex 7, 476–486.PubMedGoogle Scholar
  33. Kawaguchi, Y. &; Kubota, Y. (1998) Neurochemical features and synaptic connections of large physiologically-identified GABAergic cells in the rat frontal cortex. Neuroscience 85, 677–701.PubMedGoogle Scholar
  34. Kawaguchi, Y. &; Shindou, T. (1998) Noradrenergic excitation and inhibition of GABAergic cell types in rat frontal cortex. Journal of Neuroscience 18, 6963–6976.PubMedGoogle Scholar
  35. Kondo, S. &; Kawaguchi, Y. (2001) Slow synchronized bursts of inhibitory postsynaptic currents (0.1-0.3 Hz) by cholinergic stimulation in the rat frontal cortex in vitro. Neuroscience 107, 551–560.PubMedGoogle Scholar
  36. Krimer, L. S. &; Goldman-Rakic, P. S. (2001) Prefrontal microcircuits: Membrane properties and excitatory input of local, medium, and wide arbor interneurons. Journal of Neuroscience 21, 3788–3796.PubMedGoogle Scholar
  37. Kubota, Y., Hattori, R. &; Yui, Y. (1994) Three distinct subpopulations of GABAergic neurons in rat frontal agranular cortex. Brain Research 649, 159–173.PubMedGoogle Scholar
  38. Kubota, Y., Karube, F., Suzuki, K. &; Kawaguchi, Y. (2000) Synaptic connection patterns of fast-spiking cells, Martinotti cells and double bouquet cells in the rat frontal cortex. Society for Neuroscience Abstracts 26 37.18.Google Scholar
  39. Kubota, Y. &; Kawaguchi, Y. (1997) Two distinct subgroups of cholecystokinin-immunoreactive cortical interneurons. Brain Research 752, 175–183.PubMedGoogle Scholar
  40. Larkum, M. E., Zhu, J. J. &; Sakmann, B. (1999) A new cellular mechanism for coupling inputs arriving at different cortical layers. Nature 398, 338–341.PubMedGoogle Scholar
  41. Lewis, D. A., Pierri, J. N., Volk, D. W., Melchitzky, D. S. &; Woo, T. U. (1999) Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia. Biological Psychiatry 46, 616–626.PubMedGoogle Scholar
  42. Mccormick, D. A., Connors, B. W., Lighthall, J. W. &; Prince, D. A. (1985) Comparative electrophysiology of pyramidal and sparsely spiny stellate neurons of the neocortex. Journal of Neurophysiology 54, 782–806.PubMedGoogle Scholar
  43. Metherate, R., Cox, C. L. &; Ashe, J. H. (1992) Cellular bases of neocortical activation of neural oscillations by the nucleus basalis and endogenous acetylcholine. Journal of Neuroscience 12, 4701–4711.PubMedGoogle Scholar
  44. Meyer, A. H., Katona, I., Blatow, M., Rozov, A. &; Monyer, H. (2002) In vivo labeling of parvalbuminpositive interneurons and analysis of electrical coupling in identified neurons. Journal of Neuroscience 22, 7055–7064.PubMedGoogle Scholar
  45. Miles, R. (2000) Diversity in inhibition. Science 287, 244–246.PubMedGoogle Scholar
  46. Miles, R., Toth, K., Gulyas, A. I., Hajos, N. &; Freund, T. F. (1996) Differences between somatic and dendritic inhibition in the hippocampus. Neuron 16, 815–823.PubMedGoogle Scholar
  47. Morales, M. &; Bloom, F. E. (1997) The 5-HT3 receptor is present in different subpopulations of GABAergic neurons in the rat telencephalon. Journal of Neuroscience 17, 3157–3167.PubMedGoogle Scholar
  48. Nelson, S. B. (2002) Cortical microcircuits: Diverse or canonical? Neuron 36, 19–27.PubMedGoogle Scholar
  49. Parra, P., GulyÁs, A. I. &; Miles, R. (1998) How many subtypes of inhibitory cells in the hippocampus? Neuron 20, 983–993.PubMedGoogle Scholar
  50. Porter, J. T., Cauli, B., Tsuzuki, K., Lambolez, B., Rossier, J. &; Audinat, E. (1999) Selective excitation of subtypes of neocortical interneurons by nicotinic receptors. Journal of Neuroscience 19, 5228–5235.PubMedGoogle Scholar
  51. RamÓn Y Cajal, S. (1911) Histology of the Nervous System. Vol. 2 (translated by Swanson, N. &; Swanson, L. W.). New York: Oxford UP.Google Scholar
  52. Reyes, A., Lujan, R., Rozov, A., Burnashev, N., Somogyi, P. &; Sakmann, B. (1998) Target-cellspecific facilitation and depression in neocortical circuits. Nature Neuroscience 1, 279–285.PubMedGoogle Scholar
  53. Rudy, B. &; Mcbain, C. J. (2001) Kv3 channels: Voltagegated K+ channels designed for high-frequency repetitive firing. Trends in Neurosciences 24, 517–526.PubMedGoogle Scholar
  54. Sanchez-Vives, M. V. &; McCormick, D. A. (2000) Cellular and network mechanisms of rhythmic recurrent activity in neocortex. Nature Neuroscience 3, 1027–1034.PubMedGoogle Scholar
  55. Silva, L. R., Amitai, Y. &; Connors, B. W. (1991) Intrinsic oscillations of neocortex generated by layer 5 pyramidal neurons. Science 251, 432–435.PubMedGoogle Scholar
  56. Somogyi, P., Hodgson, A. J., Smith, A. D., Nunzi, M. G., Gorio, A. &; Wu, J.-Y. (1984) Different populations of GABAergic neurons in the visual cortex and hippocampus of cat contain somatostatinor cholecystokinin-immunoreactive material. Journal of Neuroscience 4, 2590–2603.PubMedGoogle Scholar
  57. Somogyi, P., TamÁs, G., Lujan, R. &; Buhl, E. H. (1998) Salient features of synaptic organisation in the cerebral cortex. Brain Research Review 26, 113–135.PubMedGoogle Scholar
  58. Steriade, M., Amzica, F., Neckelmann, D. &; Timofeev, I. (1998) Spike-wave complexes and fast components of cortically generated seizures. II. Extraand intracellular patterns. Journal of Neurophysiology 80, 1456–1479.PubMedGoogle Scholar
  59. Steriade, M., Nunez, A. &; Amzica, F. (1993a) A novel slow (<1 Hz) oscillation of neocortical neurons in vivo: Depolarizing and hyperpolarizing components. Journal of Neuroscience 13, 3252–3265.PubMedGoogle Scholar
  60. Steriade, M., Nunez, A. &; Amzica, F. (1993b) Intracellular analysis of relations between the slow (<1 Hz) neocortical oscillation and other sleep rhythms of the electroencephalogram. Journal of Neuroscience 13, 3266–3283.PubMedGoogle Scholar
  61. Stevens, C. F. (1998) Neuronal diversity: Too many cell types for comfort? Current Biology 8, R708–R710.PubMedGoogle Scholar
  62. TamÁs, G., Buhl, E. H., Lorincz, A. &; Somogyi, P. (2000) Proximally targeted GABAergic synapses and gap junctions synchronize cortical interneurons. Nature Neuroscience 3, 366–371.PubMedGoogle Scholar
  63. TamÁs, G., Somogyi, P. &; Buhl, E. H. (1998) Differentially interconnected networks of GABAergic interneurons in the visual cortex of the cat. Journal of Neuroscience 18, 4255–4270.PubMedGoogle Scholar
  64. Thomson, A. M. &; Deuchars, J. (1997) Synaptic interactions in neocortical local circuits: Dual intracellular recordings in vitro. Cerebral Cortex 7, 510–522.PubMedGoogle Scholar
  65. Thomson, A. M. &; West, D. C. (1986) Nmethylaspartate receptors mediate epileptiform activity evoked in some, but not all, conditions in rat neocortical slices. Neuroscience 19, 1161–1177.PubMedGoogle Scholar
  66. Thomson, A. M., West, D. C., Wang, Y. &; Bannister, A. P. (2002) 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. Cerebral Cortex 9, 936–953.Google Scholar
  67. Wang, Y., Gupta, A., Toledo-Rodriguez, M., Wu, C. Z. &; Markram, H. (2002) Anatomical, physiological, molecular and circuit properties of nest basket cells in the developing somatosensory cortex. Cerebral Cortex 12, 395–410.PubMedGoogle Scholar
  68. White, E. L. (1989) Cortical circuits: Synaptic Organization of the Cerebral Cortex Structure, Function, and Theory (edited by White, E. L. &; Keller, A.). Boston: Birkhüuser.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Yasuo Kawaguchi
    • 1
  • Satoru Kondo
    • 1
  1. 1.Division of Cerebral CircuitryNational Institute for Physiological SciencesOkazakiJapan

Personalised recommendations