Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cortical inhibitory neurons and schizophrenia

Key Points

  • Schizophrenia is a severe and chronic brain disorder that affects 1% of the population. Although psychotic symptoms, such as delusions and hallucinations, are usually the presenting and most striking clinical feature of the illness, disturbances in certain crucial cognitive functions, such as working memory, are now considered to represent core features of the illness. The degree of cognitive impairment is the best predictor of long-term functional outcome in individuals with schizophrenia, but, at present, no effective treatments for these symptoms are available. Therefore, the development of new therapeutics requires increased knowledge of the underlying disease process.

  • Working memory deficits in schizophrenia reflect dysfunction of the dorsolateral prefrontal cortex (DLPFC), and convergent lines of evidence indicate that this dysfunction is due, at least in part, to disturbances in a subpopulation of GABA (γ-aminobutyric acid) interneurons. For example, the expression of the mRNAs for the 67 kiloDalton isoform of glutamic acid decarboxylase (GAD67), an enzyme responsible for the synthesis of GABA, and for the GABA membrane transporter (GAT1) are decreased in the parvalbumin-expressing subpopulation of prefrontal GABA neurons. These changes in the parvalbumin-containing chandelier class of GABA neurons are associated with a marked post-synaptic upregulation of GABAA (GABA type A) receptors containing an α2 subunit in the axon initial segment of pyramidal cells, the synaptic target of chandelier neuron axon terminals. Convergent findings in both postmortem human brain specimens and genetically engineered mice indicate that deficient neurotrophin signalling through the tyrosine kinase Trk (tropomyosin-related kinase) receptor B (TrkB) might be a pathogenetic mechanism that underlies the reduced gene expression and impaired inhibitory neurotransmission in chandelier neurons.

  • It is proposed that the deficient inhibitory output from parvalbumin-expressing GABA neurons might impair the synchronization of DLPFC activity in the gamma-frequency oscillations that accompany normal working memory function. Consequently, pharmacological agents that selectively increase phasic GABA mediated function at the chandelier neuron inputs to pyramidal cell axon initial segments might improve working memory function in individuals with schizophrenia.

Abstract

Impairments in certain cognitive functions, such as working memory, are core features of schizophrenia. Convergent findings indicate that a deficiency in signalling through the TrkB neurotrophin receptor leads to reduced GABA (γ-aminobutyric acid) synthesis in the parvalbumin-containing subpopulation of inhibitory GABA neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia. Despite both pre- and postsynaptic compensatory responses, the resulting alteration in perisomatic inhibition of pyramidal neurons contributes to a diminished capacity for the gamma-frequency synchronized neuronal activity that is required for working memory function. These findings reveal specific targets for therapeutic interventions to improve cognitive function in individuals with schizophrenia.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Components of the disease process of schizophrenia.
Figure 2: Morphological and biochemical features of subpopulations of cortical GABA neurons in the dorsolateral prefrontal cortex.
Figure 3: Pre- and postsynaptic markers of chandelier neuron inputs to the axon initial segment of pyramidal neurons.
Figure 4: Expression of parvalbumin and calretinin mRNAs in the dorsolateral prefrontal cortex.
Figure 5: Changes in pre- and postsynaptic markers of GABA input to the axon initial segment of pyramidal neurons in the dorsolateral prefrontal cortex of individuals with schizophrenia.
Figure 6: Schematic summary of alterations in GABA circuitry in the dorsolateral prefrontal cortex of individuals with schizophrenia.
Figure 7: Reduced neurotrophin and GABA-related gene expression in the dorsolateral prefrontal cortex of individuals with schizophrenia.
Figure 8: Changes in gene expression in the prefrontal cortex of the TrkB hypomorphic mice are similar to those in individuals with schizophrenia.

References

  1. Lewis, D. A. & Lieberman, J. A. Catching up on schizophrenia: natural history and neurobiology. Neuron 28, 325–334 (2000).

    CAS  PubMed  Google Scholar 

  2. Gottesman, I. I. Schizophrenia Genesis: The Origins of Madness (Freeman, New York, 1991).

    Google Scholar 

  3. Owen, M. J., Williams, N. M. & O'Donovan, M. C. The molecular genetics of schizophrenia: new findings promise new insights. Mol. Psychiatry 9, 14–27 (2004).

    CAS  PubMed  Google Scholar 

  4. Lewis, D. A. & Levitt, P. Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci. 25, 409–432 (2002).

    CAS  PubMed  Google Scholar 

  5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatry Association, Washington, D.C., 1994).

  6. Elvevåg, B. & Goldberg, T. E. Cognitive impairment in schizophrenia is the core of the disorder. Crit. Rev. Neurobiol. 14, 1–21 (2000).

    PubMed  Google Scholar 

  7. Davidson, M. et al. Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. Am. J. Psychiatry 156, 1328–1335 (1999).

    CAS  PubMed  Google Scholar 

  8. Saykin, A. J. et al. Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch. Gen. Psychiatry 51, 124–131 (1994).

    CAS  PubMed  Google Scholar 

  9. Sitskoorn, M. M., Aleman, A., Ebisch, S. J., Appels, M. C. & Kahn, R. S. Cognitive deficits in relatives of patients with schizophrenia: a meta-analysis. Schizophr. Res. 71, 285–295 (2004).

    PubMed  Google Scholar 

  10. Green, M. F. What are the functional consequences of neurocognitive deficits in schizophrenia? Am. J. Psychiatry 153, 321–330 (1996). This review showed the central importance of cognitive deficits in long-term functional outcome in inidividuals with schizophrenia.

    CAS  PubMed  Google Scholar 

  11. Blum, B. P. & Mann, J. J. The GABAergic system in schizophrenia. Int. J. Neuropsychopharmacol. 5, 159–179 (2002).

    CAS  PubMed  Google Scholar 

  12. Benes, F. M. & Berretta, S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25, 1–27 (2001).

    CAS  PubMed  Google Scholar 

  13. Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev. Neurosci. 24, 167–202 (2001).

    CAS  PubMed  Google Scholar 

  14. Weinberger, D. R., Berman, K. F. & Zec, R. F. Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch. Gen. Psychiatry 43, 114–124 (1986). This seminal investigation showed that dysfunction of the prefrontal cortex, as reflected in reduced cerebral blood flow, was prominent when individuals with schizophrenia were asked to perform certain cognitive tasks.

    CAS  PubMed  Google Scholar 

  15. Perlstein, W. M., Carter, C. S., Noll, D. C. & Cohen, J. D. Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. Am. J. Psychiatry 158, 1105–1113 (2001).

    CAS  PubMed  Google Scholar 

  16. Callicott, J. H. et al. Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am. J. Psychiatry 160, 2209–2215 (2003).

    PubMed  Google Scholar 

  17. MacDonald, A. W. et al. Specificity of prefrontal dysfunction and context processing deficits to schizophrenia in a never medicated first-episode psychotic sample. Am. J. Psychiatry (in the press).

  18. Barch, D. M., Sheline, Y. I., Csernansky, J. G. & Snyder, A. Z. Working memory and prefrontal cortex dysfunction: specificity to schizophrenia compared with major depression. Biol. Psychiatry 53, 376–384 (2003).

    PubMed  Google Scholar 

  19. Silver, H., Feldman, P., Bilker, W. & Gur, R. C. Working memory deficit as a core neuropsychological dysfunction in schizophrenia. Am. J. Psychiatry 160, 1809–1816 (2003).

    PubMed  Google Scholar 

  20. Goldman-Rakic, P. S. Topography of cognition: parallel distributed networks in primate association cortex. Annu. Rev. Neurosci. 11, 137–156 (1988).

    CAS  PubMed  Google Scholar 

  21. Goldman-Rakic, P. S. Cellular basis of working memory. Neuron 14, 477–485 (1995). This review clearly summarizes the role of the coordinated, sustained firing of prefrontal pyramidal neurons in working memory.

    CAS  PubMed  Google Scholar 

  22. Wilson, F. A., Ó Scalaidhe, S. P. & Goldman-Rakic, P. S. Functional synergism between putative γ-aminobutyrate-containing neurons and pyramidal neurons in prefrontal cortex. Proc. Natl Acad. Sci. USA 91, 4009–4013 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Rao, S. G., Williams, G. V. & Goldman-Rakic, P. S. Destruction and creation of spatial tuning by disinhibition: GABAA blockade of prefrontal cortical neurons engaged by working memory. J. Neurosci. 20, 485–494 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Sawaguchi, T., Matsumura, M. & Kubota, K. Delayed response deficits produced by local injection of bicuculline into the dorsolateral prefrontal cortex in Japanese macaque monkeys. Exp. Brain Res. 75, 457–469 (1989).

    CAS  PubMed  Google Scholar 

  25. Constantinidis, C., Williams, G. V. & Goldman-Rakic, P. S. A role for inhibition in shaping the temporal flow of information in prefrontal cortex. Nature Neurosci. 5, 175–180 (2002).

    CAS  PubMed  Google Scholar 

  26. Akbarian, S. et al. Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch. Gen. Psychiatry 52, 258–266 (1995). The initial report of the now widely replicated deficit in GAD67 mRNA expression in the prefrontal cortex of individuals with schizophrenia.

    CAS  PubMed  Google Scholar 

  27. Volk, D. W., Austin, M. C., Pierri, J. N., Sampson, A. R. & Lewis, D. A. Decreased glutamic acid decarboxylase67 mRNA expression in a subset of prefrontal cortical γ-aminobutyric acid neurons in subjects with schizophrenia. Arch. Gen. Psychiatry 57, 237–245 (2000).

    CAS  PubMed  Google Scholar 

  28. Guidotti, A. et al. Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder. Arch. Gen. Psychiatry 57, 1061–1069 (2000).

    CAS  PubMed  Google Scholar 

  29. Mirnics, K., Middleton, F. A., Marquez, A., Lewis, D. A. & Levitt, P. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28, 53–67 (2000). This first application of microarray technology to the study of schizophrenia revealed altered expression of a group of genes that encode proteins involved in GABA neurotransmission in the prefrontal cortex of individuals with schizophrenia.

    CAS  PubMed  Google Scholar 

  30. Vawter, M. P. et al. Microarray analysis of gene expression in the prefrontal cortex in schizophrenia: a preliminary study. Schizophr. Res. 58, 11–20 (2002).

    PubMed  Google Scholar 

  31. Hashimoto, T. et al. Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. J. Neurosci. 25, 372–383 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Knable, M. B., Barci, B. M., Bartko, J. J., Webster, M. J. & Torrey, E. F. Molecular abnormalities in the major psychiatric illnesses: Classification and Regression Tree (CRT) analysis of post-mortem prefrontal markers. Mol. Psychiatry 7, 392–404 (2002).

    CAS  PubMed  Google Scholar 

  33. Benes, F. M., Todtenkopf, M. S., Logiotatos, P. & Williams, M. Glutamate decarboxylase(65)-immunoreactive terminals in cingulate and prefrontal cortices of schizophrenic and bipolar brain. J. Chem. Neuroanat. 20, 259–269 (2000).

    CAS  PubMed  Google Scholar 

  34. Asada, H. et al. Mice lacking the 65 kDa isoform of glutamic acid decarboxylase (GAD65) maintain normal levels of GAD67 and GABA in their brains but are susceptible to seizures. Biochem. Biophys. Res. Comm. 229, 891–895 (1996).

    CAS  PubMed  Google Scholar 

  35. Asada, H. et al. Cleft palate and decreased brain γ-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase. Proc. Natl Acad. Sci. USA 94, 6496–6499 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Markram, H. et al. Interneurons of the neocortical inhibitory system. Nature Rev. Neurosci. 5, 793–807 (2004). A comprehensive review of the various electrophysiological, morphological and molecular characteristics of GABA neurons in rodent cerebral cortex.

    CAS  Google Scholar 

  37. McBain, C. J. & Fisahn, A. Interneurons unbound. Nature Rev. Neurosci. 2, 11–23 (2001). An excellent review of the functional roles of GABA neurons in cortical function.

    CAS  Google Scholar 

  38. Lewis, D. A. & Lund, J. S. Heterogeneity of chandelier neurons in monkey neocortex: corticotropin-releasing factor and parvalbumin immunoreactive populations. J. Comp. Neurol. 293, 599–615 (1990).

    CAS  PubMed  Google Scholar 

  39. 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). The first report that correlated electrophysiological and morphological features of cortical GABA neurons.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Somogyi, P. A specific axo–axonal interneuron in the visual cortex of the rat. Brain Res. 136, 345–350 (1977).

    CAS  PubMed  Google Scholar 

  41. Condé, F., Lund, J. S., Jacobowitz, D. M., Baimbridge, K. G. & Lewis, D. A. Local circuit neurons immunoreactive for calretinin, calbindin D-28k, or parvalbumin in monkey prefrontal cortex: distribution and morphology. J. Comp. Neurol. 341, 95–116 (1994).

    PubMed  Google Scholar 

  42. González-Burgos, G., Krimer, L. S., Povysheva, N. V., Barrionuevo, G. & Lewis, D. A. Functional properties of fast spiking interneurons and their synaptic connections with pyramidal cells in primate dorsolateral prefrontal cortex. J. Neurophysiol. 93, 942–953 (2005).

    PubMed  Google Scholar 

  43. 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).

    CAS  PubMed  Google Scholar 

  44. Zaitsev, A. V. et al. Localization of calcium-binding proteins in physiologically and morphologically characterized interneurons of monkey dorsolateral prefrontal cortex. Cereb. Cortex 8 December 2004 (doi:10.1093/cercor/bhh218).

  45. Melchitzky, D. S., Eggan, S. M. & Lewis, D. A. Synaptic targets of calretinin-containing axon terminals in macaque monkey prefrontal cortex. Neuroscience 130, 185–195 (2005).

    CAS  PubMed  Google Scholar 

  46. Volk, D. W., Austin, M. C., Pierri, J. N., Sampson, A. R. & Lewis, D. A. GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. Am. J. Psychiatry 158, 256–265 (2001).

    CAS  PubMed  Google Scholar 

  47. Hashimoto, T. et al. Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J. Neurosci. 23, 6315–6326 (2003). Through the use of subpopulation-specific molecular markers, this study confirmed that the parvalbumin-expressing subpopulation of GABA neurons is particularly vulnerable in schizophrenia.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Woo, T. -U., Miller, J. L. & Lewis, D. A. Schizophrenia and the parvalbumin-containing class of cortical local circuit neurons. Am. J. Psychiatry 154, 1013–1015 (1997).

    CAS  PubMed  Google Scholar 

  49. Beasley, C. L., Zhang, Z. J., Patten, I. & Reynolds, G. P. Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Biol. Psychiatry 52, 708–715 (2002).

    CAS  PubMed  Google Scholar 

  50. Woo, T. -U., Whitehead, R. E., Melchitzky, D. S. & Lewis, D. A. A subclass of prefrontal γ-aminobutyric acid axon terminals are selectively altered in schizophrenia. Proc. Natl Acad. Sci. USA 95, 5341–5346 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Pierri, J. N., Chaudry, A. S., Woo, T. -U. & Lewis, D. A. Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. Am. J. Psychiatry 156, 1709–1719 (1999).

    CAS  PubMed  Google Scholar 

  52. Mody, I. & Pearce, R. A. Diversity of inhibitory neurotransmission through GABAA receptors. Trends Neurosci. 27, 569–575 (2004). An excellent review of the specific functional roles of different types of cortical GABA A receptors.

    CAS  PubMed  Google Scholar 

  53. Fritschy, J. -M. & Mohler, H. GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359, 154–194 (1995).

    CAS  PubMed  Google Scholar 

  54. Nusser, Z., Sieghart, W., Benke, D., Fritschy, J. -M. & Somogyi, P. Differential synaptic localization of two major γ-aminobutyric acid type A receptor α subunits on hippocampal pyramidal cells. Proc. Natl Acad. Sci. USA 93, 11939–11944 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Loup, F. et al. A highly sensitive immunofluorescence procedure for analyzing the subcellular distribution of GABAA receptor subunits in the human brain. J. Histochem. Cytochem. 46, 1129–1139 (1998).

    CAS  PubMed  Google Scholar 

  56. Levitan, E. S. et al. Structural and functional basis for GABAA receptor heterogeneity. Nature 335, 76–79 (1988).

    CAS  PubMed  Google Scholar 

  57. Lavoie, A. M., Tingey, J. J., Harrison, N. L., Pritchett, D. B. & Twyman, R. E. Activation and deactivation rates of recombinant GABAA receptor channels are dependent on α-subunit isoform. Biophys. J. 73, 2518–2526 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Volk, D. W. et al. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb. Cortex 12, 1063–1070 (2002). The authors showed that the presynaptic reduction in GABA transporters in chandelier axon terminals was associated with an upregulation of postsynaptic α2-containing GABA A receptors in the axon initial segments of pyramidal neurons in individuals with schizophrenia.

    PubMed  Google Scholar 

  59. Pierri, J. N., Volk, C. L., Auh, S., Sampson, A. & Lewis, D. A. Somal size of prefrontal cortical pyramidal neurons in schizophrenia: differential effects across neuronal subpopulations. Biol. Psychiatry 54, 111–120 (2003).

    PubMed  Google Scholar 

  60. Cruz, D. A., Eggan, S. M., Azmitia, E. C. & Lewis, D. A. Serotonin 1A receptors at the axon initial segment of prefrontal pyramidal neurons in schizophrenia. Am. J. Psychiatry 161, 739–742 (2004).

    PubMed  Google Scholar 

  61. Jensen, K., Chiu, C. S., Sokolova, I., Lester, H. A. & Mody, I. GABA transporter-1 (GAT1)-deficient mice: differential tonic activation of GABAA versus GABAB receptors in the hippocampus. J. Neurophysiol. 90, 2690–2701 (2003).

    CAS  PubMed  Google Scholar 

  62. Erickson, S. L. & Lewis, D. A. Postnatal development of parvalbumin- and GABA transporter-immunoreactive axon terminals in monkey prefrontal cortex. J. Comp. Neurol. 448, 186–202 (2002).

    CAS  PubMed  Google Scholar 

  63. Lewis, D. A., Cruz, D. A., Melchitzky, D. S. & Pierri, J. N. Lamina-specific deficits in parvalbumin-immunoreactive varicosities in the prefrontal cortex of subjects with schizophrenia: evidence for fewer projections from the thalamus. Am. J. Psychiatry 158, 1411–1422 (2001).

    CAS  PubMed  Google Scholar 

  64. Hanada, S., Mita, T., Nishino, N. & Tanaka, C. [3H]Muscimol binding sites increased in autopsied brains of chronic schizophrenics. Life Sci. 40, 239–266 (1987).

    Google Scholar 

  65. Benes, F. M., Vincent, S. L., Marie, A. & Khan, Y. Up-regulation of GABAA receptor binding on neurons of the prefrontal cortex in schizophrenic subjects. Neuroscience 75, 1021–1031 (1996). This study showed an increased level of GABA A receptors in the prefrontal pyramidal neurons of individuals with schizophrenia.

    CAS  PubMed  Google Scholar 

  66. Akbarian, S. et al. GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls. Cereb. Cortex 5, 550–560 (1995).

    CAS  PubMed  Google Scholar 

  67. Impagnatiello, F. et al. A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proc. Natl Acad. Sci. USA 95, 15718–15723 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Ohnuma, T., Augood, S. J., Arai, H., McKenna, P. J. & Emson, P. C. Measurement of GABAergic parameters in the prefrontal cortex in schizophrenia: focus on GABA content, GABAA receptor α-1 subunit messenger RNA and human GABA transporter-1 (HGAT-1) messenger RNA expression. Neuroscience 93, 441–448 (1999).

    CAS  PubMed  Google Scholar 

  69. Benes, F. M., Kwok, E. W., Vincent, S. L. & Todtenkopf, M. S. Reduction of nonpyramidal cells in section CA2 of schizophrenics and manic depressives. Biol. Psychiatry 44, 88–97 (1998).

    CAS  PubMed  Google Scholar 

  70. Heckers, S. et al. Differential hippocampal expression of glutamic acid decarboxylase 65 and 67 messenger RNA in bipolar disorder and schizophrenia. Arch. Gen. Psychiatry 59, 521–529 (2002).

    CAS  PubMed  Google Scholar 

  71. Cotter, D. et al. The density and spatial distribution of GABAergic neurons, labelled using calcium binding proteins, in the anterior cingulate cortex in major depressive disorder, bipolar disorder, and schizophrenia. Biol. Psychiatry 51, 377–386 (2002).

    CAS  PubMed  Google Scholar 

  72. Woo, T. -U., Walsh, J. P. & Benes, F. M. Density of glutamic acid decarboxylase 67 messenger RNA-containing neurons that express the N-methyl-D-aspartate receptor subunit NR2A in the anterior cingulate cortex in schizophrenia and bipolar disorder. Arch. Gen. Psychiatry 61, 649–657 (2004).

    CAS  PubMed  Google Scholar 

  73. Konopaske, G. T., Sweet, R. A. & Lewis, D. A. GABA transporter-1 immunoreactivity in auditory association cortex in schizophrenia. Soc. Neurosci. Abstr. 34, 110.11 (2004).

    Google Scholar 

  74. Pesold, C. et al. Reelin is preferentially expressed in neurons synthesizing γ-aminobutyric acid in cortex and hippocampus of adult rats. Proc. Natl Acad. Sci. USA 95, 3221–3226 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Liu, W. S. et al. Down-regulation of dendritic spine and glutamic acid decarboxylase 67 expressions in the reelin haploinsufficient heterozygous reeler mouse. Proc. Natl Acad. Sci. USA 98, 3477–3482 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Pesold, C., Liu, W. S., Guidotti, A., Costa, E. & Caruncho, H. J. Cortical bitufted, horizontal, and Martinotti cells preferentially express and secrete reelin in perineuronal nets, postsynaptically modulating gene expression. Proc. Natl Acad. Sci. USA 96, 3217–3222 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Dorph-Petersen, K. -A., Pierri, J. N., Sun, Z., Sampson, A. R. & Lewis, D. A. Stereological analysis of the mediodorsal thalamic nucleus in schizophrenia: volume, neuron number, and cell types. J. Comp. Neurol. 472, 449–462 (2004).

    PubMed  Google Scholar 

  78. Volk, D. W. & Lewis, D. A. Effects of a mediodorsal thalamus lesion on prefrontal inhibitory circuitry: implications for schizophrenia. Biol. Psychiatry 53, 385–389 (2003).

    PubMed  Google Scholar 

  79. Glantz, L. A. & Lewis, D. A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65–73 (2000).

    CAS  PubMed  Google Scholar 

  80. Garey, L. J. et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J. Neurol. Neurosurg. Psychiatry 65, 446–453 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Coyle, J. T., Tsai, G. & Goff, D. Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia. Ann. NY Acad. Sci. 1003, 318–327 (2003).

    CAS  PubMed  Google Scholar 

  82. Morris, B. J., Cochran, S. M. & Pratt, J. A. PCP: from pharmacology to modelling schizophrenia. Curr. Opin. Pharmacol. 5, 101–106 (2005).

    CAS  PubMed  Google Scholar 

  83. Bertolino, A. et al. Regionally specific pattern of neurochemical pathology in schizophrenia as assessed by multislice proton magnetic resonance spectroscopic imaging. Am. J. Psychiatry 153, 1554–1563 (1996).

    CAS  PubMed  Google Scholar 

  84. Lipska, B. K. & Weinberger, D. R. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23, 223–239 (2000).

    CAS  PubMed  Google Scholar 

  85. Lipska, B. K., Lerman, D. N., Khaing, Z. Z., Weickert, C. S. & Weinberger, D. R. Gene expression in dopamine and GABA systems in an animal model of schizophrenia: effects of antipsychotic drugs. Eur. J. Neurosci. 18, 391–402 (2003).

    PubMed  Google Scholar 

  86. Addington, A. M. et al. GAD1 (2q31.1), which encodes glutamic acid decarboxylase (GAD67), is associated with childhood-onset schizophrenia and cortical gray matter volume loss. Mol. Psychiatry 26 Oct 2004 (doi:10.1038/sj.mp.4001599).

  87. Yamada, M. K. et al. Brain-derived neurotrophic factor promotes the maturation of GABAergic mechanisms in cultured hippocampal neurons. J. Neurosci. 22, 7580–7585 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Huang, Z. J. et al. BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell 98, 739–755 (1999).

    CAS  PubMed  Google Scholar 

  89. Cellerino, A., Maffei, L. & Domenici, L. The distribution of brain-derived neurotrophic factor and its receptor trkB in parvalbumin-containing neurons of the rat visual cortex. Eur. J. Neurosci. 8, 1190–1197 (1996).

    CAS  PubMed  Google Scholar 

  90. Weickert, C. S. et al. Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol. Psychiatry 8, 592–610 (2003).

    CAS  PubMed  Google Scholar 

  91. Thune, J. J., Uylings, H. B. M. & Pakkenberg, B. No deficit in total number of neurons in the prefrontal cortex in schizophrenics. J. Psychiatr. Res. 35, 15–21 (2001).

    CAS  PubMed  Google Scholar 

  92. Xu, B. et al. The role of brain-derived neurotrophic factor receptors in the mature hippocampus: modulation of long-term potentiation through a presynaptic mechanism involving TrkB. J. Neurosci. 20, 6888–6897 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Monteggia, L. M. et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc. Natl Acad. Sci. USA 101, 10827–10832 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Tallon-Baudry, C., Bertrand, O., Peronnet, F. & Pernier, J. Induced gamma-band activity during the delay of a visual short-term memory task in humans. J. Neurosci. 18, 4244–4254 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Howard, M. W. et al. Gamma oscillations correlate with working memory load in humans. Cereb. Cortex 13, 1369–1374 (2003). Showed that gamma band power in the human prefrontal cortex increases directly with working memory load.

    PubMed  Google Scholar 

  96. Spencer, K. M., Nestor, P. G., Salisbury, D. F., Shenton, M. E. & McCarley, R. W. Abnormal neural synchrony in schizophrenia. J. Neurosci. 23, 7407–7411 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Cho, R. Y., Konecky, R. O. & Carter, C. S. Impaired task-set maintenance and frontal cortical gamma-band synchrony in schizophrenia. Cognitive Neuroscience Society Annual Meeting (2004).

    Google Scholar 

  98. 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). A seminal study that shows the crucial role of proximal inhibition in synchronizing pyramidal cell output.

    CAS  PubMed  Google Scholar 

  99. 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).

    CAS  PubMed  Google Scholar 

  100. Blatow, M. et al. A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex. Neuron 38, 805–817 (2003).

    CAS  PubMed  Google Scholar 

  101. Peters, A. in Cerebral Cortex Vol. 1 (eds Jones, E. G. & Peters, A.) 361–380 (Plenum, New York, 1984).

    Google Scholar 

  102. Melchitzky, D. S., Sesack, S. R. & Lewis, D. A. Parvalbumin-immunoreactive axon terminals in macaque monkey and human prefrontal cortex: laminar, regional and target specificity of type I and type II synapses. J. Comp. Neurol. 408, 11–22 (1999).

    CAS  PubMed  Google Scholar 

  103. Melchitzky, D. S., González-Burgos, G., Barrionuevo, G. & Lewis, D. A. Synaptic targets of the intrinsic axon collaterals of supragranular pyramidal neurons in monkey prefrontal cortex. J. Comp. Neurol. 430, 209–221 (2001).

    CAS  PubMed  Google Scholar 

  104. Melchitzky, D. S. & Lewis, D. A. Pyramidal neuron local axon terminals in monkey prefrontal cortex: differential targeting of subclasses of GABA neurons. Cereb. Cortex 13, 452–460 (2003).

    PubMed  Google Scholar 

  105. Pouille, F. & Scanziani, M. Enforcement of temporal fidelity in pyramidal cells by somatic feed-forward inhibition. Science 293, 1159–1163 (2001). An important investigation that shows the role of feedforward perisomatic inhibition in controlling the timing of pyramidal cell function.

    CAS  PubMed  Google Scholar 

  106. Vreugdenhil, M., Jefferys, J. G., Celio, M. R. & Schwaller, B. Parvalbumin-deficiency facilitates repetitive IPSCs and gamma oscillations in the hippocampus. J. Neurophysiol. 89, 1414–1422 (2003).

    PubMed  Google Scholar 

  107. Overstreet, L. S. & Westbrook, G. L. Synapse density regulates independence at unitary inhibitory synapses. J. Neurosci. 23, 2618–2626 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Lewis, D. A., Volk, D. W. & Hashimoto, T. Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction. Psychopharmacology 174, 143–150 (2004).

    CAS  PubMed  Google Scholar 

  109. Löw, K. et al. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131–134 (2000).

    PubMed  Google Scholar 

  110. Carpenter, W. T. Jr, Buchanan, R. W., Kirkpatrick, B. & Breier, A. F. Diazepam treatment of early signs of exacerbation in schizophrenia. Am. J. Psychiatry 156, 299–303 (1999).

    PubMed  Google Scholar 

  111. Winterer, G. & Weinberger, D. R. Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci. 27, 683–690 (2004).

    CAS  PubMed  Google Scholar 

  112. Moghaddam, B. Bringing order to the glutamate chaos in schizophrenia. Neuron 40, 881–884 (2003).

    CAS  PubMed  Google Scholar 

  113. Sesack, S. R., Hawrylak, V. A., Melchitzky, D. S. & Lewis, D. A. Dopamine innervation of a subclass of local circuit neurons in monkey prefrontal cortex: ultrastructural analysis of tyrosine hydroxylase and parvalbumin immunoreactive structures. Cereb. Cortex 8, 614–622 (1998).

    CAS  PubMed  Google Scholar 

  114. Kondo, M., Sumino, R. & Okado, H. Combinations of AMPA receptor subunit expression in individual cortical neurons correlate with expression of specific calcium-binding proteins. J. Neurosci. 17, 1570–1581 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Spencer, K. M. et al. Neural synchrony indexes disordered perception and cognition in schizophrenia. Proc. Natl Acad. Sci. USA (2004).

  116. Cruz, D. A., Eggan, S. M. & Lewis, D. A. Postnatal development of pre- and post-synaptic GABA markers at chandelier cell inputs to pyramidal neurons in monkey prefrontal cortex. J. Comp. Neurol. 465, 385–400 (2003).

    PubMed  Google Scholar 

  117. 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).

    CAS  PubMed  Google Scholar 

  118. Diamond, A. in Principles of Frontal Lobe Function (eds Stuss, D. T. & Knight, R. T.) 466–503 (Oxford Univ. Press, London, 2002).

    Google Scholar 

  119. Lewis, D. A., Glantz, L. A., Pierri, J. N. & Sweet, R. A. Altered cortical glutamate neurotransmission in schizophrenia: evidence from morphological studies of pyramidal neurons. Ann. NY Acad. Sci. 1003, 102–112 (2003).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Work by the authors cited in this manuscript was supported by grants from the National Institutes of Health and by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (T.H.). The authors thank M. Brady and L. Konopka for excellent assistance with the figures and text.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David A. Lewis.

Ethics declarations

Competing interests

D.A.L. receives investigator-initiated research support from Lilly, Pfizer and Merck, and serves as a consultant for Pfizer.

Related links

Related links

DATABASES

Entrez

BDNF

GAD65

GAD67

GAT1

TrkB

FURTHER INFORMATION

Lewis's Laboratory

Glossary

PSYCHOSIS

This refers to distortions in inferential thinking, such as delusions (fixed, false beliefs that are firmly held in the face of contradictory evidence), and perceptual disturbances, such as hallucinations. Auditory hallucinations, usually experienced as voices distinct from one's own thoughts, are most common in schizophrenia.

WORKING MEMORY

The active maintenance of limited amounts of information for a short period of time to guide thought processes or sequences of behaviour. Working memory is typically assessed through delayed response tasks in which a stimulus cue is briefly presented and removed, a delay period ensues, and then a response is required based on information contained in the stimulus cue.

DORSOLATERAL PREFRONTAL CORTEX

(DLPFC). Those regions on the dorsal surface of the primate frontal lobe that are located rostral to the motor and premotor regions, and which include Brodmann's areas 9 and 46.

PYRAMIDAL NEURONS

These constitute 75% of cortical neurons, and are recognized by their triangular cell bodies, a single apical dendrite directed toward the cortical surface and an array of basilar dendrites. The dendrites of these neurons are studded with many spines, and their axons project into the white matter and provide excitatory projections to other cortical regions or subcortical structures.

GABA NEURONS

These comprise 25% of cortical neurons, have smooth or sparsely spiny dendrites and provide axons that project locally within the cortical grey matter.

REELIN

Reelin is a large protein that is secreted into the extracellular matrix by Cajal–Retzius cells. It regulates the migration of cortical neurons during development. The absence of reelin in the reeler mouse results in a distinctive alteration of the normal cellular architecture of the cortex.

BENZODIAZEPINE

Benzodiazepines bind to GABAA receptors, where they increase the frequency of opening of Cl channels in the presence of GABA, but do not directly open channels in the absence of GABA. At present, the available benzodiazepines are not selective for GABAA receptors that contain the α2 subunit, and so produce a range of effects, such as the sedation mediated by the α1 subunit, which can impair cognitive processes.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lewis, D., Hashimoto, T. & Volk, D. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6, 312–324 (2005). https://doi.org/10.1038/nrn1648

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn1648

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing