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.
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.
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Lewis, D. A. & Lieberman, J. A. Catching up on schizophrenia: natural history and neurobiology. Neuron 28, 325–334 (2000).
Gottesman, I. I. Schizophrenia Genesis: The Origins of Madness (Freeman, New York, 1991).
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).
Lewis, D. A. & Levitt, P. Schizophrenia as a disorder of neurodevelopment. Annu. Rev. Neurosci. 25, 409–432 (2002).
American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 4th edn (American Psychiatry Association, Washington, D.C., 1994).
Elvevåg, B. & Goldberg, T. E. Cognitive impairment in schizophrenia is the core of the disorder. Crit. Rev. Neurobiol. 14, 1–21 (2000).
Davidson, M. et al. Behavioral and intellectual markers for schizophrenia in apparently healthy male adolescents. Am. J. Psychiatry 156, 1328–1335 (1999).
Saykin, A. J. et al. Neuropsychological deficits in neuroleptic naive patients with first-episode schizophrenia. Arch. Gen. Psychiatry 51, 124–131 (1994).
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).
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.
Blum, B. P. & Mann, J. J. The GABAergic system in schizophrenia. Int. J. Neuropsychopharmacol. 5, 159–179 (2002).
Benes, F. M. & Berretta, S. GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology 25, 1–27 (2001).
Miller, E. K. & Cohen, J. D. An integrative theory of prefrontal cortex function. Annu. Rev. Neurosci. 24, 167–202 (2001).
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.
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).
Callicott, J. H. et al. Complexity of prefrontal cortical dysfunction in schizophrenia: more than up or down. Am. J. Psychiatry 160, 2209–2215 (2003).
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).
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).
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).
Goldman-Rakic, P. S. Topography of cognition: parallel distributed networks in primate association cortex. Annu. Rev. Neurosci. 11, 137–156 (1988).
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.
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).
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).
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).
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).
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.
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).
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).
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.
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).
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).
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).
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).
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).
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).
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.
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.
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).
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.
Somogyi, P. A specific axo–axonal interneuron in the visual cortex of the rat. Brain Res. 136, 345–350 (1977).
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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.
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).
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).
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).
Levitan, E. S. et al. Structural and functional basis for GABAA receptor heterogeneity. Nature 335, 76–79 (1988).
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).
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.
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).
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).
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).
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).
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).
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).
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.
Akbarian, S. et al. GABAA receptor subunit gene expression in human prefrontal cortex: comparison of schizophrenics and controls. Cereb. Cortex 5, 550–560 (1995).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Glantz, L. A. & Lewis, D. A. Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch. Gen. Psychiatry 57, 65–73 (2000).
Garey, L. J. et al. Reduced dendritic spine density on cerebral cortical pyramidal neurons in schizophrenia. J. Neurol. Neurosurg. Psychiatry 65, 446–453 (1998).
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).
Morris, B. J., Cochran, S. M. & Pratt, J. A. PCP: from pharmacology to modelling schizophrenia. Curr. Opin. Pharmacol. 5, 101–106 (2005).
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).
Lipska, B. K. & Weinberger, D. R. To model a psychiatric disorder in animals: schizophrenia as a reality test. Neuropsychopharmacology 23, 223–239 (2000).
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).
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).
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).
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).
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).
Weickert, C. S. et al. Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol. Psychiatry 8, 592–610 (2003).
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).
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).
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).
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).
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.
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).
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).
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.
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).
Blatow, M. et al. A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex. Neuron 38, 805–817 (2003).
Peters, A. in Cerebral Cortex Vol. 1 (eds Jones, E. G. & Peters, A.) 361–380 (Plenum, New York, 1984).
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).
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).
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).
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.
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).
Overstreet, L. S. & Westbrook, G. L. Synapse density regulates independence at unitary inhibitory synapses. J. Neurosci. 23, 2618–2626 (2003).
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).
Löw, K. et al. Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290, 131–134 (2000).
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).
Winterer, G. & Weinberger, D. R. Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci. 27, 683–690 (2004).
Moghaddam, B. Bringing order to the glutamate chaos in schizophrenia. Neuron 40, 881–884 (2003).
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).
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).
Spencer, K. M. et al. Neural synchrony indexes disordered perception and cognition in schizophrenia. Proc. Natl Acad. Sci. USA (2004).
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).
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).
Diamond, A. in Principles of Frontal Lobe Function (eds Stuss, D. T. & Knight, R. T.) 466–503 (Oxford Univ. Press, London, 2002).
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).
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.
D.A.L. receives investigator-initiated research support from Lilly, Pfizer and Merck, and serves as a consultant for Pfizer.
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 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.
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.
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Lewis, D., Hashimoto, T. & Volk, D. Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 6, 312–324 (2005). https://doi.org/10.1038/nrn1648
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