Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-77c89778f8-7drxs Total loading time: 0 Render date: 2024-07-16T16:12:09.832Z Has data issue: false hasContentIssue false

17 - Development of thalamocortical circuitry and the pathophysiology of schizophrenia

Published online by Cambridge University Press:  04 August 2010

By
Darlene S. Melchitzky  and
David A. Lewis
Edited by
Matcheri S. Keshavan ,
James L. Kennedy  and
Robin M. Murray
Darlene S. Melchitzky
Affiliation:
Mercyhurst College, Erie, USA
David A. Lewis
Affiliation:
University of Pittsburgh, Pittsburgh, USA
Matcheri S. Keshavan
Affiliation:
University of Pittsburgh
James L. Kennedy
Affiliation:
Clarke Institute of Psychiatry, Toronto
Robin M. Murray
Affiliation:
Institute of Psychiatry, London
Get access

Summary

Schizophrenia is a multithetic disorder in which the diverse signs and illness symptoms arise as a result of dysfunction in a number of brain regions. Individuals with schizophrenia perform poorly on cognitive tasks that require the use of working memory: the ability to maintain information "on line" in order to guide behavior. Both imaging and postmortem studies have revealed abnormalities in the thalamus of subjects with schizophrenia. Evidence for abnormalities in mediodorsal nucleus (MDN) to dorsolateral prefrontal cortex (DLPFC) projections includes reductions of both pre- and postsynaptic markers for the axons. The discussed findings suggest that alterations in MDN-DLPFC circuitry play a critical role in the pathophysiology of cognitive dysfunction in schizophrenia. Relatively few studies have examined details of the organization of MDN-DLPFC circuitry in primates, and much of our understanding of the functional attributes of this circuitry represents reasonable but speculative extrapolation from studies of sensory thalamic systems.

Keywords

cognitive dysfunctiondorsolateral prefrontal cortexmediodorsal nucleusthalamocortical circuitryschizophreniapathophysiology
Type
Chapter
Information
Neurodevelopment and Schizophrenia , pp. 310 - 329
Publisher: Cambridge University Press
Print publication year: 2004

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Akbarian, S., Kim, J. J., Potkin, S. G.et al. (1995). Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 52: 258–266CrossRefGoogle ScholarPubMed
Akil, M., Pierri, J. N., Whitehead, R. E.et al. (1999). Lamina-specific alteration in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry 156: 1580–1589CrossRefGoogle Scholar
Alexander, G. E. (1982). Functional development of frontal association cortex in monkeys: behavioral and electrophysiological studies. Neurosci Res Prog Bull 20: 471–479
Alexander, G. E., Goldman, P. S. (1978). Functional development of the dorsolateral prefrontal cortex: an analysis utilizing reversible cryogenic depression. Brain Res 143: 233–249CrossRefGoogle Scholar
Anderson, S. A., Classey, J. D., Condé, F., Lund, J. S., Lewis, D. A. (1995). Synchronous development of pyramidal neuron dendritic spines and parvalbumin-immunoreactive chandelier neuron axon terminals in layer III of monkey prefrontal cortex. Neuroscience 67: 7–22CrossRefGoogle ScholarPubMed
Barbas, H., Haswell Henion, T. H., Dermon, C. R. (1991). Diverse thalamic projections to the prefrontal cortex in the rhesus monkey. J Comp Neurol 313: 65–94CrossRefGoogle ScholarPubMed
Benes, F. M., Davidson, J., Bird, E. D. (1986). Quantitative cytoarchitectural studies of the cerebral cortex of schizophrenics. Arch Gen Psychiatry 43: 31–35CrossRefGoogle ScholarPubMed
Bourgeois, J.-P., Goldman-Rakic, P. S., Rakic, P. (1994). Synaptogenesis in the prefrontal cortex of rhesus monkeys. Cereb Cortex 4: 78–96CrossRefGoogle ScholarPubMed
Bunge, S. A., Dudukovic, N. M., Thomason, M. E., Vaidya, C. J., Gabrieli, J. D. E. (2002). Immature frontal lobe contributions to cognitive control in children: Evidence from MRI. Neuron 33: 311CrossRefGoogle Scholar
Byne, W., Buchsbaum, M. S., Kemether, E.et al. (2001). Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder. Arch Gen Psychiatry 58: 133–140CrossRefGoogle ScholarPubMed
Byne, W., Buchsbaum, M. S., Mattiace, L. A.et al. (2002). Postmortem assessment of thalamic nuclear volumes in subjects with schizophrenia. Am J Psychiatry 159: 59–65CrossRefGoogle ScholarPubMed
Casey, B. J., Giedd, J. N., Thomas, K. M. (2000). Structural and functional brain development and its relation to cognitive development. Biol Psychol 54: 241–257CrossRefGoogle ScholarPubMed
Condé, F., Lund, J. S., Jacobowitz, D. M., Baimbridge, K. G., Lewis, D. A. (1994). Local circuit neurons immunoreactive for calretinin, calbindin D-28k, or parvalbumin in monkey prefrontal cortex: distribution and morphology. J Comp Neurol 341: 95–116CrossRefGoogle ScholarPubMed
Cruz, D. A., Eggan, S. M., Lewis, D. A. (2003). Postnatal development of pre- and post-synaptic GABA markers at chandelier cell inputs to pyramidal neurons in monkey prefrontal cortex. J Comp Neurol 465: 385–400CrossRefGoogle Scholar
DeFelipe, J., Jones, E. G. (1991). Parvalbumin immunoreactivity reveals layer IV of monkey cerebral cortex as a mosaic of microzones of thalamic afferent terminations. Brain Res 562: 39–47CrossRefGoogle ScholarPubMed
DeFelipe, J., Hendry, S. H. C., Jones, E. G., Schmechel, D. (1985). Variability in the terminations of GABAergic chandelier cell axons on initial segments of pyramidal cell axons in the monkey sensory-motor cortex. J Comp Neurol 231: 364–384CrossRefGoogle ScholarPubMed
Diamond, A. (1985). Development of the ability to use recall to guide action, as indicated by infants' performances on AB. Child Devel 56: 868–883CrossRefGoogle Scholar
Diamond, A. (2002). Normal development of prefrontal cortex from birth to young adulthood: cognitive functions, anatomy, and biochemistry. In Principles of Frontal Lobe Function, ed. D. T. Stuss, R. T. Knight. London: Oxford University Press, pp. 466–503CrossRef
Elvevåg, B., Goldberg, T. E. (2000). Cognitive impairment in schizophrenia is the core of the disorder. Crit Rev Neurobiol 14: 1–21CrossRefGoogle ScholarPubMed
Erickson, S. L., Lewis, D. A. (2000). Prefrontal cortical inputs to monkey mediodorsal thalamus. Soc Neurosci Abstr 26: 1237Google Scholar
Erickson, S. L., Lewis, D. A. (2002). Postnatal development of parvalbumin- and GABA transporter-immunoreactive axon terminals in monkey prefrontal cortex. J Comp Neurol 448: 186–202CrossRefGoogle ScholarPubMed
Funahashi, S., Bruce, C. J., Goldman-Rakic, P. S. (1989). Mnemonic coding of visual space in the monkey's dorsolateral prefrontal cortex. J Neurophysiol 61: 331–349CrossRefGoogle ScholarPubMed
Fuster, J. M. (1997). The Prefrontal Cortex: Anatomy, Physiology, and Neuropsychology of the Frontal Lobe. Philadelphia, PA: Lippincott-Raven
Fuster, J. J., Alexander, G. E. (1971). Neuron activity related to short-term memory. Science 173: 652–654CrossRefGoogle ScholarPubMed
Ghosh, A., Antonini, A., McConnell, S. K., Shatz, C. J. (1990). Requirement for subplate neurons in the formation of thalamocortical connections. Nature 347: 179–181CrossRefGoogle ScholarPubMed
Giedd, J. N. (1999). Brain development during childhood and adolescence: a longitudinal MRI study. Nat Neurosci 2: 861–863CrossRefGoogle ScholarPubMed
Giguere, M., Goldman-Rakic, P. S. (1988). Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys. J Comp Neurol 277: 195–213CrossRefGoogle ScholarPubMed
Gilbert, A. R., Rosenberg, D. R., Harenski, K.et al. (2001). Thalamic volumes in patients with first-episode schizophrenia. Am J Psychiatry 158: 618–624CrossRefGoogle ScholarPubMed
Glantz, L. A., Lewis, D. A. (2000). Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 57: 65–73CrossRefGoogle Scholar
Goldman-Rakic, P. S. (1987). Development of cortical circuitry and cognitive function. Child Devel 58: 601–622CrossRefGoogle ScholarPubMed
Goldman-Rakic, P. S. (1994). Working memory dysfunction in schizophrenia. J Neuropsychiatry 6: 348–357Google Scholar
Goldman-Rakic, P. S. (1995). Cellular basis of working memory. Neuron 14: 477–485CrossRefGoogle ScholarPubMed
Goldman-Rakic, P. S., Porrino, L. J. (1985). The primate mediodorsal (MD) nucleus and its projection to the frontal lobe. J Comp Neurol 242: 535–560CrossRefGoogle ScholarPubMed
Grutzendler, J., Kasthuri, N., Gan, W. B. (2002). Long-term dendritic spine stability in the adult cortex. Nature 420: 812–816CrossRefGoogle ScholarPubMed
Guidotti, A., Auta, J., Davis, J. M.et al. (2000). Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder. Arch Gen Psychiatry 57: 1061–1069CrossRefGoogle ScholarPubMed
Harrison, P. J., Lewis, D. A. (2003). Neuropathology in schizophrenia. In Schizophrenia, 2nd edn, ed. S. Hirsch, D. R. Weinberger. Oxford: Blackwell Science, Oxford University Press, pp. 310–325CrossRef
Hashimoto, T., Volk, D. W., Eggan, S. M.et al. (2003). Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia. J Neurosci 23: 6315–6326CrossRefGoogle Scholar
Heizmann, C. W. (1984). Parvalbumin an intracellular calcium-binding protein. Distribution properties and possible roles in mammalian cells. Experientia 40: 910–921CrossRefGoogle ScholarPubMed
Huttenlocher, P. R. (1979). Synaptic density in human frontal cortex: developmental changes and effects of aging. Brain Res 163: 195–205Google ScholarPubMed
Isseroff, A., Rosvold, H. E., Galkin, T. W., Goldman-Rakic, P. S. (1982). Spatial memory impairments following damage to the mediodorsal nucleus of the thalamus in rhesus monkeys. Brain Res 232: 97–113CrossRefGoogle ScholarPubMed
Jones, E. G., Hendry, S. H. C., DeFelipe, J., Benson, D. L. (1994). GABA neurons and their role in activity-dependent plasticity of adult primate visual cortex. In Cerebral Cortex, Vol. 10: Primary Visual Cortex in Primates, ed. A. Peters, K. S. Rockland. New York: Plenum Press, pp. 61–140CrossRef
Konick, L. C., Friedman, L. (2001). Meta-analysis of thalamic size in schizophrenia. Biol Psychiatry 49: 28–38CrossRefGoogle Scholar
Kuroda, M., Yokofujita, J., Murakami, K. (1998). An ultrastructural study of the neural circuit between the prefrontal cortex and the mediodorsal nucleus of the thalamus. Prog Neurobiol 54: 417–458CrossRefGoogle ScholarPubMed
Levitt, J. B., Lewis, D. A., Yoshioka, T., Lund, J. S. (1993). Topography of pyramidal neuron intrinsic connections in macaque monkey prefrontal cortex (areas 9 and 46). J Comp Neurol 338: 360–376CrossRefGoogle Scholar
Lewis, D. A. (2000). Is there a neuropathology of schizophrenia?The Neuroscientist 6: 208–218CrossRefGoogle Scholar
Lewis, D. A. (2002). Neural circuitry approaches to understanding the pathophysiology of schizophrenia. In Neuropsychopharmacology: The Fifth Generation of Progress, ed. K. L. Davis, D. S. Charney, J. T. Coyle, C. B. Nemeroff. Philadelphia, PA: Lippincott Williams and Wilkins, pp. 729–743
Lewis, D. A., Levitt, P. (2002). Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 25: 409–432CrossRefGoogle ScholarPubMed
Lewis, D. A., Lieberman, J. A. (2000). Catching up on schizophrenia: natural history and neurobiology. Neuron 28: 325–334CrossRefGoogle ScholarPubMed
Lewis, D. A., Lund, J. S. (1990). Heterogeneity of chandelier neurons in monkey neocortex: corticotropin-releasing factor and parvalbumin immunoreactive populations. J Comp Neurol 293: 599–615CrossRefGoogle ScholarPubMed
Lewis, D. A., Cruz, D. A., Melchitzky, D. S., Pierri, J. N. (2001). Lamina-specific reductions in parvalbumin-immunoreactive axon terminals in the prefrontal cortex of subjects with schizophrenia: evidence for decreased projections from the thalamus. Am J Psychiatry 158: 1411–1422CrossRefGoogle Scholar
Lund, J. S., Holbach, S. (1991). Postnatal development of thalamic recipient neurons in monkey striate cortex: I. A comparison of spine acquisition and dendritic growth of layer 4C alpha and beta spiny stellate neurons. J Comp Neurol 309: 115–128CrossRefGoogle ScholarPubMed
McCarley, R. W., Wible, C. G., Frumin, M.et al. (1999). MRI anatomy of schizophrenia. Biol Psychiatry 45: 1099–1119CrossRefGoogle ScholarPubMed
Melchitzky, D. S., Lewis, D. A. (2003). Preferential targeting of parvalbumin interneurons by local axon terminals of supragranular pyramidal neurons in monkey prefrontal cortex. Cereb Cortex 13: 452–460CrossRefGoogle Scholar
Melchitzky, D. S., Sesack, S. R., Pucak, M. L., Lewis, D. A. (1998). Synaptic targets of pyramidal neurons providing intrinsic horizontal connections in monkey prefrontal cortex. J Comp Neurol 390: 211–2243.0.CO;2-4>CrossRefGoogle ScholarPubMed
Melchitzky, D. S., Sesack, S. R., Lewis, D. A. (1999). Parvalbumin-immunoreactive axon terminals in monkey and human prefrontal cortex: Laminar, regional and target specificity of type I and type II synapses. J Comp Neurol 408: 11–223.0.CO;2-T>CrossRefGoogle ScholarPubMed
Melchitzky, D. S., Gonzalez-Burgos, G., Barrionuevo, G., Lewis, D. A. (2001). Synaptic targets of the intrinsic axon collaterals of supragranular pyramidal neurons in monkey prefrontal cortex. J Comp Neurol 430: 209–2213.0.CO;2-#>CrossRefGoogle ScholarPubMed
Pakkenberg, B. (1990). Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumbens in schizophrenics. Arch Gen Psychiatry 47: 1023–1028CrossRefGoogle ScholarPubMed
Park, S., Holzman, P. S. (1992). Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry 49: 975–982CrossRefGoogle ScholarPubMed
Pearlson, G. D., Marsh, L. (1999). Structural brain imaging in schizophrenia: a selective review. Biol Psychiatry 46: 627–649CrossRefGoogle ScholarPubMed
Pierri, J. N., Volk, C. L. E., Auh, S., Sampson, A., Lewis, D. A. (2001). Decreased somal size of deep layer 3 pyramidal neurons in the prefrontal cortex in subjects with schizophrenia. Arch Gen Psychiatry 58: 466–473CrossRefGoogle ScholarPubMed
Pierri, J. N., Volk, C. L. E., Auh, S., Sampson, A., Lewis, D. A. (2003). Somal size of prefrontal cortical pyramidal neurons in schizophrenia: differential effects across neuronal subpopulations. Biol Psychiatry 54: 111–120CrossRefGoogle ScholarPubMed
Popken, G. J., Bunney, W. E. Jr, Potkin, S. G., Jones, E. G. (2000). Subnucleus-specific loss of neurons in medial thalamus of schizophrenics. Proc Natl Acad Sci USA 97: 9276–9280CrossRefGoogle ScholarPubMed
Portas, C. M., Goldstein, J. M., Shenton, M. E.et al. (1998). Volumetric evaluation of the thalamus in schizophrenic male patients using magnetic resonance imaging. Biol Psychiatry 43: 649–659CrossRefGoogle ScholarPubMed
Pucak, M. L., Levitt, J. B., Lund, J. S., Lewis, D. A. (1996). Patterns of intrinsic and associational circuitry in monkey prefrontal cortex. J Comp Neurol 376: 614–6303.0.CO;2-4>CrossRefGoogle ScholarPubMed
Rajkowska, G., Selemon, L. D., Goldman-Rakic, P. S. (1998). Neuronal and glial somal size in the prefrontal cortex: a postmortem morphometric study of schizophrenia and Huntington disease. Arch Gen Psychiatry 55: 215–224CrossRefGoogle ScholarPubMed
Rakic, P. (1977). Prenatal development of the visual system in rhesus monkey. Philos Trans R Soc Lond Ser B 278: 245–260CrossRefGoogle ScholarPubMed
Rao, S. G., Williams, G. V., Goldman-Rakic, P. S. (1999). Isodirectional tuning of adjacent interneurons and pyramidal cells during working memory: evidence for microcolumnar organization in PFC. J Neurophysiol 81: 1903–1916CrossRefGoogle ScholarPubMed
Selemon, L. D., Goldman-Rakic, P. S. (1999). The reduced neuropil hypothesis: a circuit based model of schizophrenia. Biol Psychiatry 45: 17–25CrossRefGoogle ScholarPubMed
Siekmeier, P. J., Hoffman, R. E. (2002). Enhanced semantic priming in schizophrenia: a computer model based on excessive pruning of local connections in association cortex. Br J Psychiatry 180: 345–350CrossRefGoogle ScholarPubMed
Sowell, E. R., Thompson, P. M., Tessner, K. D., Toga, A. W. (2001). Mapping continued brain growth and gray matter density reduction in dorsal frontal cortex: inverse relationships during postadolescent brain maturation. J Neurosci 21: 8819–8829CrossRefGoogle ScholarPubMed
Volk, D. W., Lewis, D. A. (2003). Effects of a mediodorsal thalamus lesion on prefrontal inhibitory circuitry: implications for schizophrenia. Biol Psychiatry 53: 385–389CrossRefGoogle Scholar
Volk, D. W., Austin, M. C., Pierri, J. N., Sampson, A. R., Lewis, D. A. (2000). Decreased GAD67 mRNA expression in a subset of prefrontal cortical GABA neurons in subjects with schizophrenia. Arch Gen Psychiatry 57: 237–245CrossRefGoogle Scholar
Volk, D. W., Austin, M. C., Pierri, J. N., Sampson, A. R., Lewis, D. A. (2001). GABA transporter-1 mRNA in the prefrontal cortex in schizophrenia: decreased expression in a subset of neurons. Am J Psychiatry 158: 256–265CrossRefGoogle Scholar
Volk, D. W., Pierri, J. N., Fritschy, J.-M., Auh, S., Sampson, A. R., Lewis, D. A. (2002). Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb Cortex 12: 1063–1070CrossRefGoogle Scholar
Weinberger, D. R., Berman, K. F., Zec, R. F. (1986). Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence. Arch Gen Psychiatry 43: 114–124CrossRefGoogle ScholarPubMed
Woo, T.-U., Pucak, M. L., Kye, C. H., Matus, C. V., Lewis, D. A. (1997). Peripubertal refinement of the intrinsic and associational circuitry in monkey prefrontal cortex. Neuroscience 80: 1149–1158CrossRefGoogle ScholarPubMed
Young, K. A., Manaye, K. F., Liang, C.-L., Hicks, P. B., German, D. C. (2000). Reduced number of mediodorsal and anterior thalamic neurons in schizophrenia. Biol Psychiatry 47: 944–953CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure coreplatform@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×