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Repeated phencyclidine in monkeys results in loss of parvalbumin-containing axo-axonic projections in the prefrontal cortex

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Abstract

Rationale

Repeated exposure to the N-methyl-d-aspartate antagonist, phencyclidine, has been shown to result in biochemical and cognitive changes similar to aspects of schizophrenia. Recently, emerging evidence indicated that the symptoms of schizophrenia might result at least in part from dysfunction of local circuit neurons containing parvalbumin, including a loss of their axo-axonic projections to pyramidal neurons.

Objectives

In this report, we test if repeated exposure to phencyclidine in the primate shares this change to parvalbumin-containing cells and their axo-axonic structures.

Materials and methods

Eight adult male African green monkeys were treated with saline or phencyclidine (0.3 mg/kg BID × 14 days) and, after 8 days drug-free, perfused and fixed, and the principal sulcus was collected (Walker’s area 46) for immunohistochemical analysis.

Results

Prior treatment with phencyclidine resulted in a 40% reduction in the density of parvalbumin-containing axo-axonic structures. There was no apparent change in the lengths or laminar location of the axo-axonic projections. Additionally, there was no change in the total density or laminar location of parvalbumin-containing or calretinin-containing cell bodies in area 46.

Conclusions

These results indicate that repeated treatment with phencyclidine results in plastic changes in parvalbumin-containing local circuit neurons in the prefrontal cortex similar to that reported in schizophrenia and that these changes may contribute to the common cognitive disruption seen in both schizophrenic patients and the phencyclidine monkey model.

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References

  • Abdul-Monim Z, Neill JC, Reynolds GP (2007) Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat. J Psychopharmacol (in press). DOI 10.1177/0269881106067097

  • Akbarian S, Kim JJ, Potkin SG, Hagman JO, Tafazzoli A, Bunney WE Jr, Jones EG (1995) Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics. Arch Gen Psychiatry 52:258–266

    PubMed  CAS  Google Scholar 

  • Beasley CL, Reynolds GP (1997) Parvalbumin-immunoreactive neurons are reduced in the prefrontal cortex of schizophrenics. Schizophr Res 24:349–355

    Article  PubMed  CAS  Google Scholar 

  • Beasley CL, Zhang ZJ, Patten I, Reynolds GP (2002) Selective deficits in prefrontal cortical GABAergic neurons in schizophrenia defined by the presence of calcium-binding proteins. Biol Psychiatry 52:708–715

    Article  PubMed  CAS  Google Scholar 

  • Benes FM, McSparren J, Bird ED, SanGiovanni JP, Vincent SL (1991) Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Arch Gen Psychiatry 48:996–1001

    PubMed  CAS  Google Scholar 

  • Caillard O, Moreno H, Schwaller B, Llano I, Celio MR, Marty A (2000) Role of the calcium-binding protein parvalbumin in short-term synaptic plasticity. Proc Natl Acad Sci USA 97:13372–13377

    Article  PubMed  CAS  Google Scholar 

  • Celio MR (1986) Parvalbumin in most gamma-aminobutyric acid-containing neurons of the rat cerebral cortex. Science 231:995–997

    Article  PubMed  CAS  Google Scholar 

  • Chard PS, Bleakman D, Christakos S, Fullmer CS, Miller RJ (1993) Calcium buffering properties of calbindin D28k and parvalbumin in rat sensory neurones. J Physiol 472:341–357

    PubMed  CAS  Google Scholar 

  • Cochran SM, Kennedy M, McKerchar CE, Steward LJ, Pratt JA, Morris BJ (2003) Induction of metabolic hypofunction and neurochemical deficits after chronic intermittent exposure to phencyclidine: differential modulation by antipsychotic drugs. Neuropsychopharmacology 28:265–275

    Article  PubMed  CAS  Google Scholar 

  • Conde F, Lund JS, Jacobowitz DM, Baimbridge KG, Lewis DA (1994) Local circuit neurons immunoreactive for calretinin, calbindin D-28k or parvalbumin in monkey prefrontal cortex: distribution and morphology. J Comp Neurol 341:95–116

    Article  PubMed  CAS  Google Scholar 

  • Constantinidis C, Williams GV, Goldman-Rakic PS (2002) A role for inhibition in shaping the temporal flow of information in prefrontal cortex. Nat Neurosci 5:175–180

    Article  PubMed  CAS  Google Scholar 

  • Cotter D, Landau S, Beasley C, Stevenson R, Chana G, MacMillan L, Everall I (2002) 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

    Article  PubMed  CAS  Google Scholar 

  • Cruz DA, Eggan SM, Lewis DA (2003) Postnatal development of pre- and postsynaptic GABA markers at chandelier cell connections with pyramidal neurons in monkey prefrontal cortex. J Comp Neurol 465:385–400

    Article  PubMed  Google Scholar 

  • Daviss SR, Lewis DA (1995) Local circuit neurons of the prefrontal cortex in schizophrenia: selective increase in the density of calbindin-immunoreactive neurons. Psychiatry Res 59:81–96

    Article  PubMed  CAS  Google Scholar 

  • DeFelipe J, Hendry SH, Jones EG, 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 231:364–384

    Article  PubMed  CAS  Google Scholar 

  • Dombrowski SM, Hilgetag CC, Barbas H (2001) Quantitative architecture distinguishes prefrontal cortical systems in the rhesus monkey. Cereb Cortex 11:975–988

    Article  PubMed  CAS  Google Scholar 

  • Gabbott PL, Bacon SJ (1996) Local circuit neurons in the medial prefrontal cortex (areas 24a, b, c, 25 and 32) in the monkey: II. Quantitative areal and laminar distributions. J Comp Neurol 364:609–636

    Article  PubMed  CAS  Google Scholar 

  • Goldman-Rakic PS (1995) Cellular basis of working memory. Neuron 14:477–485

    Article  PubMed  CAS  Google Scholar 

  • Hajszan T, Leranth C, Roth RH (2006a) Subchronic phencyclidine treatment decreases the number of dendritic spine synapses in the Rat prefrontal cortex. Biol Psychiatry 60(6):639–644

    Article  PubMed  CAS  Google Scholar 

  • Hajszan T, Leranth C, Roth RH (2006b) Subchronic phencyclidine treatment decreases the number of dendritic spine synapses in the rat prefrontal cortex. Biol Psychiatry 60:639–644

    Article  PubMed  CAS  Google Scholar 

  • Jentsch JD, Redmond DE Jr, Elsworth JD, Taylor JR, Youngren KD, Roth RH (1997) Enduring cognitive deficits and cortical dopamine dysfunction in monkeys after long-term administration of phencyclidine. Science 277:953–955

    Article  PubMed  CAS  Google Scholar 

  • Jentsch JD, Dazzi L, Chhatwal JP, Verrico CD, Roth RH (1998a) Reduced prefrontal cortical dopamine, but not acetylcholine, release in vivo after repeated, intermittent phencyclidine administration to rats. Neurosci Lett 258:175–178

    Article  PubMed  CAS  Google Scholar 

  • Jentsch JD, Taylor JR, Roth RH (1998b) Subchronic phencyclidine administration increases mesolimbic dopaminergic system responsivity and augments stress- and psychostimulant-induced hyperlocomotion. Neuropsychopharmacology 19:105–113

    Article  PubMed  CAS  Google Scholar 

  • Jentsch JD, Roth RH, Taylor JR (2000) Role for dopamine in the behavioral functions of the prefrontal corticostriatal system: implications for mental disorders and psychotropic drug action. Prog Brain Res 126:433–453

    Article  PubMed  CAS  Google Scholar 

  • Keilhoff G, Becker A, Grecksch G, Wolf G, Bernstein HG (2004) Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia. Neuroscience 126:591–598

    Article  PubMed  CAS  Google Scholar 

  • Klausberger T, Magill PJ, Marton LF, Roberts JD, Cobden PM, Buzsaki G, Somogyi P (2003) Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo. Nature 421:844–848

    Article  PubMed  CAS  Google Scholar 

  • Lewis DA (2000) GABAergic local circuit neurons and prefrontal cortical dysfunction in schizophrenia. Brain Res Rev 31:270–276

    Article  PubMed  CAS  Google Scholar 

  • Lund JS, Lewis DA (1993) Local circuit neurons of developing and mature macaque prefrontal cortex: golgi and immunocytochemical characteristics. J Comp Neurol 328:282–312

    Article  PubMed  CAS  Google Scholar 

  • Melchitzky DS, Lewis DA (2003) Pyramidal neuron local axon terminals in monkey prefrontal cortex: differential targeting of subclasses of GABA neurons. Cereb Cortex 13:452–460

    Article  PubMed  Google Scholar 

  • Melchitzky DS, Sesack SR, Lewis DA (1999) 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

    Article  PubMed  CAS  Google Scholar 

  • Melchitzky DS, Gonzalez-Burgos G, Barrionuevo G, Lewis DA (2001) Synaptic targets of the intrinsic axon collaterals of supragranular pyramidal neurons in monkey prefrontal cortex. J Comp Neurol 430:209–221

    Article  PubMed  CAS  Google Scholar 

  • Moghaddam B, Adams BW (1998) Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281:1349–1352

    Article  PubMed  CAS  Google Scholar 

  • Morrow BA, Elsworth JD, Roth RH (2002) Male rats exposed to cocaine in utero demonstrate elevated expression of Fos in the prefrontal cortex in response to environment. Neuropsychopharmacology 26:275–285

    Article  PubMed  CAS  Google Scholar 

  • Morrow BA, Elsworth JD, Roth RH (2005) Prenatal exposure to cocaine selectively disrupts the development of parvalbumin containing local circuit neurons in the medial prefrontal cortex of the rat. Synapse 56:1–11

    Article  PubMed  CAS  Google Scholar 

  • Peters A, Harriman KM (1990) Different kinds of axon terminals forming symmetric synapses with the cell bodies and initial axon segments of layer II/III pyramidal cells. I. Morphometric analysis. J Neurocytol 19:154–174

    Article  PubMed  CAS  Google Scholar 

  • Pierri JN, Chaudry AS, Woo TU, Lewis DA (1999) Alterations in chandelier neuron axon terminals in the prefrontal cortex of schizophrenic subjects. Am J Psychiatry 156:1709–1719

    PubMed  CAS  Google Scholar 

  • Reynolds GP, Abdul-Monim Z, Neill JC, Zhang ZJ (2004) Calcium binding protein markers of GABA deficits in schizophrenia-postmortem studies and animal models. Neurotox Res 6:57–61

    Article  PubMed  Google Scholar 

  • Rujescu D, Bender A, Keck M, Hartmann AM, Ohl F, Raeder H, Giegling I, Genius J, McCarley RW, Moller HJ, Grunze H (2006) A pharmacological model for psychosis based on N-methyl-d-aspartate receptor hypofunction: molecular, cellular, functional and behavioral abnormalities. Biol Psychiatry 59:721–729

    Article  PubMed  CAS  Google Scholar 

  • Seamans JK, Gorelova N, Durstewitz D, Yang CR (2001) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 21:3628–3638

    PubMed  CAS  Google Scholar 

  • Spencer KM, Nestor PG, Niznikiewicz MA, Salisbury DF, Shenton ME, McCarley RW (2003) Abnormal neural synchrony in schizophrenia. J Neurosci 23:7407–7411

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Williams SM, Goldman-Rakic PS, Leranth C (1992) The synaptology of parvalbumin-immunoreactive neurons in the primate prefrontal cortex. J Comp Neurol 320:353–369

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgment

This work was supported by a grant from the National Institute of Mental Health, MH57483. We thank Mrs. Dottie Cameron, as always, for her excellent technical work.

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Authors and Affiliations

  1. Neuropsychopharmacology Research Unit, Departments of Pharmacology and Psychiatry, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520-8066, USA

    John D. Elsworth & Robert H. Roth

  2. Yale University School of Medicine, Suite 8300, 300 George St., New Haven, CT, 06511, USA

    Bret A. Morrow

  3. Neuropsychopharmacology Research Unit, Department of Psychiatry, Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06520-8066, USA

    Bret A. Morrow

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  1. Bret A. Morrow
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  2. John D. Elsworth
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  3. Robert H. Roth
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Correspondence to Bret A. Morrow.

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Morrow, B.A., Elsworth, J.D. & Roth, R.H. Repeated phencyclidine in monkeys results in loss of parvalbumin-containing axo-axonic projections in the prefrontal cortex. Psychopharmacology 192, 283–290 (2007). https://doi.org/10.1007/s00213-007-0708-0

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