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Chronic administration of atypical antipsychotics improves behavioral and synaptic defects of STOP null mice

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Abstract

Introduction

Recent studies have suggested that schizophrenia is associated with alterations in the synaptic connectivity involving cytoskeletal proteins. The microtubule-associated protein stable tubule only polypeptide (STOP) plays a key role in neuronal architecture and synaptic plasticity, and it has been demonstrated that STOP gene deletion in mice leads to a phenotype mimicking aspects of positive and negative symptoms and cognitive deficits classically observed in schizophrenic patients. In STOP null mice, behavioral defects are associated with synaptic plasticity abnormalities including defects in long-term potentiation. In these mice, long-term administration of typical antipsychotics has been shown to partially alleviate behavioral defects but, as in humans, such a treatment was poorly active on deficits related to negative symptoms and cognitive impairments. Here, we assessed the effects of risperidone and clozapine, two atypical antipsychotics, on STOP null mice behavior and synaptic plasticity.

Results

Long-term administration of either drug results in alleviation of behavioral alterations mimicking some negative symptoms and partial amelioration of some cognitive defects in STOP null mice. Interestingly, clozapine treatment also improves synaptic plasticity of the STOP null animals by restoring long-term potentiation in the hippocampus.

Discussion

All together, the pharmacological reactivity of STOP null mice to antipsychotics evokes the pharmacological response of humans to such drugs. Totally, our study suggests that STOP null mice may provide a useful preclinical model to evaluate pharmacological properties of antipsychotic drugs.

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Abbreviations

APs:

Antipsychotics

DISC1:

Disrupted in schizophrenia 1

MAP6:

Microtubule-associated protein 6

PPI:

Prepulse inhibition

STOP:

Stable tubule only polypeptide

WT:

Wild type

LTP:

Long-term potentiation

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Acknowledgments

We thank C. Dumont and D. Proietto for technical help.

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Authors and Affiliations

  1. SynapCell SAS, Bâtiment Biopolis, 5 avenue du Grand Sablon, 38700, La Tronche, France

    David Delotterie, Geoffrey Ruiz, Corinne Roucard, Yann Roche & Karine Bressand

  2. Institut National de la Santé et de la Recherche Medicale Unité 836, Institut des Neurosciences de Grenoble, Université Joseph Fourier, 38042, Grenoble Cedex 9, France

    Geoffrey Ruiz, Jacques Brocard, Annie Schweitzer & Annie Andrieux

  3. Groupe Physiopathologie du Cytosquelette, Institut de Recherches en Technologies et Sciences pour le Vivant Direction des Sciences du Vivant, Commissariat à l’Énergie Atomique, 38054, Grenoble Cedex 9, France

    Geoffrey Ruiz, Jacques Brocard, Annie Schweitzer & Annie Andrieux

  4. Université Claude Bernard Lyon 1, EA 4166, Centre Hospitalier le Vinatier, 69677, Bron Cedex, France

    Marie-Françoise Suaud-Chagny

Authors
  1. David Delotterie
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  2. Geoffrey Ruiz
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  3. Jacques Brocard
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  4. Annie Schweitzer
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  5. Corinne Roucard
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  6. Yann Roche
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  7. Marie-Françoise Suaud-Chagny
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  8. Karine Bressand
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  9. Annie Andrieux
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Corresponding authors

Correspondence to Karine Bressand or Annie Andrieux.

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Karine Bressand and Annie Andrieux shared the supervision of this study equally.

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Delotterie, D., Ruiz, G., Brocard, J. et al. Chronic administration of atypical antipsychotics improves behavioral and synaptic defects of STOP null mice. Psychopharmacology 208, 131–141 (2010). https://doi.org/10.1007/s00213-009-1712-3

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  • DOI: https://doi.org/10.1007/s00213-009-1712-3

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