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Phosphodiesterase type IV inhibition prevents sequestration of CREB binding protein, protects striatal parvalbumin interneurons and rescues motor deficits in the R6/2 mouse model of Huntington’s disease

Authors

  • Carmela Giampà,

    1. Laboratory of Neuroanatomy, Santa Lucia Foundation at the European Center for Brain Research, Via del Fosso Fiorano 64, 00143 Rome, Italy
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    • *

      C.G. and S.M. contributed equally to this work.

  • Silvia Middei,

    1. CNR Institute for Neuroscience, Rome, Italy
    2. Department of Experimental Neurosciences, Santa Lucia Foundation at the European Center for Brain Research, Rome, Italy
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    • *

      C.G. and S.M. contributed equally to this work.

  • Stefano Patassini,

    1. Laboratory of Neuroanatomy, Santa Lucia Foundation at the European Center for Brain Research, Via del Fosso Fiorano 64, 00143 Rome, Italy
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  • Antonella Borreca,

    1. Laboratory of Neuroanatomy, Santa Lucia Foundation at the European Center for Brain Research, Via del Fosso Fiorano 64, 00143 Rome, Italy
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  • Fabrizia Marullo,

    1. Laboratory of Neuroanatomy, Santa Lucia Foundation at the European Center for Brain Research, Via del Fosso Fiorano 64, 00143 Rome, Italy
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  • Daunia Laurenti,

    1. Laboratory of Neuroanatomy, Santa Lucia Foundation at the European Center for Brain Research, Via del Fosso Fiorano 64, 00143 Rome, Italy
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  • Giorgio Bernardi,

    1. Laboratory of Neuroanatomy, Santa Lucia Foundation at the European Center for Brain Research, Via del Fosso Fiorano 64, 00143 Rome, Italy
    2. Department of Neuroscience, University of Rome Tor Vergata, Rome, Italy
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  • Martine Ammassari-Teule,

    1. CNR Institute for Neuroscience, Rome, Italy
    2. Department of Experimental Neurosciences, Santa Lucia Foundation at the European Center for Brain Research, Rome, Italy
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  • Francesca R. Fusco

    1. Laboratory of Neuroanatomy, Santa Lucia Foundation at the European Center for Brain Research, Via del Fosso Fiorano 64, 00143 Rome, Italy
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Dr Francesca R. Fusco, as above.
E-mail: f.fusco@hsantalucia.it

Abstract

The phosphodiesterase type IV inhibitor rolipram increases cAMP response element-binding protein (CREB) phosphorylation and exerts neuroprotective effects in both the quinolinic acid rat model of Huntington’s disease (DeMarch et al., 2007) and the R6/2 mouse including sparing of striatal neurons, prevention of neuronal intranuclear inclusion formation and attenuation of microglial reaction (DeMarch et al., 2008). In this study, we sought to determine if rolipram has a beneficial role in the altered distribution of CREB binding protein in striatal spiny neurons and in the motor impairments shown by R6/2 mutants. Moreover, we investigated whether rolipram treatment altered the degeneration of parvalbuminergic interneurons typical of Huntington’s disease (Fusco et al., 1999). Transgenic mice and their wild-type controls from a stable colony maintained in our laboratory were treated with rolipram (1.5 mg/kg) or saline daily starting from 4 weeks of age. The cellular distribution of CREB binding protein in striatal spiny neurons was assessed by immunofluorescence, whereas parvalbuminergic neuron degeneration was evaluated by cell counts of immunohistochemically labeled tissue. Motor coordination and motor activity were also examined. We found that rolipram was effective in preventing CREB binding protein sequestration into striatal neuronal intranuclear inclusions, sparing parvalbuminergic interneurons of R6/2 mice, and rescuing their motor coordination and motor activity deficits. Our findings demonstrate the possibility of reversing pharmacologically the behavioral and neuropathological abnormalities of symptomatic R6/2 mice and underline the potential therapeutic value of phosphodiesterase type IV inhibitors in Huntington’s disease.

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