Risperidone and NAP protect cognition and normalize gene expression in a schizophrenia mouse model

Sci Rep. 2015 Nov 10;5:16300. doi: 10.1038/srep16300.

Abstract

Mutated disrupted in schizophrenia 1 (DISC1), a microtubule regulating protein, leads to schizophrenia and other psychiatric illnesses. It is hypothesized that microtubule stabilization may provide neuroprotection in schizophrenia. The NAP (NAPVSIPQ) sequence of activity-dependent neuroprotective protein (ADNP) contains the SxIP motif, microtubule end binding (EB) protein target, which is critical for microtubule dynamics leading to synaptic plasticity and neuroprotection. Bioinformatics prediction for FDA approved drugs mimicking SxIP-like motif which displace NAP-EB binding identified Risperidone. Risperidone or NAP effectively ameliorated object recognition deficits in the mutated DISC1 mouse model. NAP but not Risperidone, reduced anxiety in the mutated mice. Doxycycline, which blocked the expression of the mutated DISC1, did not reverse the phenotype. Transcripts of Forkhead-BOX P2 (Foxp2), a gene regulating DISC1 and associated with human ability to acquire a spoken language, were increased in the hippocampus of the DISC1 mutated mice and were significantly lowered after treatment with NAP, Risperidone, or the combination of both. Thus, the combination of NAP and standard of care Risperidone in humans may protect against language disturbances associated with negative and cognitive impairments in schizophrenia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cognition / drug effects*
  • Disease Models, Animal
  • Doxycycline / pharmacology
  • Female
  • Gene Expression Regulation / drug effects*
  • Hippocampus / metabolism
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / chemistry
  • Microtubule-Associated Proteins / metabolism
  • Molecular Dynamics Simulation
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / metabolism
  • Neuroprotective Agents / pharmacology*
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Phenotype
  • Protein Binding
  • Protein Structure, Tertiary
  • Risperidone / chemistry
  • Risperidone / metabolism
  • Risperidone / pharmacology*
  • Schizophrenia / genetics
  • Schizophrenia / metabolism
  • Schizophrenia / pathology

Substances

  • Disc1 protein, mouse
  • EB1 protein, mouse
  • EB3 protein, mouse
  • Microtubule-Associated Proteins
  • Nerve Tissue Proteins
  • Neuroprotective Agents
  • Oligopeptides
  • davunetide
  • Risperidone
  • Doxycycline