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

Sinaya Vaisburd,Illana Gozes,Eliezer Giladi,Adva Yeheskel,Zeev Shemer

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.

Highlights

Memory, it should be borne in mind that the proportion of individuals with DISC1 mutations suffering from schizophrenia is rather small[7]
DISC1 has been associated with verbal fluency in schizophrenia[13] and a recent study revealed a link between DISC1 and Forkhead -BOX P2 (FOXP2), the gene associated with human ability to acquire spoken language, with FOXP2 regulating DISC1 transcripts[14]
Controls included DOX treatment, at the adult state, which blocked the expression of the mutated DISC1 gene, DOX application did not reverse the phenotype, suggesting that DISC1 expression is important for brain development and the mutated DISC1 expression results in permanent damage

Summary

Introduction

Memory, it should be borne in mind that the proportion of individuals with DISC1 mutations suffering from schizophrenia is rather small[7]. NAP has been proven to be a neuroprotective agent by interacting with its target, the MT end- binding (EB) proteins through its SIP motif[8]. DISC1 has been associated with verbal fluency in schizophrenia[13] and a recent study revealed a link between DISC1 and Forkhead -BOX P2 (FOXP2), the gene associated with human ability to acquire spoken language, with FOXP2 regulating DISC1 transcripts[14]. Three amino acids distinguish the human FOXP2 protein from the mouse one. We set up to evaluate NAP, as a treatment against cognitive deficits and impairments in Foxp[2] expression in a DISC1 mutated mouse model for schizophrenia. Controls included doxycycline treatment which blocked the expression of the mutated gene and Risperidone, a frequently used neuroleptic

Methods

Results

Conclusion