title: Risperidone and NAP protect cognition and normalize gene expression in a schizophrenia mouse model.
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.
authors.affiliation: The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University 69978, Israel.
authors.forename: Sinaya
authors.initials: S
authors.lastname: Vaisburd
authors.affiliation: The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University 69978, Israel.
authors.forename: Zeev
authors.initials: Z
authors.lastname: Shemer
authors.affiliation: The Bioinformatics Unit, George S. Wise Faculty of Life Sciences, Tel Aviv University 69978, Israel.
authors.forename: Adva
authors.initials: A
authors.lastname: Yeheskel
authors.affiliation: The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University 69978, Israel.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Giladi
authors.affiliation: The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Sagol School of Neuroscience and Adams Super Center for Brain Studies, Tel Aviv University 69978, Israel.
authors.forename: Illana
authors.initials: I
authors.lastname: Gozes
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010641:Phenotype; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018967:Risperidone / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C498794:Disc1 protein, mouse; C584107:EB1 protein, mouse; C522423:EB3 protein, mouse; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D009842:Oligopeptides; C425904:davunetide; D018967:Risperidone; D004318:Doxycycline