title: Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition.
abstract: Cyclin-dependent kinase 5 is activated by small subunits, of which p35 is the most abundant. The functions of cyclin-dependent kinase 5 signalling in cognition and cognitive disorders remains unclear. Here, we show that in schizophrenia, a disorder associated with impaired cognition, p35 expression is reduced in relevant brain regions. Additionally, the expression of septin 7 and OPA1, proteins downstream of truncated p35, is decreased in schizophrenia. Mimicking a reduction of p35 in heterozygous knockout mice is associated with cognitive endophenotypes. Furthermore, a reduction of p35 in mice results in protein changes similar to schizophrenia post-mortem brain. Hence, heterozygous p35 knockout mice model both cognitive endophenotypes and molecular changes reminiscent of schizophrenia. These changes correlate with reduced acetylation of the histone deacetylase 1 target site H3K18 in mice. This site has previously been shown to be affected by truncated p35. By restoring H3K18 acetylation with the clinically used specific histone deacetylase 1 inhibitor MS-275 both cognitive and molecular endophenotypes of schizophrenia can be rescued in p35 heterozygous knockout mice. In summary, we suggest that reduced p35 expression in schizophrenia has an impact on synaptic protein expression and cognition and that these deficits can be rescued, at least in part, by the inhibition of histone deacetylase 1.
authors.affiliation: Department for Neuroscience, King’s College, London SE5 9NU, UK.
authors.forename: Olivia
authors.initials: O
authors.lastname: Engmann
authors.forename: Tibor
authors.initials: T
authors.lastname: Hortobágyi
authors.forename: Ruth
authors.initials: R
authors.lastname: Pidsley
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.forename: Hans-Gert
authors.initials: HG
authors.lastname: Bernstein
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kreutz
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
authors.forename: Margareta
authors.initials: M
authors.lastname: Nikolic
authors.forename: Karl Peter
authors.initials: KP
authors.lastname: Giese
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods; D000704:Analysis of Variance; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics; D058068:Endophenotypes; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D007266:Inhibition, Psychological; D007398:Interpersonal Relations; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009088:Mucoproteins / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010770:Phosphotransferases; D011180:Postmortem Changes; D011725:Pyridines / Q000494:pharmacology; D012201:Reward; D012559:Schizophrenia / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058112:Septins / Q000378:metabolism*; D012737:Sex Factors; D013569:Synapses / Q000378:metabolism
chemical_list: D001549:Benzamides; C492236:Cdk5r1 protein, mouse; D018797:Cell Cycle Proteins; D056572:Histone Deacetylase Inhibitors; D009088:Mucoproteins; D009419:Nerve Tissue Proteins; D011725:Pyridines; C010393:lysin, gastropoda; C089495:neuronal Cdk5 activator (p25-p35); C118739:entinostat; D010770:Phosphotransferases; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; C113158:SEPTIN7 protein, human; D058112:Septins