Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition

Olivia Engmann, Tibor Hortobágyi, Ruth Pidsley, Claire Troakes, Hans Gert Bernstein, Michael R. Kreutz, Jonathan Mill, Margareta Nikolic, Karl Peter Giese

Research output: Contribution to journalArticle

65 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2408-2421
Number of pages14
JournalBrain
Volume134
Issue number8
DOIs
Publication statusPublished - Aug 1 2011

Keywords

  • animal models
  • brain
  • cognition
  • schizophrenia
  • signalling

ASJC Scopus subject areas

  • Clinical Neurology

Fingerprint Dive into the research topics of 'Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition'. Together they form a unique fingerprint.

  • Cite this

    Engmann, O., Hortobágyi, T., Pidsley, R., Troakes, C., Bernstein, H. G., Kreutz, M. R., Mill, J., Nikolic, M., & Giese, K. P. (2011). Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition. Brain, 134(8), 2408-2421. https://doi.org/10.1093/brain/awr155