Determinants of psychosis vulnerability: Focus on MEF2- and glucocorticoid signaling

Publication Type:

Thesis

Authors:

Speksnijder, N.

Source:

LACDR, Medical Pharmacology, Leiden University, Volume PhD, Leiden, p.160 (2013)

ISBN:

9789053357613

Keywords:

Myocyte enhancer factor 2; Glucocorticoid receptor; Schizophrenia; Psychosis; Hippocampus; CA1; Roscovitine; Amphetamine

Abstract:

Schizophrenia is heritable, but even in monozygotic twins differences in susceptibly exists. What is causing this difference in genetically identical individuals? The objective of this thesis was to identify novel susceptibility genes and pathways for psychosis in a psychostimulant mouse model which is considered a model for psychosis. Genome-wide analysis of transcripts in the hippocampal CA1, driving mesocortical dopaminergic activity, which has a prominent role in schizophrenia, revealed differential expression of target genes of Myocyte Enhancer Factor 2 (MEF2) and Glucocorticoid Receptor (GR). This suggest that this gene network is involved in sensitivity to amphetamine. In primary hippocampal neurons, knockdown of MEF2 reduced the expression of c-Jun and abolished its regulation by GR. Moreover, activation of MEF2 by neuronal depolarization was attenuated by glucocorticoids, suggesting a mutual feedback regulation of these transcription factors. Finally, in vivo MEF2 and GR appeared to be active in the induction phase of amphetamine sensitization. Overall, the findings suggest that in the hippocampus activation of GR can modulate the role of MEF2 target genes in induction of behavioral sensitization. This finding points to the hippocampus as an exciting target for further studies on the role of MEF2 and GR in the precipitation of psychosis susceptibility.

02/12/2013