Chronic hyperdopaminergic activity of schizophrenia is associated with increased ΔFosB levels and cdk-5 signaling in the nucleus accumbens

Abstract

Chronic subcortical hyperdopaminergic activity is associated with the positive symptoms of schizophrenia and is a hallmark feature of a number of animal models of the disorder. However, the molecular changes induced by increased dopaminergic activity associated with schizophrenia are not clear. Increased levels of ΔFosB have been found in association with chronic subcortical hyperdopaminergic activity following repeated cocaine or amphetamine administration. Therefore, we investigated ΔFosB signaling in a putative neurodevelopmental animal model of schizophrenia showing chronic subcortical hyperdopaminergic activity. Increased protein levels of the transcription factor ΔFosB as well as cyclin-dependent kinase-5 (cdk-5), p35, p25 and the GluR2 subunit of the AMPA glutamate receptor were observed in the nucleus accumbens (NA). Cdk-5, p35 and GlurR2 are all proteins regulated by ΔFosB, while p25 is a degradation product of p35. Increased total protein levels of cdk-5, p35 and p25 resulted in increased cdk-5 kinase activity as determined by increased phosphorylation of dopamine and adenosine regulated phosphoprotein-32 (DARPP32) at Thr75 in the NA. DARPP32 Thr75 is selectively phosphorylated by cdk-5 and phosphorylation of DARPP32 at Thr75 suppresses DARPP32 activity, a critical step in the regulation of both glutamatergic and dopaminergic activity in neurons. We also found that apomorphine-induced locomotor activity was further increased following intra-accumbens infusions of roscovitine, a cdk-5 blocker, in a dose-dependent manner. Our results indicate that chronic hyperdopaminergic activity, as seen in schizophrenia, may affect glutamate and dopamine function in the NA via ΔFosB-mediated transcriptional modulation.