Activation of a ΔFOSB dependent gene expression pattern in the dorsolateral prefrontal cortex of patients with major depressive disorder

Abstract

Background: A ΔFOSB mediated transcriptional response in the nucleus accumbens (NAc) is induced by chronic social stress in rodent and a 50% down-regulation of ΔFOSB has been also reported in the NAc of eight depressed subjects. To evaluate the role of ΔFOSB in the prefrontal cortex which is critically involved in negative cognitive bias associated with major depressive disorder (MDD) we have quantified the mRNA levels of ΔFOSB and of five of its major target genes in the Brodmann area 46 from 24 patients with MDD (11 with psychotic symptoms) and 12 controls.

Method: Expression of the six genes has been quantified by a real-time quantitative PCR method: ΔFOSB, GRIA2 (encoding the GluR2 subunit of the AMPA receptor), SPARCL1 (encoding hevin), SG3 (encoding the secretogranin III), PCP4 (encoding the Purkinje cell protein 4), ATP6V0C (encoding a subunit of the lysosomal ATPase).

Results: Expression of ΔFOSB and GRIA2 was significantly up-regulated (≈ 1.60) in the BA 46 of MDD patients. Overexpression of SCG3 and PCP4 was restricted to psychotic subjects. The mRNA levels of GRIA2, SCG3 and PCP4 were strongly correlated in the depressed group.

Limitations: All the patients were treated by antidepressants and the number of subjects in each subgroup was rather small.

Conclusions: Induction of a ΔFOSB mediated transcriptional pattern in the prefrontal cortex is opposite to the down-regulation observed in the NAc. The major consequence might be a shift in the excitability of the glutamatergic synapses which depends on GluR2 (high in the NAc and low in the BA 46).