Effects of a Cc2d1a/Freud-1 Knockdown in the Hippocampus on Behavior, the Serotonin System, and BDNF

The serotonin 5-HT receptor is one of the most abundant and widely distributed brain serotonin (5-HT) receptors that play a major role in the modulation of emotions and behavior. The 5-HT receptor gene ( ) is under the control of transcription factor Freud-1 (also known as ). Here, using adeno-associated virus (AAV) constructs in vivo, we investigated effects of a in the hippocampus of C57BL/6J mice on behavior, the brain 5-HT system, and brain-derived neurotrophic factor (BDNF). AAV particles carrying the pAAV_H1-2_shRNA-Freud-1_Syn_EGFP plasmid encoding a short-hairpin RNA targeting mouse mRNA had an antidepressant effect in the forced swim test 5 weeks after virus injection. The knockdown impaired spatiotemporal memory as assessed in the Morris water maze. pAAV_H1-2_shRNA-Freud-1_Syn_EGFP decreased mRNA and protein levels. Furthermore, the upregulated 5-HT and its metabolite 5-hydroxyindoleacetic acid but not their ratio. The failed to increase mRNA and protein levels of but diminished a 5-HT receptor functional response. Meanwhile, the reduced mRNA expression and CREB phosphorylation and upregulated mRNA. The knockdown enhanced the expression of a BDNF precursor (proBDNF protein), which is known to play a crucial part in neuroplasticity. Our data indicate that transcription factor is implicated in the pathogenesis of depressive disorders not only via the 5-HT receptor and transcription factor CREB but also through an influence on BDNF.