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

Elena M. Kondaurova,Dmitry V. Eremin,Vladimir S. Naumenko,Alexander Ya. Rodnyy,Yulia D. Grygoreva,Tatiana V. Ilchibaeva,Alexandra V. Plyusnina

doi:10.3390/ijms222413319

Abstract

The serotonin 5-HT1A 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-HT1A receptor gene (Htr1a) is under the control of transcription factor Freud-1 (also known as Cc2d1a/Freud-1). Here, using adeno-associated virus (AAV) constructs in vivo, we investigated effects of a Cc2d1a/Freud-1 knockdown 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 Cc2d1a/Freud-1 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 Cc2d1a/Freud-1 mRNA and protein levels. Furthermore, the Cc2d1a/Freud-1 knockdown upregulated 5-HT and its metabolite 5-hydroxyindoleacetic acid but not their ratio. The Cc2d1a/Freud-1 knockdown failed to increase mRNA and protein levels of Htr1a but diminished a 5-HT1A receptor functional response. Meanwhile, the Cc2d1a/Freud-1 knockdown reduced Creb mRNA expression and CREB phosphorylation and upregulated cFos 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 Cc2d1a/Freud-1 is implicated in the pathogenesis of depressive disorders not only via the 5-HT1A receptor and transcription factor CREB but also through an influence on BDNF.

Highlights

It is well known that brain serotonin (5-HT) plays an important role in the regulation of many physiological processes and is involved in the control of various types of normal and pathological behaviors, including depression [1,2,3,4]
We focused on the Cc2d1a/Freud-1 involvement in the regulation of the 5-HT1A receptor and its function in behavioral plasticity as well as in 5-HT–brain-derived neurotrophic factor (BDNF) cross-talk
We showed that the partial Cc2d1a/Freud-1 downregulation in the hippocampus resulted in a spatiotemporal memory disturbance as assessed in the Morris water maze; in the retention test, the mice spent less time in the target quarter

Summary

Introduction

It is well known that brain serotonin (5-HT) plays an important role in the regulation of many physiological processes and is involved in the control of various types of normal and pathological behaviors, including depression [1,2,3,4]. Numerous studies show a key function of the serotonin 5-HT1A receptor in the regulation of the functional state of the brain 5-HT system [4] In this regard, this receptor has attracted the attention of many researchers. The postsynaptic 5-HT1A receptor is downregulated in several cortical regions in depression [17,18,19,20,21] and anxiety [22,23,24], whereas the 5-HT1A autoreceptor is overexpressed in depression [14,25,26] In this context, elevated 5-HT1A autoreceptor expression tends to reduce the activity of 5-HT neurons, while underexpression of the postsynaptic 5-HT1A receptor may blunt a behavioral response to 5-HT. These data indicate that the 5-HT1A receptor is a major determinant of predisposition to mental disorders

Methods

Discussion

Conclusion