Dendritic spines are the central postsynaptic machinery that determines synaptic function. The F-actin within dendritic spines regulates their dynamic formation and elimination. Rai14 is an F‑actin-regulating protein with a membrane‑shaping function. Here, we identified the roles of Rai14 for the regulation of dendritic spine dynamics associated with stress-induced depressive-like behaviors. Rai14-deficient neurons failed to maintain a proper dendritic spine density in the Rai14+/- mouse brain, resulting in impaired functional synaptic activity. Rai14 was protected from degradation by complex formation with Tara, and accumulated in the dendritic spine neck, thereby enhancing spine maintenance. Concurrently, Rai14 deficiency in mice altered gene expression profile relevant to depressive conditions and increased depressive-like behaviors. Moreover, Rai14 expression was reduced in the prefrontal cortex of the mouse stress model, which was blocked by antidepressant treatment. Thus, we propose that Rai14-dependent regulation of dendritic spines may underlie the plastic changes of neuronal connections relevant to depressive-like behaviors.

The brains from two 9-week-old male Rai14+/- mice and two male wild-type littermate controls and two 9-week-old female Rai14+/- mice and two female wild-type littermate controls were used for RNA sequencing. The mice were deeply anesthetized with isoflurane inhalation and transcardially perfused with PBS. Then brains except the cerebellum and pons (left cerebral hemispheres) were isolated and kept in RNAlaterTM Solution (Invitrogen) with dry ice and subjected for further RNA-Seq library construction and transcriptome sequencing.

RNA-Seq library construction, transcriptome sequencing, and expression profiling were performed by Macrogen (Macrogen, Inc., Seoul, Korea, http://www.macrogen.com/). Briefly, the mRNA from each brain sample was pooled for RNA-Seq library construction using TruSeq Stranded mRNA LT Sample Prep Kit (Illumina, San Diego, CA, USA). The mRNA library was subjected to paired-end transcriptome sequencing (Illumina platform).