Activity of Arhgef4 is modulated through Staufen1 in neurons.

The role of Arhgef4, also known as adenomatous polyposis coli (APC)-stimulated guanine nucleotide exchange factor 1 (Asef1), has been identified in colorectal cancers. Interestingly, Arhgef4 is more highly expressed in brain regions than intestinal regions, suggesting a role in neurons. In our previous study, we reported that Arhgef4 negatively regulates the level of PSD-95 in excitatory post-synaptic regions by binding with Staufen1. However, modulation of Arhgef4 guanine nucleotide exchange factor (GEF) activity in neurons has not been reported. We examined the configuration of protein interactions when Arhgef4 binds to APC and/or Staufen1. Arhgef4 simultaneously binds to Staufen1 with APC. Staufen1 overexpression blocked the GEF activity of Arhgef4. Consistent with this, Staufen1 overexpression blocked the Arhgef4-induced increase in dendritic protrusions in cultured neurons. Taken together, our data suggest that the GEF activity of Arhgef4 could be negatively modulated by Staufen1 binding.

Rho Guanine Nucleotide Exchange Factor 4 (Arhgef4) Deficiency Enhances Spatial and Object Recognition Memory.

Guanine nucleotide exchange factors (GEFs) play multiple functional roles in neurons. In a previous study, we reported that Arhgef4 (Rho guanine nucleotide exchange factor 4) functioned as a negative regulator of the excitatory synaptic function by sequestering postsynaptic density protein 95 (PSD-95). However, the role of Arhgef4 in behavior has not been examined. We performed comprehensive behavioral tests in knockout (KO) mice to investigate of the effects of Arhgef4 deficiency. We found that the expressed PSD-95 particle size was significantly increased in hippocampal neuronal cultures from Arhgef4 KO mice, which is consistent with the previous in vitro findings. Arhgef4 KO mice exhibited general motor activity and anxiety-like behavior comparable to those of the wild type littermates. However, spatial memory and object recognition memory were significantly enhanced in the Arhgef4 KO mice. Taken together, these data confirm the role of Arhgef4 as a negative synaptic regulator at the behavioral level.

The difference in sleep, depression, anxiety, and Internet addiction between Korean adolescents with different circadian preference.

OBJECTIVES: Compared to adults, adolescents tend to prefer evening times developmentally. The orientation toward evening times is associated with behavioral and emotional problems. Thus, this study examined the association of circadian preference with sleep-related variables, depression, anxiety, and Internet addiction in Korean adolescents. MATERIALS AND METHODS: Participants completed the questionnaires measuring sleep pattern, sleep problem, depression, anxiety, and Internet addiction. RESULTS: Among 765 students (age range: 13-17 years), 211 students (N male= 134) were allocated into morning types (MT) and 258 adolescents (N male= 147) were allocated into evening types (ET) based on scores of the Morningness-Eveningness Scale. Adolescents without circadian preference (N = 296) were defined as neither type (NT). ET, compared to MT and NT, woke up later in the weekend, showed delays in bedtimes, and spent shorter time sleeping. They also reported a higher level of daytime sleepiness, insomnia, and depression than NT. However, the group difference in wake time on school days was not significant, and adolescents showed mild insomnia regardless of their circadian preference. Although smartphone using time in the weekend was significantly different between groups, group difference in Internet addiction was significant only when gender was adjusted. CONCLUSION: Circadian preference was associated with sleep patterns and sleep problems in Korean adolescents. ET showed significantly different sleep patterns compared to MT and NT. ET not only reported a higher level of daytime sleepiness and insomnia but also more depressive symptoms compared to NT. These findings suggest that the uniqueness of adolescence and environmental factors seemed to influence the association of circadian preference with mental problem.

Postsynaptic density protein 95 (PSD-95) is transported by KIF5 to dendritic regions.

Postsynaptic density protein 95 (PSD-95) is a pivotal postsynaptic scaffolding protein in excitatory neurons. Although the transport and regulation of PSD-95 in synaptic regions is well understood, dendritic transport of PSD-95 before synaptic localization still remains to be clarified. To evaluate the role of KIF5, conventional kinesin, in the dendritic transport of PSD-95 protein, we expressed a transport defective form of KIF5A (ΔMD) that does not contain the N-terminal motor domain. Expression of ΔMD significantly decreased PSD-95 level in the dendrites. Consistently, KIF5 was associated with PSD-95 in in vitro and in vivo assays. This interaction was mediated by the C-terminal tail regions of KIF5A and the third PDZ domain of PSD-95. Additionally, the ADPDZ3 (the association domain of NMDA receptor and PDZ3 domain) expression significantly reduced the levels of PSD-95, glutamate receptor 1 (GluA1) in dendrites. The association between PSD-95 and KIF5A was dose-dependent on Staufen protein, suggesting that the Staufen plays a role as a regulatory role in the association. Taken together, our data suggest a new mechanism for dendritic transport of the AMPA receptor-PSD-95.

The Effects of Group Cognitive Behavioral Therapy on the Improvement of Depression and Anxiety in Adolescents with Problematic Internet Use.

OBJECTIVES: The overuse of the Internet among adolescents has increased dramatically in recent years, leading to pathological or problematic Internet use. Cognitive behavioral therapy (CBT) is known to be effective for the treatment of problematic Internet use, particularly for adolescents. The aim of the present study was to evaluate the therapeutic efficacy of group CBT for problematic Internet use in adolescents. METHODS: A total of 17 patients aged 12-17 years who met Young's diagnostic questionnaire criteria of problematic Internet use participated in a school-based eight-session group CBT program. The level of problematic Internet use among participating students was measured using Young's Internet Addiction Scale (IAS). Depression and anxiety levels were evaluated using the Children's Depression Inventory (CDI) and the State-Trait Anxiety Inventory (STAI), respectively. Each construct was assessed at baseline, immediately after the intervention, and at a one-month follow-up visit. Statistical significance was based on a p-value of <0.05. RESULTS: Immediately after the program, the IAS, CDI, and State Anxiety Inventory (SAI) scores were significantly lower than before the program. At the one-month follow-up assessment, the IAS scores remained low, and the CDI and SAI scores were even lower than immediately after the program. CONCLUSION: Group CBT was effective for adolescents with problematic Internet use, and was also demonstrated to improve depression and anxiety.