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Son, Hyeonwi,Baek, Ji Hyeong,Go, Bok Soon,Jung, Doo-hyuk,Sontakke, Sneha B.,Chung, Hye Jin,Lee, Dong Hoon,Roh, Gu Seob,Kang, Sang Soo,Cho, Gyeong Jae,Choi, Wan Sung,Lee, Dong Kun,Kim, Hyun Joon Elsevier 2018 NEUROPHARMACOLOGY - Vol.143 No.-
<P><B>Abstract</B></P> <P>Emerging evidence has shown the low levels of glutamate (Glu) and glutamine (Gln) and the hypoactivity in the cortex of patients with depression. The hypoactivity is closely related with low frequency of glutamatergic signaling that is affected by the levels of Glu and Gln. Thus, we hypothesized that there might be a causality among low levels of Glu and Gln, hypoactive glutamatergic neurotransmissions, and depressive behaviors. Here, we found low Glu and Gln levels and low frequency of spontaneous excitatory postsynaptic current (sEPSC) of glutamatergic neurons in the medial prefrontal cortex (mPFC) of chronic immobilization stress (CIS)-induced depressed mice. The depressed mice also showed hypoactive Gln synthetase (GS). Inhibition of GS by methionine sulfoximine (MSO) decreased Glu and Gln levels and increased depressive behaviors with low frequency of sEPSC in the mPFC, indicating that Glu and Gln decrements cause hypoactive glutamatergic neurotransmissions and depressive behaviors. Both Glu and Gln could increase sEPSC of glutamatergic neurons in the mPFC on slice patch, but only Gln overcame MSO to increase sEPSC, suggesting that exogenous Gln would recover CIS-induced low frequency of sEPSC caused by hypoactive GS and act as an antidepressant. Expectedly, Gln supplementation showed antidepressant effects against CIS; it increased glutamatergic neurotransmissions with Glu and Gln increment in the mPFC and attenuated depressive behaviors. Moreover, selective glutamatergic activation in the mPFC by optogenetics decreased depressive behavior. In conclusion, depressive behaviors evoked by chronic stress were due to hypoactive glutamatergic neurons in the mPFC caused by low levels of Glu and Gln, and exogenous Gln can be used as an alternative antidepressant to increase glutamatergic neurotransmission.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Chronic stress decreased GS activity and Glu and Gln levels in the mPFC. </LI> <LI> Chronic stress reduced glutamatergic sEPSCs but not sIPSCs in the mPFC. </LI> <LI> GS activity inhibition resulted in the similar phenotype of chronic stress. </LI> <LI> Gln increased glutamatergic sEPSCs regardless of GS inhibition on a slice. </LI> <LI> Gln increased Glu and Gln levels and sEPSCs in the mPFC against chronic stress. </LI> </UL> </P>
( Gyeong Wha Kim ),( Soon Woong Jung ),( Hyeonwi Son ),( Sujeong Kim ),( Jungil Choi ),( Dong Hoon Lee ),( Gu Seob Roh ),( Sang Soo Kang ),( Gyeong Jae Cho ),( Wan Sung Choi ),( Hyun Joon Kim ) 생화학분자생물학회(구 한국생화학분자생물학회) 2014 BMB Reports Vol.47 No.6
Regulators of G-protein signaling (RGS) proteins regulate certain G-protein-coupled receptor (GPCR)-mediated signaling pathways. The GABAB receptor (GABABR) is a GPCR that plays a role in the stress response. Previous studies indicate that acute immobilization stress (AIS) decreases RGS4 in the prefrontal cortex (PFC) and hypothalamus (HY) and suggest the possibility of a signal complex composed of RGS4 and GABABR. Therefore, in the present study, we tested whether RGS4 associates with GABABR in these brain regions. We found the co-localization of RGS4 and GABABR subtypes in the PFC and HY using double immunohistochemistry and confirmed a direct association between GABAB2R and RGS4 proteins using co-immunoprecipitation. Furthermore, we found that AIS decreased the amount of RGS4 bound to GABAB2R and the number of double-positive cells. These results indicate that GABABR forms a signal complex with RGS4 and suggests that RGS4 is a regulator of GABABR. [BMB Reports 2014; 47(6): 324-329]
Jeon, Byeong Tak,Jeong, Eun Ae,Park, Sun-Young,Son, Hyeonwi,Shin, Hyun Joo,Lee, Dong Hoon,Kim, Hyun Joon,Kang, Sang Soo,Cho, Gyeong Jae,Choi, Wan Sung,Roh, Gu Seob Harwood Academic Publishers 2013 Neurotoxicity research Vol.23 No.3
<P>Rho-associated coil kinase (ROCK) inhibitors reportedly prevent neurodegeneration, and abnormal ROCK activation in the central nervous system induces neurite collapse and retraction. However, it is unclear whether the ROCK inhibitor Y-27632 directly protects hippocampal neurons from excitotoxicity. Here, we determined the effects of Y-27632 on neuroprotection following kainic acid (KA)-induced seizures in mice and during glutamate-induced excitotoxicity in HT22 cells. One day after Y-27632 injection, mice were treated with KA and killed 1-2 days later. Fluoro-Jade B and rapid Golgi staining showed that Y-27632 protected against KA-induced neurodegeneration and neurite dystrophy. Y-27632 inhibited increases in hippocampal RhoA and ROCK2 in KA-treated mice as determined by western blot analysis. Immunohistochemical analysis revealed ROCK2-positive neurons and astrocytes in the KA-treated hippocampus. In HT22 cells, Y-27632 also protected neurons and neurite formation during glutamate-induced excitotoxicity in vitro. These results indicate that ROCK inhibition modulates neurite growth and protects neurons from excitotoxicity-induced cell death.</P>