The Effects Of BDNF Val66Met Polymorphism On Lipopolysaccharide-induced Dperessive-like Behavior

Depression is a common mental disorder, characterized by sadness, loss of interesting or pleasure, feelings of guilt or low self-worth et.al. A recent World Health Organization study showed that more than350million people of all ages globally suffer from depression. Long-lasting and with moderate or severe intensity, depression may become a serious health condition, at its worst, depression can lead to suicide, which results in around1million deaths every year. Therefore, comprehensive research into the aetiology and pathophysiology of depression bears unique significance. It has been hypothesized that the pathophysiology of depression is closely related to various neurobiological changes. For instance, inflammation is thought to inlolve in depression either directly or indirectly. The past two decades have witnessed aburgeoning area of preclinical and clinical researchlinking psychiatric illnesses to inflammatoryprocesses. Most of the evidence that links inflammationand MDD (Major depressive disorder) comes from these observations:MDD isassociated with raised inflammatory markers; Inflammatory medical illnessesdare associated with greater rates ofmajor depression; Patients treated with cytokines for variousillnesses are at increased risk of developingmajor depressive illness. However, not all victims of inflammation suffer depression, which suggests that the incidence of depression varies among individuals, and one of the main causes for this variety is gene polymorphism.Recent researches show that a mutation of BDNF gene which changes valine66into methionine can block BDNF trafficking and then decrease activity-dependent release of BDNF. This is a common type of BDNF gene polymorphism. Heterozygous human carriers of this mutation BDNFMet have smaller hippocampal volume and impaired hippocampus-dependent memory functions. Moreover, this BDNF SNP (BDNFVal66Met) had been reported to exhibit higher susceptibility to a variety of neuropsychiatric disorders including, anxiety,bipolar disorder and schizophrenia. However, studies on depression showed ambiguous results:some researchers found that BDNFVal66Met gene carreiers exhibited higher susceptibility to depression; Johannes Schumacher et.al reported that people carrying the Met allele accounted for a higher percentage of patients with depression and anxiety disorders; the study on BDNFMet knock-in mice indicated that BDNFMet mutant mice exhibited poorer episodic memory performance, a symptom often observed in subjects with MDD (Major depressive disorder). Whereas, S Sen et al. reported that people carrying the Val allele get higher trait anxiety and higher mean neuroticism scores in the NEO personalitymeasurement and are therefore at higher risk of developing depression.In this study, we utilized BDNF+/Metmutant mice to investigate the effect of BDNF Val66Met gene polymorphism on Lipopolysaccharide (LPS)-induced inflammation and on the depression-like behavior responses of mice to this inflammation. It is also aimed at analyzing their molecular and cellular mechanisms.The results are summarized as follows:1, LPS can induce sickness behaviors among wild-type andBDNF+/MetmiceAfter6h of intracerebroventricular injection of LPS, untreated group and injection group mice all showed some loss of the weight, and after24h of injection, when compared with the untreated group, wild-type andBDNF+/Met miceshowed a lot of loss of the weight as well as significantly sickness behaviors.2, LPS changes the locomotor activity among wild-type andBDNF+/Met miceAt the time-point of6h after injection, both wild-type mice and BDNF+/Met mice performed reduced locomotion, but there was no significant difference among wild-type mice and BDNF+/Metmice. While, their locomotion recovered to the normal level24h after the injection. 3,BDNF+/Met mice are resistant to central LPS-induced depression-like behaviorAccording to the forced swimming test (FST) and tail suspension test (TST) they were indicated that wild-type mice and BDNF+/Metmice after intracerebroventricular injection of LPS, showed significantly longer immobility timewhen compared with the untreated group, additionally, after injection, wild-type mice showed longer immobility time compared with BDNF+/Met mice. It illustrated that BDNF+/Met mice were not so likely to show up the depressive-like behavior induced by LPS, when compared with wild-type mice.4, After intracerebroventricular injection of LPS, the increase of TNF-a expression in BDNF+/Met mice was less than that of wild-type mice.From the results of Real-time quantitative PCR detection for inflammatory factors IL-1α, IL-1β, TNF-a, it wasdemonstrated that after injection of LPS, the expression of IL-1α, IL-1β, TNF-a were increased in hippocampus of wild-type and BDNF+/Met mice. In BDNF+/Metmice, IL-1α and IL-1βwere increased which was consistent with injected wild-type mice. However, the increase of TNF-a was not so much as wild-type mice.5, The activation degree of microglia in BDNF+/Met mice was lower than that of the wild-type mice after injection LPS.We initially examined lba-1, CD11b, GFAP gene and protein expression at24h after intracerebroventricular injection of LPS, using Real time PCR, western blot andimmunohistochemistry. Compared with the untreated mice, significantly increase of lba-1and CD11b observed in hippocampus of wild-type mice and BDNF+/Met mice. After the injection of LPS, the wild-type mice showed a higher increase of Iba-1and CD11b when compared with BDNF+/Met mice.Moreover, after injection,compared with the untreated mice, the expression of GFAP increased in hippocampus of wild-type mice and BDNF+/Met mice,and the expression of GFAP showed an increase of theBDNF+/Met mice with injection, giving the same tendency as the wild-type mice.6, After stimulate with LPS, cultured BDNF+/Met microglia cells can’t be activatedWhen cultured wild-type and BDNF+/Met microglia cells, we found that compared with untreated cells, LPS injected wile-type microglia cells showed a significante increase in lba-1, but there was no change in BDNF+/Met microglia cells. It proved that BDNF+/Metmicroglia cells were insensitivity to injection of LPS.Conclusion:Our data proved that after the injection of LPS, wild-type mice and BDNF+/Metmice showed different responsesto the depressive-like behavior induced by LPS. The reason of the difference was that the activation degree of microglia in hippocampus of BDNF+/Met mice was lower than that of the wild-type mice. And the expression of TNF-a was also lower than the wild-type mice. Additionally, we found cultured BDNF+/Metmicroglia cells were insensitivity to injection of LPS. Over all, it could be concluded that BDNFMet mutation played a significantroleto reduce and control the inflammatory process induced by LPS.