Role Of BDNF Signal Pathways In Neuroplasticity And Depression

Objectives:Depression is a psychiatric disease which is featured with a low sustained emotion and brain dysfunctions in clinical medicine. Depression is one of the most common life-threatening neuropsychiatric disorders and has been associated with a wide range of neuronal structural changes in brain regions, but its pathological mechanisms have not yet been completely understood. Increasing evidence has indicated that depression is related to structural changes resulting from synaptic plasticity in specific brain regions. A new study has found that stress could lead to nerve tissue atrophy and nerve cells lost in the key regions that regulated the emotions including the prefrontal cortex,hippocampus and the amygdala. There are morphological changes in these brain regions. The present study was designed to investigate the role of BDNF-Limk1-Actin signal pathways on neuronal structural synaptic plasticity in the rat model of chronic, unpredictable, mild, stress (CUMS)-induced depression through the combination of such as morphology, molecular biology and behavioral techniques. To further examine the underlying mechanisms of neotrofin-induced antidepressant-like effects and neural protection in the amygdala as well as the mechanisms of curcumin-induced antidepressant-like effects and neural protection in the prefrontal cortex.Methods:Male Wistar rats were randomly allocated to one of the following four groups:(a) control group (non-stressed group), (b) CUMS group, (c) neotrofin or curcumin followed by CUMS, (d) vehicle treatment followed by CUMS. Except the non-stressed control animals, rats in the rest of three groups were exposed to stress regime for a continuous six-week period. Curcumin(40mg/kg) or neotrofin(60mg/kg) was intraperitoneally (i.p.) administered in a constant volume 30 minutes prior to the stress exposure once a day for six weeks. Following the 6-week of stress regime, rats were subjected to a set of behavioral tests that included open-field test, forced swimming test and sucrose preference test. Thereafter, the animals were sacrificed and the specific tissue was subjected to morphological and biochemical examinations. Western blot and immunofluorescence were performed to determine the changes of BDNF(brain-derived neurotrophic factor), PSD-95(postsynaptic density protein 95), synaptophysin, p-limkl and p-cofilin expression. The changes of gene level of BDNF, PSD-95 and synaptophysin were examined with the technology of RT-PCR.Results:(1) Open-field test showed that CUMS exposure was associated with significantly reduced the number of crossings and rearings in comparison with non-stressed control animals (p<0.05). CUMS exposure also significantly increased immobility time and decreased swimming time in rats as compared to the non-stressed control animals in forced swimming test (p<0.05). Sucrose preference test showed that CUMS exposure significantly reduced sucrose consumption as compared to the non-stressed control group (p<0.05). (2) Western blot showed a 6-week exposure to CUMS was associated with down regulations of BDNF, PSD-95, synaptophysin in the amygdala. In compared with the CUMS group and NaCl group,chronic administration of neotrofin was useful to ameliorate depressive-like behavior and might possess neuroprotective effects in this CUMS-treated animal model of depression. Western blot showed that neotrofin treatment up-regulated the expression of BDNF, PSD-95 and synaptophysin expression in the amygdala. (3) Western blot and immunofluorescence showed a 6-week exposure to CUMS was associated with down regulations of BDNF, PSD-95, synaptophysin, p-limkl and p-cofilin expression in prefrontal cortex region. Besides, the results of RT-PCR suggested the gene level of BDNF, PSD-95 and synaptophysin was reduced in the prefrontal cortex regions of the CUMS rats as compared to the non-stressed control animals. (4) In compared with the CUMS group and DMSO group, systemic administration of curcumin was useful to ameliorate depressive-like behavior and might possess neuroprotective effects in this CUMS-treated animal model of depression.Western blot and immunofluorescence showed that curcumin treatment up-regulated the expression of BDNF, PSD-95, synaptophysin, p-limkl and p-cofilin expression in prefrontal cortex region of CUMS-exposed animals. RT-PCR results suggested the gene level of BDNF, PSD-95 and synaptophysin was reversed in the prefrontal cortex regions of the curcumin-administrated rats compared with CUMS and DMSO animals.Conclusions:1. CUMS could induce depressive-like behaviors that is associated with neuronal structural synaptic plasticity in the amygdala and the prefrontal cortex regions.2. This neuronal structural synaptic plasticity may be associated with the reduction of BDNF, which results to decreasing the expression of those proteins including p-limk1, p-cofilin and actin. The changes of the above molecules affect the PSD-95 and synaptophysin expression that involved in the maintenance of synapses.3. Chronic long-term administration of neotrofin can ameliorate depressive-like behavior and the antidepressant-like action of neotrofin appears to be mediated by regulating neuronal structural synaptic plasticity.4. Systematic administration of curcumin is useful to ameliorate depressive-like behavior and the antidepressant-like action of curcumin appears to be mediated by BDNF-Limkl-actin signaling pathway. In conclusion, the results of above suggested that systematic administration of neotrofin is useful to ameliorate depressive-like behavior and might possess neuroprotective effects in this CUMS-treated animal model of depression.