Mechanisms Underlying the Regulation of Fear Memory Formation by Brain-Derived Neurotrophic Factor

• Main Authors: Li-Chin Ou, 歐莉琴
• Other Authors: Po-Wu Gean
• Format: Others
• Language: zh-TW
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/62721259942251442223

博士 === 國立成功大學 === 基礎醫學研究所 === 97 === Long-term potentiation (LTP), a form of synaptic plasticity, is a putative cellular mechanism for learning and memory. Brain-derived neurotrophic factor (BDNF) is widely identified that it modulates synaptic plasticity and learning and memory. This thesis mainly describes the molecular mechanisms underlying the regulation of amygdala-dependent fear memory formation by BDNF. Our data reveal that calcium influx through NR2B-containing NMDA receptor and L-type voltage-dependent calcium channel (L-VDCC) activated PKA and CaMKIV to phosphorylate CREB at ser-133. Activated CREB bound to BDNF promoter region of exon I and III to initiate BDNF expression. Moreover, BDNF arose from precursor pro-BDNF, which was proteolytically cleaved to mature BDNF by plasmin, and bound to TrkB receptor tyrosine kinase. Activated TrkB receptor associated with its adaptor protein, Shc, and, thus, Shc recruited Ras and PI3K to activate MAPK. Fear conditioning induced BDNF expression not only 1 h but also 12 h after training. We try to find out the functional role of early- and late-expressed BDNF in regulating fear memory formation. Our results indicate that pre-training blockade of BDNF signaling impaired fear memory in a test carried out 1 or 7 days after training. By contrast, interfering BDNF signaling 9 h after fear conditioning, which did not affect memory retention measured 1 day after training, impaired memory when the rats were tested 7 days after training. Furthermore, we found a BDNF-dependent expression of growth-associated protein 43 (GAP-43), a marker of newly formed synapses, in the amygdala 7 days after fear training. In parallel, conditioned rats had more number of spines and branches, and higher AMPA/NMDA ratio in pyramidal cells. These data suggest early-expressed BDNF processes the consolidation of newly acquired memory and late-expressed BDNF is required for the persistence of fear memory. In summary, these results demonstrate candidate signaling pathways regulated BDNF expression and coupled to TrkB receptor activation. BDNF-mediated structural modifications of synaptic connections in the amygdala are required in the persistence of long-term fear memory. Thus, BDNF may become an avenue of therapeutic intervention for the treatment of fear-related mental disorders, like post-traumatic stress disorders.