Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder.
Because the majority of patients with posttraumatic stress disorder (PTSD) exhibit long-lasting traumatic fear memory, we hypothesize that enhanced fear memory consolidation is closely involved in the pathophysiology of PTSD. Brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are crucial for hippocampal-dependent learning and memory. In particular, differential induction of BDNF gene transcripts mediated by histone acetylation plays a role in the consolidation of fear memory. In the present study, total and exon-specific mRNA and protein levels of BDNF and TrkB in the hippocampus after contextual fear conditioning (FC) were compared between rats subjected to single prolonged stress (SPS) and sham treatment. In addition, we examined the degree of histone acetylation at the promoter of each exon of the BDNF gene by chromatin immunoprecipitation (ChIP). We previously demonstrated a significant increase in contextual freezing in SPS rats. In the present study, SPS rats also showed increased total BDNF mRNA (including exons I, IV) and BDNF protein levels in the hippocampus after FC, accompanied by increased acetylation of histone H3 and H4 at the promoter of exon I and IV relative to sham-treated rats. Furthermore, the TrkB protein levels in the hippocampus of SPS rats were significantly higher than those in sham rats. These findings suggest that the enhanced levels of BDNF as well as TrkB along with epigenetic regulation of the BDNF gene during fear memory consolidation is, at least in part, associated with long-lasting fear memory in patients with PTSD.
Takei
Shiro
S
Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Morinobu
Shigeru
S
Yamamoto
Shigeto
S
Fuchikami
Manabu
M
Matsumoto
Tomoya
T
Yamawaki
Shigeto
S
D000107:Acetylation; D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation / Q000379:methods; D003213:Conditioning, Psychological / Q000502:physiology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005239:Fear; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013313:Stress Disorders, Post-Traumatic / Q000473:pathology* / Q000503:physiopathology
D019208:Brain-Derived Neurotrophic Factor; D006657:Histones; D012333:RNA, Messenger; D020813:Receptor, trkB