Post-traumatic stress disorder (PTSD) is the only major mental disorder for which a cause is considered to be known: that is, an event that involves threat to the physical integrity of oneself or others and induces a response of intense fear, helplessness or horror. Although PTSD is still largely regarded as a psychological phenomenon, over the past three decades the growth of the biological PTSD literature has been explosive, and thousands of references now exist. Ultimately, the impact of an environmental event, such as a psychological trauma, must be understood at organic, cellular and molecular levels. This Review attempts to present the current state of this understanding on the basis of psychophysiological, structural and functional neuroimaging, and endocrinological, genetic and molecular biological studies in humans and in animal models.

Biological studies of post-traumatic stress disorder

http://molecular-ethology.biochem.s.u-tokyo.ac.jp/neuro-seminar/ftp-box/coagonist.pdf

Synaptic and Extrasynaptic NMDA Receptors Are Gated by Different Endogenous Coagonists

https://sites.oxy.edu/clint/physio/article/Fearconditioningsynapticplasticityandtheamygdalaimplicationsforposttraumaticstressdisorder.pdf

Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder

Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.

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Chronic Glutamate Toxicity in Neurodegenerative Diseases—What is the Evidence?

Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders.

Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder

Neuronal plasticity induced by changes in synaptic morphology and function is well known to play a pivotal role in leaning and memory as well as adaptation to stress. It is suggested that these plastic changes are due to orchestration of alterations in gene expression in the brain. Recent advances in molecular biology have provided evidence that epigenetic mechanisms, such as DNA methylation and histone modification, are crucial to gene transcription in the mammalian brain. Our research group has recently investigated the involvement of histone actylation at the promoter of the brain-derived neurotrophic factor (BDNF) gene in stress-induced reduction in BDNF, as well as in fear conditioning-induced enhancement of BDNF, in the rat hippocampus. The results of the stress study demonstrated that single-immobilization stress significantly reduced the levels of total, exon I, and exon IV BDNF mRNA, and also significantly reduced acetylation levels of histone H3, but not H4, at the promoter of exons I, IV, and VI. The results of the fear conditioning study showed that footshock stress significantly increased the levels of total, exon I, and exon IV BDNF mRNA, with significantly increased acetylation levels of both histone H3 and H4, at the promoter of exons I and IV, followed by enhanced freezing to fear-context exposure. These findings suggest that changes in BDNF transcription in the rat hippocampus in response to stressful stimuli are, at least in part, regulated by histone acetylation status.

/pdf/epigenetic-regulation-of-bdnf-gene-in-response-to-stress-orbgwxztoh.pdf

Epigenetic Regulation of BDNF Gene in Response to Stress

Given that impairment of fear extinction plays a pivotal role in the pathophysiology of posttraumatic stress disorder (PTSD), drugs that facilitate fear extinction may be useful as novel treatments for PTSD. Histone deacetylase (HDAC) inhibitors have recently been shown to enhance fear extinction in animal studies. Using a single prolonged stress (SPS) paradigm, an animal model of PTSD, we examined whether the HDAC inhibitor vorinostat can facilitate fear extinction in rats, and elucidated the mechanism by which vorinostat enhanced fear extinction, focusing on the N-methyl-d-aspartate (NMDA) receptor signals in the hippocampus. Seven days after SPS, rats received contextual fear conditioning, followed by 2-day extinction training. Vorinostat was intraperitoneally injected immediately after second extinction training session. Contextual fear response was assessed 24 h after vorinostat injection. Hippocampal tissues were dissected 2 h after vorinostat injection. The levels of mRNA and protein tested were measured by RT-PCR or western blotting, respectively. Systemic administration of vorinostat with extinction training significantly enhanced fear extinction in SPS rats as compared with the controls. Furthermore, vorinostat enhanced the hippocampal levels of NR2B and calcium/calmodulin kinase II (CaMKII) α and β proteins, accompanied by increases in the levels of acetylated histone H3 and H4. These findings suggest that vorinostat ameliorated the impaired fear extinction in SPS rats, and this effect was associated with an increase in histone acetylation and thereby enhancement of NR2B and CaMKII in the hippocampus. Our results may provide new insight into the molecular and therapeutic mechanisms of PTSD.

/pdf/vorinostat-ameliorates-impaired-fear-extinction-possibly-via-541his098s.pdf

Vorinostat ameliorates impaired fear extinction possibly via the hippocampal NMDA-CaMKII pathway in an animal model of posttraumatic stress disorder

Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene.

https://ir.lib.hiroshima-u.ac.jp/files/public/3/30879/20141016175945649552/JPsychiatrRes_44_1069.pdf

Shiro Takei

Papers

Enhanced hippocampal BDNF/TrkB signaling in response to fear conditioning in an animal model of posttraumatic stress disorder

Epigenetic Regulation of BDNF Gene in Response to Stress

Vorinostat ameliorates impaired fear extinction possibly via the hippocampal NMDA-CaMKII pathway in an animal model of posttraumatic stress disorder

Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene.

Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder