Advances in Zebrafish as a Comprehensive Model of Mental Disorders

Figure 3

Overview of the mechanism of CNS diseases. (a) PTSD. (A) Shorter telomeres increase the risk of stress-related illnesses and early death such as PTSD in susceptible people. Traumatic events in childhood have also been linked to shorter telomere lengths in PTSD patients. BDNF encodes neurotrophin that plays an important role in the growth, differentiation, maturation, and survival of immature neurons as well as in the regulation of prominent plasticity, neurotransmission, and receptor sensitivity in mature neurons. Molecular chaperone FK506-binding protein 5 (FKBP5) is a key regulator of the stress hormone system that mediates the response to traumatic stress. The association of FKBP5 gene polymorphism with childhood maltreatment can predict the severity of PTSD symptoms [82]. ADCYAP1R1 is a high affinity receptor for PACAP, which is related to estrogen-dependent regulation. Genetic susceptibility to PTSD may depend on PAC1 expression in the cortex [83]. COMT (Catechol-O-methyltransferase) regulates cortical function, and there is a gene-environment interaction between the Val158Met polymorphism in human COMT and the type of traumatic events experienced in the risk of PTSD [84]. (B) The level of GR and cortisol in the HPI axis. Glucocorticoids are mediators of the HPA axis, mediated by GR, and then exert effects on physiological functions. Lower cortisol levels in morning specifically correlate HPA axis dysfunction with PTSD hyperalert symptoms [85]. (C) The key brain regions associated with PTSD symptoms were the prefrontal cortex, anterior cingulated cortex, amygdala, and hippocampus, and they are involved in the formation of emotion and fear memory and recovery. (b) Extracellular matrix (ECM) levels of AD mechanisms. One of the manifestations of AD is the increase of TNC (Tenascin-C), which induces inflammation. TNC promotes the stability of PNNs (perineuronal net) and reduces the scavenging capacity of Aβ protein. HP (heparin) and HSPGs (heparan sulfate proteoglycans), DSPGs (dermatan sulfate proteoglycans) and HA (hyaluronic acid), and TENASCIN-R (TNR) are increased in AD. HP with different molecular weights (MW) affects the generation of Aβ by regulating the β-sheet secondary structure. HSPGs promote the formation of Aβ fibrils, inhibit amyloid proteolysis, and promote Aβ production. DSPGs maintain the stability of Aβ. HA inhibits the maturation of OPCs, causes demyelination, and reduces the supply of brain oxygen and glucose (O2/G). TNR may prevent lipofuscin from destroying neurons. Others like reelin and keratan are decreased in AD. Reproduced with permission from [86]. (c) Pathways and injury mechanisms of dopaminergic neurotoxins in PD. Here, 6-OHDA (6-hydroxydopamine) reaches dopaminergic neurons via the SNc (substantia nigra pars compacta) or the striatum. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), rotenone, and paraquat can cross the BBB. In this study, the metabolite of MPTP, MPP+, is transported to dopaminergic neurons via DAT (dopamine transporter). These substances induce oxidative stress, ultimately leading to the neuronal death. Reproduced with permission from [87]. (d) Mechanism of epilepsy mediated by mTOR signaling pathway. Reproduced with permission from [88].