| Abstract |
Brain-derived neurotrophic factor (BDNF) has been implicated in higher-order cognitive functions and in psychiatric disorders such as depression andschizophrenia. BDNF modulates synaptic transmission and plasticity primarily through the TrkB receptor, but the molecules involved in BDNF-mediated synaptic modulation are largely unknown. Myosin VI (Myo6) is a minus end-directed actin-based motor found in neurons that express Trk receptors. Here we report that Myo6 and a Myo6-binding protein,GIPC1, form a complex that can engage TrkB. Myo6 andGIPC1were necessary for BDNF-TrkB-mediated facilitation of long-term potentiation in postnatal day 12-13 (P12-13) hippocampus. Moreover, BDNF-mediated enhancement of glutamate release from presynaptic terminals depended not only upon TrkB but also upon Myo6 andGIPC1. Similar defects in basal synaptic transmission as well as presynaptic properties were observed in Myo6 andGIPC1mutant mice. Together, these results define an important role for the Myo6-GIPC1motor complex in presynaptic function and in BDNF-TrkB-mediated synaptic plasticity. |
| Abstract |
schizophreniais one of the major psychiatric disorders. It is a disorder of complex inheritance, involving both heritable and environmental factors. DNA methylation is an inheritable epigenetic modification that stably alters gene expression. We reasoned that genetic modifications that are a result of environmental stimuli could also make a contribution. We have performed 26 high-resolution genome-wide methylation array analyses to determine the methylation status of 27,627 CpG islands and compared the data between patients and healthy controls. Methylation profiles of DNAs were analyzed in six pools: 220schizophrenia病人;220 age-matched healthy controls; 110 femaleschizophrenia病人;110年与他lthy females; 110 maleschizophrenia病人;110年与他lthy males. We also investigated the methylation status of 20 individual patient DNA samples (eight females and 12 males. We found significant differences in the methylation profile betweenschizophreniaand control DNA pools. We found new candidate genes that principally participate in apoptosis, synaptic transmission and nervous system development (GABRA2, LIN7B, CASP3). Methylation profiles differed between the genders. In females, the most important genes participate in apoptosis and synaptic transmission (XIAP, GABRD, OXT, KRT7), whereas in the males, the implicated genes in the molecular pathology of the disease were DHX37, MAP2K2, FNDC4 andGIPC1. Data from the individual methylation analyses confirmed, the gender-specific pools results. Our data revealed major differences in methylation profiles betweenschizophreniapatients and controls and between male and female patients. The dysregulated activity of the candidate genes could play a role inschizophreniapathogenesis. |