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Transgenic overexpression of furin increases epileptic susceptibility.

ABSTRACT: The proprotein convertase Furin plays crucial roles in the pathology of many diseases. However, the specific role of furin in epilepsy remains unclear. In our study, furin protein was increased in the temporal neocortex of epileptic patients and in the hippocampus and cortex of epileptic mice. The furin transgenic (TG) mice showed increased susceptibility to epilepsy and heightened epileptic activity compared with wild-type (WT) mice. Conversely, lentivirus-mediated knockdown of furin restrained epileptic activity. Using whole-cell patch clamp, furin knockdown and overexpression influenced neuronal inhibitory by regulating postsynaptic gamma-aminobutyric acid A receptor (GABA_AR)-mediated synaptic transmission. Importantly, furin influenced the expression of GABA_AR ?2/3 membrane and total protein in epileptic mice by changing transcription level of GABA_AR ?2/3, not the protein degradation. These results reveal that furin may regulate GABA_AR-mediated inhibitory synaptic transmission by altering the transcription of GABA_AR ?2/3 subunits in epilepsy; this finding could provide new insight into epilepsy prevention and treatment.

SUBMITTER: Yang Y

PROVIDER: S-EPMC6193048 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Transgenic overexpression of furin increases epileptic susceptibility.

Yang Yi Y He Miaoqing M Tian Xin X Guo Yi Y Liu Feng F Li Yun Y Zhang Haiqing H Lu Xi X Xu Demei D Zhou Ruijiao R Ma Yuanlin Y Wang Wei W Chen Guojun G Hu Yida Y Wang Xuefeng X

Cell death & disease 20181017 11

The proprotein convertase Furin plays crucial roles in the pathology of many diseases. However, the specific role of furin in epilepsy remains unclear. In our study, furin protein was increased in the temporal neocortex of epileptic patients and in the hippocampus and cortex of epileptic mice. The furin transgenic (TG) mice showed increased susceptibility to epilepsy and heightened epileptic activity compared with wild-type (WT) mice. Conversely, lentivirus-mediated knockdown of furin restrained ...[more]

PMID: 30333479

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Project description:Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOEdev) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOEdev exposed and unexposed mice, avoidance and arousal behaviors were examined 7-15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOEdev exposed and unexposed mice were examined 7 days after predator stress. CRHOEdev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOEdev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOEdev, males developed significant avoidance only when exposed to both CRHOEdev and stress. Quantitative real-time-PCR analysis indicated that CRHOEdev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOEdev did not. Similar to CRHOEdev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOEdev exposure in males, but not in females. These findings indicate that forebrain CRH hyper-signaling in early-life is sufficient to increase enduring effects of adult trauma and attenuate Crhr2 expression changes in response to stress in males. These data support growing evidence for significant sex differences in response to trauma, and support further study of CRHR2 as a candidate mechanism for PTSD risk.

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Transgenic overexpression of furin increases epileptic susceptibility.

Publications

Transgenic overexpression of furin increases epileptic susceptibility.

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