PDF(Pubmed)
Abstract：
UNASSIGNED: Disrupted in schizophrenia-1 (DISC1) is a scaffolding protein whose mutated form has been linked to schizophrenia, bipolar affective disorders, and recurrent major depression. DISC1 regulates multiple signaling pathways involved in neurite outgrowth and cortical development and binds directly to glycogen synthase kinase-3β (GSK-3β). Since ketamine activates GSK-3β, we examined the impact of ketamine on DISC1 and GSK-3β expression.
UNASSIGNED: Postnatal day 7 rat pups were treated with ketamine with and without the non-specific GSK-3β antagonist, lithium. Cleaved-caspase-3, GSK-3β and DISC1 levels were measured by immunoblots and DISC1 co-localization in neurons by immunofluorescence. Binding of DISC1 to GSK-3β was determined by co-immunoprecipitation. Neurite outgrowth was determined by measuring dendrite and axon length in primary neuronal cell cultures treated with ketamine and lithium.
UNASSIGNED: Ketamine decreased DISC1 in a dose and time-dependent manner. This corresponded to decreases in phosphorylated GSK-3β, which implicates increased GSK-3β activity. Lithium significantly attenuated ketamine-induced decrease in DISC1 levels. Ketamine decreased co-immunoprecipitation of DISC1 with GSK-3β and axonal length.
UNASSIGNED: These findings confirmed that acute administration of ketamine decreases in DISC1 levels and axonal growth. Lithium reversed this effect. This interaction provides a link between DISC1 and ketamine-induced neurodegeneration.
UNASSIGNED: Postnatal day 7 rat pups were treated with ketamine with and without the non-specific GSK-3β antagonist, lithium. Cleaved-caspase-3, GSK-3β and DISC1 levels were measured by immunoblots and DISC1 co-localization in neurons by immunofluorescence. Binding of DISC1 to GSK-3β was determined by co-immunoprecipitation. Neurite outgrowth was determined by measuring dendrite and axon length in primary neuronal cell cultures treated with ketamine and lithium.
UNASSIGNED: Ketamine decreased DISC1 in a dose and time-dependent manner. This corresponded to decreases in phosphorylated GSK-3β, which implicates increased GSK-3β activity. Lithium significantly attenuated ketamine-induced decrease in DISC1 levels. Ketamine decreased co-immunoprecipitation of DISC1 with GSK-3β and axonal length.
UNASSIGNED: These findings confirmed that acute administration of ketamine decreases in DISC1 levels and axonal growth. Lithium reversed this effect. This interaction provides a link between DISC1 and ketamine-induced neurodegeneration.
摘要：
■在精神分裂症中被破坏-1（DISC1）是一种支架蛋白，其突变形式与精神分裂症有关，双相情感障碍,和复发性重度抑郁症。DISC1调节参与神经突生长和皮质发育的多种信号通路，并直接与糖原合酶激酶-3β（GSK-3β）结合。由于氯胺酮激活GSK-3β，我们研究了氯胺酮对DISC1和GSK-3β表达的影响。
■出生后第7天的幼鼠用氯胺酮治疗，有无非特异性GSK-3β拮抗剂，锂。通过免疫印迹和通过免疫荧光在神经元中的DISC1共定位来测量切割的caspase-3，GSK-3β和DISC1水平。通过共免疫沉淀测定DISC1与GSK-3β的结合。通过测量用氯胺酮和锂处理的原代神经元细胞培养物中的树突和轴突长度来确定神经元生长。
■氯胺酮以剂量和时间依赖性方式降低DISC1。这对应于磷酸化GSK-3β的减少，这意味着GSK-3β活性增加。锂显著减弱氯胺酮诱导的DISC1水平降低。氯胺酮降低了DISC1与GSK-3β和轴突长度的共免疫沉淀。
■这些发现证实了急性施用氯胺酮降低了DISC1水平和轴突生长。锂逆转了这种效应。这种相互作用提供了DISC1和氯胺酮诱导的神经变性之间的联系。
■出生后第7天的幼鼠用氯胺酮治疗，有无非特异性GSK-3β拮抗剂，锂。通过免疫印迹和通过免疫荧光在神经元中的DISC1共定位来测量切割的caspase-3，GSK-3β和DISC1水平。通过共免疫沉淀测定DISC1与GSK-3β的结合。通过测量用氯胺酮和锂处理的原代神经元细胞培养物中的树突和轴突长度来确定神经元生长。
■氯胺酮以剂量和时间依赖性方式降低DISC1。这对应于磷酸化GSK-3β的减少，这意味着GSK-3β活性增加。锂显著减弱氯胺酮诱导的DISC1水平降低。氯胺酮降低了DISC1与GSK-3β和轴突长度的共免疫沉淀。
■这些发现证实了急性施用氯胺酮降低了DISC1水平和轴突生长。锂逆转了这种效应。这种相互作用提供了DISC1和氯胺酮诱导的神经变性之间的联系。
