Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition
Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition
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DOI：
10.1523/jneurosci.1748-05.2005
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发表时间：
2005-08-31
影响因子：
5.3
通讯作者：
Maier, SF
中科院分区：
文献类型：
--
作者：
Bilbo, SD;Biedenkapp, JC;Maier, SF
我们曾报道过，新生儿感染会导致成年后免疫挑战后的记忆障碍。在这里，我们探讨了早期感染导致的事件是否会改变成年大鼠对随后免疫挑战的反应，这可能会损害记忆。在实验1中，出生后第4天外周感染大肠杆菌，增加了细胞因子和皮质酮在周边，和细胞因子和小胶质细胞标记基因表达的新生儿幼崽海马。接下来，用E.大肠杆菌或PBS成年后注射脂多糖（LPS）或生理盐水，1 - 24 h后处死。在新生儿感染的盐水对照组中，小胶质细胞标志物mRNA在海马中升高。此外，LPS诱导的胶质细胞标记物mRNA在海马中的神经胶质细胞感染的大鼠更大的增加，并且这种增加在24小时与对照组相比仍然升高。在LPS后，经腹腔感染的大鼠在海马和皮质内表现出更快的白细胞介素-1 β（IL-1 β）增加，并在皮质内表现出延长的反应。外周细胞因子或皮质酮无组间差异。实验2：E.大肠杆菌或PBS作为成年人接受生理盐水或集中施用的胱天蛋白酶-1抑制剂，其在学习事件和随后的LPS攻击前1小时特异性地阻止IL-1 β的合成。Caspase-1抑制完全防止LPS诱导的记忆障碍在腹腔感染的大鼠。这些数据表明，IL-1 β参与了新生儿感染导致的大脑中发生的一系列免疫/炎症事件，这可能有助于成年后的认知改变。
We have reported that neonatal infection leads to memory impairment after an immune challenge in adulthood. Here we explored whether events occurring as a result of early infection alter the response to a subsequent immune challenge in adult rats, which may then impair memory. In experiment 1, peripheral infection with Escherichia coli on postnatal day 4 increased cytokines and corticosterone in the periphery, and cytokine and microglial cell marker gene expression in the hippocampus of neonate pups. Next, rats treated neonatally with E. coli or PBS were injected in adulthood with lipopolysaccharide (LPS) or saline and killed 1 - 24 h later. Microglial cell marker mRNA was elevated in hippocampus in saline controls infected as neonates. Furthermore, LPS induced a greater increase in glial cell marker mRNA in hippocampus of neonatally infected rats, and this increase remained elevated at 24 h versus controls. After LPS, neonatally infected rats exhibited faster increases in interleukin-1 beta (IL-1 beta) within the hippocampus and cortex and a prolonged response within the cortex. There were no group differences in peripheral cytokines or corticosterone. In experiment 2, rats treated neonatally with E. coli or PBS received as adults either saline or a centrally administered caspase-1 inhibitor, which specifically prevents the synthesis of IL-1 beta, 1 h before a learning event and subsequent LPS challenge. Caspase-1 inhibition completely prevented LPS-induced memory impairment in neonatally infected rats. These data implicate IL-1 beta in the set of immune/inflammatory events that occur in the brain as a result of neonatal infection, which likely contribute to cognitive alterations in adulthood.