Delayed injury of hippocampal interneurons after neonatal hypoxia-ischemia and therapeutic hypothermia in a murine model.
Delayed injury of hippocampal interneurons after neonatal hypoxia-ischemia and therapeutic hypothermia in a murine model.
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DOI：
10.1002/hipo.22965
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发表时间：
2018-08
期刊：
影响因子：
3.5
通讯作者：
Northington FJ
中科院分区：
文献类型：
--
作者：
Chavez-Valdez R;Emerson P;Goffigan-Holmes J;Kirkwood A;Martin LJ;Northington FJ
尽管使用治疗性低温（TH），新生儿缺氧缺血（HI）后仍会出现迟发性海马损伤和记忆障碍。HI后海马锥体细胞迅速死亡，但延迟性细胞死亡和中间神经元（INs）损伤的特征尚不清楚。我们假设HI后INs的损伤：i）与锥体细胞的损伤不同步，ii）与损伤严重程度无关，iii）对TH无反应。在p10通过单侧右侧颈动脉结扎和缺氧45分钟（FiO 2 =0.08）在C57 BL 6小鼠中诱导HI。HI后4 h将小鼠随机分为常温组（36 ℃，NT）和TH组（31 ℃），并以麻醉暴露的假手术组作为对照。HI后24 h（p11）或8 d（p18）取脑组织进行观察。检测VEGF 1、GAD 65/67、PSD 95、小清蛋白（PV）和钙结合蛋白-1（Calb 1）。采用甲酚紫染色和TUNEL法检测细胞死亡情况。使用p18时的海马萎缩和星形胶质细胞增多来评估损伤严重程度，并与PV+ INs.VGlut1水平在HI后24 h下降30%，而GAD 65/67水平在HI后8 d下降约50%，下降局限于CA 1和CA 3。在HI后24小时，前脑中的PSD 95水平降低了65%，并且在HI后8天保持低水平。在假手术小鼠中，PV+ IN的数量（每mm 2）和p11和p18之间的分支增加，但在NT和TH小鼠中没有增加，导致p18时损伤小鼠中PV+ IN减少21 - 52%。Calb 1蛋白和mRNA在HI损伤小鼠中也减少。在p18时，在所有受伤的小鼠中，INs的体树突磨损是明显的，没有细胞死亡的证据。海马萎缩和星形胶质细胞增生与p18时PV+ IN的数量均不相关。因此，HI暴露在海马中具有长期持续的影响，损害GABA能系统的发育，而TH仅具有部分保护作用，与海马损伤的程度无关。
Delayed hippocampal injury and memory impairments follow neonatal hypoxia-ischemia (HI) despite the use of therapeutic hypothermia (TH). Death of hippocampal pyramidal cells occurs acutely after HI, but characterization of delayed cell death and injury of interneurons (INs) is unknown. We hypothesize that injury of INs after HI is: i) asynchronous to that of pyramidal cells, ii) independent of injury severity, and iii) unresponsive to TH. HI was induced in C57BL6 mice at p10 with unilateral right carotid ligation and 45 min of hypoxia (FiO2=0.08). Mice were randomized to normothermia (36⁰C,NT) or TH (31⁰C) for 4h after HI and anesthesia-exposed shams were use as controls. Brains were studied at 24h (p11) or 8d (p18) after HI. Vglut1, GAD65/67, PSD95, parvalbumin (PV) and calbindin-1 (Calb1) were measured. Cell death was assessed using cresyl violet staining and TUNEL assay. Hippocampal atrophy and astroglyosis at p18 were used to assess injury severity and to correlate with number of PV+INs. VGlut1 level decreased by 30% at 24h after HI, while GAD65/67 level decreased by ~50% in forebrain 8d after HI, a decrease localized in CA1 and CA3. PSD95 levels decreased in forebrain by 65% at 24h after HI and remained low 8 days after HI. PV+INs increased in numbers (per mm2) and branching between p11 and p18 in sham mice but not in NT and TH mice, resulting in 21 to 52% fewer PV+INs in injured mice at p18. Calb1 protein and mRNA were also reduced in HI injured mice. At p18, somatodendritic attrition of INs was evident in all injured mice without evidence of cell death. Neither hippocampal atrophy nor astroglyosis correlated with the number of PV+INs at p18. Thus, HI exposure has long lasting effects in the hippocampus impairing the development of the GABAergic system with only partial protection by TH independent of the degree of hippocampal injury.
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影响因子：
2.9
作者：
Diaz J;Abiola S;Kim N;Avaritt O;Flock D;Yu J;Northington FJ;Chavez-Valdez R
通讯作者：
Chavez-Valdez R
影响因子：
4.5
作者：
Heckers, Stephan;Konradi, Christine
通讯作者：
Konradi, Christine
影响因子：
2.5
作者：
Bosman, LWJ;Heinen, K;Brussaard, AB
通讯作者：
Brussaard, AB
影响因子：
2.2
作者：
Baron, Ida Sue;Brandt, Jason;Litman, Fern R.
通讯作者：
Litman, Fern R.
影响因子：
158.5
作者：
Azzopardi, Denis;Strohm, Brenda;Edwards, A. David
通讯作者：
Edwards, A. David