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Delayed injury of hippocampal interneurons after neonatal hypoxia-ischemia and therapeutic hypothermia in a murine model.

ABSTRACT: 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 (36?°C, NT) or TH (31?°C) for 4?hr after HI and anesthesia-exposed shams were use as controls. Brains were studied at 24?hr (p11) or 8 days (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 24?hr after HI, while GAD65/67 level decreased by ?50% in forebrain 8 days after HI, a decrease localized in CA1 and CA3. PSD95 levels decreased in forebrain by 65% at 24?hr 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 21-52% fewer PV?+?INs in injured mice at p18. Calb1 protein and mRNA were also reduced in HI injured mice at p18. 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. © 2018 Wiley Periodicals, Inc.

SUBMITTER: Chavez-Valdez R

PROVIDER: S-EPMC6432630 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Delayed injury of hippocampal interneurons after neonatal hypoxia-ischemia and therapeutic hypothermia in a murine model.

Chavez-Valdez Raul R Emerson Paul P Goffigan-Holmes Janasha J Kirkwood Alfredo A Martin Lee J LJ Northington Frances J FJ

Hippocampus 20180801 8

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 r ...[more]

PMID: 29781223

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Project description:Hippocampal injury following neonatal hypoxia-ischemia (HI) leads to memory impairments despite therapeutic hypothermia (TH). In the hippocampus, the expression of calbindin-1 (Calb1), a Ca2+-buffering protein, increases during postnatal development and decreases with aging and neurodegenerative disorders. Since persistent Ca2+ dysregulation after HI may lead to ongoing injury, persistent changes in hippocampal expression of Calb1 may contribute to memory impairments after neonatal HI. We hypothesized that, despite TH, neonatal HI persistently decreases Calb1 expression in the hippocampus, a change associated with memory deficits in the mouse. We induced cerebral HI in C57BL6 mice at postnatal day 10 (P10) with right carotid ligation and 45 min of hypoxia (FiO2 = 0.08), followed by normothermia (36°C, NT) or TH (31°C) for 4 h with anesthesia-shams as controls. Nissl staining and glial fibrillary acidic protein (GFAP) immunohistochemistry (IHC) were used to grade brain injury and astrogliosis at P11, P18, and P40 prior to the assessment of Calb1 expression by IHC. The subset of mice followed to P40 also performed a memory behavior task (Y-maze) at P22-P26. Nonparametric statistics stratified by sex were applied. In both anterior and posterior coronal brain sections, hippocampal Calb1 expression doubled between P11 and P40 due to an increase in the cornus ammonis (CA) field (Kruskal-Wallis [KW] p < 0.001) and not the dentate gyrus (DG). Neonatal HI produced delayed (P18) and late (P40) deficits in the expression of Calb1 exclusively in the CA field (KW p = 0.02) in posterior brain sections. TH did not attenuate Calb1 deficits after HI. Thirty days after HI injury (at P40), GFAP scores in the hippocampus (p < 0.001, r = -0.47) and CA field (p < 0.001, r = -0.39) of posterior brain sections inversely correlated with their respective Calb1 expression. Both sexes demonstrated deficits in Y-maze testing, including approximately 40% lower spontaneous alterations performance and twice as much total impairment compared to sham mice (KW p < 0.001), but it was only in females that these deficits correlated with the Calb1 expression in the hippocampal CA field (p < 0.05) of the posterior sections. Hippocampal atrophy after neonatal HI also correlated with worse deficits in Y-maze testing, but it did not predict Calb1 deficits. Neonatal HI produces a long-lasting Calb1 deficit in the hippocampal CA field during development, which is not mitigated by TH. Late Calb1 deficit after HI may be the result of persistent astrogliosis and can lead to memory impairment, particularly in female mice.

Project description:Therapeutic hypothermia is the standard of clinical care for moderate neonatal hypoxic-ischemic encephalopathy. We investigated the independent and interactive effects of hypoxia-ischemia (HI) and temperature on neuronal survival and injury in basal ganglia and cerebral cortex in neonatal piglets. Male piglets were randomized to receive HI injury or sham procedure followed by 29 h of normothermia, sustained hypothermia induced at 2 h, or hypothermia with rewarming during fentanyl-nitrous oxide anesthesia. Viable and injured neurons and apoptotic profiles were counted in the anterior putamen, posterior putamen, and motor cortex at 29 h after HI injury or sham procedure. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) identified genomic DNA fragmentation to confirm cell death. Though hypothermia after HI preserved viable neurons in the anterior and posterior putamen, hypothermia prevented neuronal injury in only the anterior putamen. Hypothermia initiated 2 h after injury did not protect against apoptotic cell death in either the putamen or motor cortex, and rewarming from hypothermia was associated with increased apoptosis in the motor cortex. In non-HI shams, sustained hypothermia during anesthesia was associated with neuronal injury and corresponding viable neuron loss in the anterior putamen and motor cortex. TUNEL confirmed increased neurodegeneration in the putamen of hypothermic shams. Anesthetized, normothermic shams did not show abnormal neuronal cytopathology in the putamen or motor cortex, thereby demonstrating minimal contribution of the anesthetic regimen to neuronal injury during normothermia. We conclude that the efficacy of hypothermic protection after HI is region specific and that hypothermia during anesthesia in the absence of HI may be associated with neuronal injury in the developing brain. Studies examining the potential interactions between hypothermia and anesthesia, as well as with longer durations of hypothermia, are needed.

Dataset Information

Delayed injury of hippocampal interneurons after neonatal hypoxia-ischemia and therapeutic hypothermia in a murine model.

Publications

Delayed injury of hippocampal interneurons after neonatal hypoxia-ischemia and therapeutic hypothermia in a murine model.

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