Delayed Injury of Hippocampal Interneurons After Neonatal Hypoxia-ischemia and Therapeutic Hypothermia in a Murine Model

Overview

Journal Hippocampus

Publisher Wiley

Date 2018 May 22

PMID 29781223

Citations 35

Authors

Raul Chavez-Valdez

Paul Emerson

Janasha Goffigan-Holmes

Alfredo Kirkwood

Lee J Martin

Frances J Northington

Affiliations

Soon will be listed here.

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 (FiO = 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 mm ) 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.

Citing Articles

Neonatal hypoxia-ischemia alters the events governing the hippocampal critical period of postnatal synaptic plasticity leading to deficits in working memory in mice.

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Blood glucose and β-hydroxybutyrate predict significant brain injury after hypoxia-ischemia in neonatal mice.

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Effect of Early Inhibition of Toll-Like Receptor 4 on Hippocampal Plasticity in a Neonatal Rat Model of Hypoxic-Ischemic Brain Damage.

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References

Martin L . Neuronal death in amyotrophic lateral sclerosis is apoptosis: possible contribution of a programmed cell death mechanism. J Neuropathol Exp Neurol. 1999; 58(5):459-71. DOI: 10.1097/00005072-199905000-00005. View

Huang Z, Kirkwood A, Pizzorusso T, Porciatti V, Morales B, Bear M . BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex. Cell. 1999; 98(6):739-55. DOI: 10.1016/s0092-8674(00)81509-3. View

Gadian D, Aicardi J, Watkins K, Porter D, Mishkin M, Vargha-Khadem F . Developmental amnesia associated with early hypoxic-ischaemic injury. Brain. 2000; 123 Pt 3:499-507. DOI: 10.1093/brain/123.3.499. View

Maguire E, Gadian D, Johnsrude I, Good C, Ashburner J, Frackowiak R . Navigation-related structural change in the hippocampi of taxi drivers. Proc Natl Acad Sci U S A. 2000; 97(8):4398-403. PMC: 18253. DOI: 10.1073/pnas.070039597. View

Szabo G, Kartarova Z, Hoertnagl B, Somogyi R, Sperk G . Differential regulation of adult and embryonic glutamate decarboxylases in rat dentate granule cells after kainate-induced limbic seizures. Neuroscience. 2000; 100(2):287-95. DOI: 10.1016/s0306-4522(00)00275-x. View

Northington F, Ferriero D, Graham E, Traystman R, Martin L . Early Neurodegeneration after Hypoxia-Ischemia in Neonatal Rat Is Necrosis while Delayed Neuronal Death Is Apoptosis. Neurobiol Dis. 2001; 8(2):207-19. DOI: 10.1006/nbdi.2000.0371. View

Pfaffl M . A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29(9):e45. PMC: 55695. DOI: 10.1093/nar/29.9.e45. View

Benes F, Berretta S . GABAergic interneurons: implications for understanding schizophrenia and bipolar disorder. Neuropsychopharmacology. 2001; 25(1):1-27. DOI: 10.1016/S0893-133X(01)00225-1. View

Del Rio J, Soriano E, Ferrer I . Development of GABA-immunoreactivity in the neocortex of the mouse. J Comp Neurol. 1992; 326(4):501-26. DOI: 10.1002/cne.903260403. View

10.

Pfaffl M, Tichopad A, Prgomet C, Neuvians T . Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper--Excel-based tool using pair-wise correlations. Biotechnol Lett. 2004; 26(6):509-15. DOI: 10.1023/b:bile.0000019559.84305.47. View

11.

Graham E, Sheldon R, Flock D, Ferriero D, Martin L, ORiordan D . Neonatal mice lacking functional Fas death receptors are resistant to hypoxic-ischemic brain injury. Neurobiol Dis. 2004; 17(1):89-98. DOI: 10.1016/j.nbd.2004.05.007. View

12.

Haas M, Vickers J, Dickson T . Binding partners L1 cell adhesion molecule and the ezrin-radixin-moesin (ERM) proteins are involved in development and the regenerative response to injury of hippocampal and cortical neurons. Eur J Neurosci. 2004; 20(6):1436-44. DOI: 10.1111/j.1460-9568.2004.03620.x. View

13.

Somogyi P, Klausberger T . Defined types of cortical interneurone structure space and spike timing in the hippocampus. J Physiol. 2004; 562(Pt 1):9-26. PMC: 1665488. DOI: 10.1113/jphysiol.2004.078915. View

14.

Bosman L, Heinen K, Spijker S, Brussaard A . Mice lacking the major adult GABAA receptor subtype have normal number of synapses, but retain juvenile IPSC kinetics until adulthood. J Neurophysiol. 2005; 94(1):338-46. DOI: 10.1152/jn.00084.2005. View

15.

Pekny M, Nilsson M . Astrocyte activation and reactive gliosis. Glia. 2005; 50(4):427-434. DOI: 10.1002/glia.20207. View

16.

Marlow N, Rose A, Rands C, Draper E . Neuropsychological and educational problems at school age associated with neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2005; 90(5):F380-7. PMC: 1721935. DOI: 10.1136/adc.2004.067520. View

17.

Hefft S, Jonas P . Asynchronous GABA release generates long-lasting inhibition at a hippocampal interneuron-principal neuron synapse. Nat Neurosci. 2005; 8(10):1319-28. DOI: 10.1038/nn1542. View

18.

Johnston M . Excitotoxicity in perinatal brain injury. Brain Pathol. 2005; 15(3):234-40. PMC: 8095755. DOI: 10.1111/j.1750-3639.2005.tb00526.x. View

19.

Shankaran S, Laptook A, Ehrenkranz R, Tyson J, McDonald S, Donovan E . Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005; 353(15):1574-84. DOI: 10.1056/NEJMcps050929. View

20.

Luhmann H, Prince D . Postnatal maturation of the GABAergic system in rat neocortex. J Neurophysiol. 1991; 65(2):247-63. DOI: 10.1152/jn.1991.65.2.247. View