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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2018

Open Access 01-12-2018 | Research

Neonatal hyperglycemia induces CXCL10/CXCR3 signaling and microglial activation and impairs long-term synaptogenesis in the hippocampus and alters behavior in rats

Authors: Katherine M. Satrom, Kathleen Ennis, Brian M. Sweis, Tatyana M. Matveeva, Jun Chen, Leif Hanson, Akhil Maheshwari, Raghavendra Rao

Published in: Journal of Neuroinflammation | Issue 1/2018

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Abstract

Background

Hyperglycemia is common in extremely low gestational age newborns (ELGAN) and is associated with increased mortality and morbidity, including abnormal neurodevelopment. Hippocampus-mediated cognitive deficits are common in this population, but the specific effects of hyperglycemia on the developing hippocampus are not known.

Methods

The objective of this study was to determine the acute and long-term effects of hyperglycemia on the developing hippocampus in neonatal rats using a streptozotocin (STZ)-induced model of hyperglycemia. STZ was injected on postnatal day (P) 2, and littermates in the control group were injected with an equivalent volume of citrate buffer. The acute effects of hyperglycemia on markers of oxidative stress, inflammatory cytokines, microglial activation, and reactive astrocytosis in the hippocampus were determined in the brain tissue collected on P6. The long-term effects on hippocampus-mediated behavior and hippocampal dendrite structure were determined on P90.

Results

On P6, the transcript and protein expression of markers of oxidative stress and inflammatory cytokines, including the CXCL10/CXCR3 pathway, were upregulated in the hyperglycemia group. Histological evaluation revealed microglial activation and astrocytosis. The long-term assessment on P90 demonstrated abnormal performance in Barnes maze neurobehavioral testing and altered dendrite structure in the hippocampus of formerly hyperglycemic rats.

Conclusions

Neonatal hyperglycemia induces CXCL10/CXCR3 signaling, microglial activation, and astrocytosis in the rat hippocampus and alters long-term synaptogenesis and behavior. These results may explain the hippocampus-specific cognitive deficits common in ELGAN who experience neonatal hyperglycemia.
Literature
1.
Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, Ong K, vanWeissenbruch M, Midgley P, Thompson M, Thio M, et al. Prevalence and determinants of hyperglycemia in very low birth weight infants: cohort analyses of the NIRTURE study. J Pediatr. 2010;157:715–719 e711–3.CrossRef
2.
Ramel SE, Long JD, Gray H, Durrwachter-Erno K, Demerath EW, Rao R. Neonatal hyperglycemia and diminished long-term growth in very low birth weight preterm infants. J Perinatol. 2013;33:882–6.CrossRefPubMed
3.
van der Lugt NM, Smits-Wintjens VE, van Zwieten PH, Walther FJ. Short and long term outcome of neonatal hyperglycemia in very preterm infants: a retrospective follow-up study. BMC Pediatr. 2010;10:52.CrossRefPubMedPubMedCentral
4.
Hays SP, Smith EO, Sunehag AL. Hyperglycemia is a risk factor for early death and morbidity in extremely low birth-weight infants. Pediatrics. 2006;118:1811–8.CrossRefPubMed
5.
Kao LS, Morris BH, Lally KP, Stewart CD, Huseby V, Kennedy KA. Hyperglycemia and morbidity and mortality in extremely low birth weight infants. J Perinatol. 2006;26:730–6.CrossRefPubMed
6.
Perlman JM. Neurobehavioral deficits in premature graduates of intensive care—potential medical and neonatal environmental risk factors. Pediatrics. 2001;108:1339–48.CrossRefPubMed
7.
Aanes S, Bjuland KJ, Skranes J, Lohaugen GC. Memory function and hippocampal volumes in preterm born very-low-birth-weight (VLBW) young adults. NeuroImage. 2015;105:76–83.CrossRefPubMed
8.
Rao R, Hershey T. The impact of hypoglycemia on the developing brain. Transl Endocrinol Met. 2012;3:23.
9.
Rao R, Nashawaty M, Fatima S, Ennis K, Tkac I. Neonatal hyperglycemia alters the neurochemical profile, dendritic arborization and gene expression in the developing rat hippocampus. NMR Biomed. In press
10.
Gisslen T, Ennis K, Bhandari V, Rao R. Recurrent hypoinsulinemic hyperglycemia in neonatal rats increases PARP-1 and NF-kappaB expression and leads to microglial activation in the cerebral cortex. Pediatr Res. 2015;78:513–9.CrossRefPubMed
11.
Tayman C, Yis U, Hirfanoglu I, Oztekin O, Goktas G, Bilgin BC. Effects of hyperglycemia on the developing brain in newborns. Pediatr Neurol. 2014;51:239–45.CrossRefPubMed
12.
13.
Wang T, Zhang X, Li JJ. The role of NF-kappaB in the regulation of cell stress responses. Int Immunopharmacol. 2002;2:1509–20.CrossRefPubMed
14.
d'Avila JC, Lam TI, Bingham D, Shi J, Won SJ, Kauppinen TM, Massa S, Liu J, Swanson RA. Microglial activation induced by brain trauma is suppressed by post-injury treatment with a PARP inhibitor. J Neuroinflammation. 2012;9:31.PubMedPubMedCentral
15.
Nelson TE, Gruol DL. The chemokine CXCL10 modulates excitatory activity and intracellular calcium signaling in cultured hippocampal neurons. J Neuroimmunol. 2004;156:74–87.CrossRefPubMed
16.
Biber K, Dijkstra I, Trebst C, De Groot CJ, Ransohoff RM, Boddeke HW. Functional expression of CXCR3 in cultured mouse and human astrocytes and microglia. Neuroscience. 2002;112:487–97.CrossRefPubMed
17.
Xia MQ, Bacskai BJ, Knowles RB, Qin SX, Hyman BT. Expression of the chemokine receptor CXCR3 on neurons and the elevated expression of its ligand IP-10 in reactive astrocytes: in vitro ERK1/2 activation and role in Alzheimer’s disease. J Neuroimmunol. 2000;108:227–35.CrossRefPubMed
18.
19.
Klein RS, Lin E, Zhang B, Luster AD, Tollett J, Samuel MA, Engle M, Diamond MS. Neuronal CXCL10 directs CD8+ T-cell recruitment and control of West Nile virus encephalitis. J Virol. 2005;79:11457–66.CrossRefPubMedPubMedCentral
20.
Riemer C, Schultz J, Burwinkel M, Schwarz A, Mok SW, Gultner S, Bamme T, Norley S, van Landeghem F, Lu B, et al. Accelerated prion replication in, but prolonged survival times of, prion-infected CXCR3−/− mice. J Virol. 2008;82:12464–71.CrossRefPubMedPubMedCentral
21.
Liu L, Callahan MK, Huang D, Ransohoff RM. Chemokine receptor CXCR3: an unexpected enigma. Curr Top Dev Biol. 2005;68:149–81.CrossRefPubMed
22.
Ahmadi Z, Arababadi MK, Hassanshahi G. CXCL10 activities, biological structure, and source along with its significant role played in pathophysiology of type I diabetes mellitus. Inflammation. 2013;36:364–71.CrossRefPubMed
23.
Rosa JS, Mitsuhashi M, Oliver SR, Ogura M, Flores RL, Pontello AM, Galassetti PR. Ex vivo TCR-induced leukocyte gene expression of inflammatory mediators is increased in type 1 diabetic patients but not in overweight children. Diabetes Metab Res Rev. 2010;26:33–9.CrossRefPubMedPubMedCentral
24.
Tanaka S, Aida K, Nishida Y, Kobayashi T. Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes. Endocr J. 2013;60:837–45.CrossRefPubMed
25.
Tanaka S, Nishida Y, Aida K, Maruyama T, Shimada A, Suzuki M, Shimura H, Takizawa S, Takahashi M, Akiyama D, et al. Enterovirus infection, CXC chemokine ligand 10 (CXCL10), and CXCR3 circuit: a mechanism of accelerated beta-cell failure in fulminant type 1 diabetes. Diabetes. 2009;58:2285–91.CrossRefPubMedPubMedCentral
26.
27.
Shigihara T, Oikawa Y, Kanazawa Y, Okubo Y, Narumi S, Saruta T, Shimada A. Significance of serum CXCL10/IP-10 level in type 1 diabetes. J Autoimmun. 2006;26:66–71.CrossRefPubMed
28.
Bonner-Weir S, Trent DF, Honey RN, Weir GC. Responses of neonatal rat islets to streptozotocin: limited B-cell regeneration and hyperglycemia. Diabetes. 1981;30:64–9.CrossRefPubMed
29.
Kermorvant-Duchemin E, Pinel AC, Lavalette S, Lenne D, Raoul W, Calippe B, Behar-Cohen F, Sahel JA, Guillonneau X, Sennlaub F. Neonatal hyperglycemia inhibits angiogenesis and induces inflammation and neuronal degeneration in the retina. PLoS One. 2013;8:e79545.CrossRefPubMedPubMedCentral
30.
Portha B, Levacher C, Picon L, Rosselin G. Diabetogenic effect of streptozotocin in the rat during the perinatal period. Diabetes. 1974;23:889–95.CrossRefPubMed
31.
Takada J, Machado MA, Peres SB, Brito LC, Borges-Silva CN, Costa CE, Fonseca-Alaniz MH, Andreotti S, Lima FB. Neonatal streptozotocin-induced diabetes mellitus: a model of insulin resistance associated with loss of adipose mass. Metabolism. 2007;56:977–84.CrossRefPubMed
32.
Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ. Brain development in rodents and humans: identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol. 2013;106-107:1–16.CrossRefPubMed
33.
Hagberg H, Ichord R, Palmer C, Yager JY, Vannucci SJ. Animal models of developmental brain injury: relevance to human disease. A summary of the panel discussion from the Third Hershey Conference on Developmental Cerebral Blood Flow and Metabolism. Dev Neurosci. 2002;24:364–6.CrossRefPubMed
34.
Rao R, Sperr D, Ennis K, Tran P. Postnatal age influences hypoglycemia-induced poly(ADP-ribose) polymerase-1 activation in the brain regions of rats. Pediatr Res. 2009;66:642–7.CrossRefPubMedPubMedCentral
35.
Sherwood NM, Timiras PS: A steriotaxic Atlas of the Developing Rat Brain. Berkeley: University of California Press; 1970.
36.
Raman L, Hamilton KL, Gewirtz JC, Rao R. Effects of chronic hypoxia in developing rats on dendritic morphology of the CA1 subarea of the hippocampus and on fear-potentiated startle. Brain Res. 2008;1190:167–74.CrossRefPubMed
37.
Won SJ, Yoo BH, Kauppinen TM, Choi BY, Kim JH, Jang BG, Lee MW, Sohn M, Liu J, Swanson RA, Suh SW. Recurrent/moderate hypoglycemia induces hippocampal dendritic injury, microglial activation, and cognitive impairment in diabetic rats. J Neuroinflammation. 2012;9:182.PubMedPubMedCentral
38.
Barnes CA. Memory deficits associated with senescence: a neurophysiological and behavioral study in the rat. J Comp Physiol Psychol. 1979;93:74–104.CrossRefPubMed
39.
Sharma S, Rakoczy S, Brown-Borg H. Assessment of spatial memory in mice. Life Sci. 2010;87:521–36.CrossRefPubMed
40.
Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, Vanhole C, Palmer CR, van Weissenbruch M, Midgley P, Thompson M, Thio M, Cornette L, et al. Early insulin therapy in very-low-birth-weight infants. N Engl J Med. 2008;359:1873–84.CrossRefPubMed
41.
Graham ML, Janecek JL, Kittredge JA, Hering BJ, Schuurman HJ. The streptozotocin-induced diabetic nude mouse model: differences between animals from different sources. Comp Med. 2011;61:356–60.PubMedPubMedCentral
42.
Grieb P. Intracerebroventricular streptozotocin injections as a model of Alzheimer’s disease: in search of a relevant mechanism. Mol Neurobiol. 2016;53:1741–52.CrossRefPubMed
43.
Antonelli A, Ferrari SM, Corrado A, Ferrannini E, Fallahi P. CXCR3, CXCL10 and type 1 diabetes. Cytokine Growth Factor Rev. 2014;25:57–65.CrossRefPubMed
44.
Bajova H, Nelson TE, Gruol DL. Chronic CXCL10 alters the level of activated ERK1/2 and transcriptional factors CREB and NF-kappaB in hippocampal neuronal cell culture. J Neuroimmunol. 2008;195:36–46.CrossRefPubMedPubMedCentral
45.
Bhowmick S, Duseja R, Das S, Appaiahgiri MB, Vrati S, Basu A. Induction of IP-10 (CXCL10) in astrocytes following Japanese encephalitis. Neurosci Lett. 2007;414:45–50.CrossRefPubMed
46.
Kreutzberg GW. Microglia: a sensor for pathological events in the CNS. Trends Neurosci. 1996;19:312–8.CrossRefPubMed
47.
Coleman E, Judd R, Hoe L, Dennis J, Posner P. Effects of diabetes mellitus on astrocyte GFAP and glutamate transporters in the CNS. Glia. 2004;48:166–78.CrossRefPubMed
48.
Tang YP, Wang H, Feng R, Kyin M, Tsien JZ. Differential effects of enrichment on learning and memory function in NR2B transgenic mice. Neuropharmacology. 2001;41:779–90.CrossRefPubMed
49.
Fox CJ, Russell KI, Wang YT, Christie BR. Contribution of NR2A and NR2B NMDA subunits to bidirectional synaptic plasticity in the hippocampus in vivo. Hippocampus. 2006;16:907–15.CrossRefPubMed
50.
Hemmings SJ, Spafford D, Neonatal STZ. Model of type II diabetes mellitus in the Fischer 344 rat: characteristics and assessment of the status of the hepatic adrenergic receptors. Int J Biochem Cell Biol. 2000;32:905–19.CrossRefPubMed
51.
52.
Parkinson JR, Hyde MJ, Gale C, Santhakumaran S, Modi N. Preterm birth and the metabolic syndrome in adult life: a systematic review and meta-analysis. Pediatrics. 2013;131:e1240–63.CrossRefPubMed
53.
Tinnion R, Gillone J, Cheetham T, Embleton N. Preterm birth and subsequent insulin sensitivity: a systematic review. Arch Dis Child. 2014;99:362–8.CrossRefPubMed
54.
Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006;295:1681–7.CrossRefPubMed
55.
Tottman AC, Alsweiler JM, Bloomfield FH, Pan M, Harding JE. Relationship between measures of neonatal glycemia, neonatal illness, and 2-year outcomes in very preterm infants. J Pediatr. 2017;188:115–21.CrossRefPubMed
56.
Rognlien AG, Wollen EJ, Atneosen-Asegg M, Saugstad OD. Increased expression of inflammatory genes in the neonatal mouse brain after hyperoxic reoxygenation. Pediatr Res. 2015;77:326–33.CrossRefPubMed
57.
Rosa AP, Jacques CE, de Souza LO, Bitencourt F, Mazzola PN, Coelho JG, Mescka CP, Dutra-Filho CS. Neonatal hyperglycemia induces oxidative stress in the rat brain: the role of pentose phosphate pathway enzymes and NADPH oxidase. Mol Cell Biochem. 2015;403:159–67.CrossRefPubMed
58.
Aarnoudse-Moens CS, Smidts DP, Oosterlaan J, Duivenvoorden HJ, Weisglas-Kuperus N. Executive function in very preterm children at early school age. J Abnorm Child Psychol. 2009;37:981–93.CrossRefPubMedPubMedCentral
59.
Burnett AC, Anderson PJ, Lee KJ, Roberts G, Doyle LW, Cheong JLY, Victorian Infant Collaborative Study G. Trends in executive functioning in extremely preterm children across 3 birth eras. Pediatrics. 2018;141
Metadata
Title
Neonatal hyperglycemia induces CXCL10/CXCR3 signaling and microglial activation and impairs long-term synaptogenesis in the hippocampus and alters behavior in rats
Authors
Katherine M. Satrom
Kathleen Ennis
Brian M. Sweis
Tatyana M. Matveeva
Jun Chen
Leif Hanson
Akhil Maheshwari
Raghavendra Rao
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2018
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-018-1121-9

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