Skip to main content
SpringerLink
Log in

Severe Uncontrolled Maternal Hyperglycemia Induces Microsomia and Neurodevelopment Delay Accompanied by Apoptosis, Cellular Survival, and Neuroinflammatory Deregulation in Rat Offspring Hippocampus

  • Original Research
  • Published:
Cellular and Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Maternal diabetes constitutes an unfavorable intrauterine environment for offspring development. Although it is known that diabetes can cause brain alterations and increased risk for neurologic disorders, the relationship between neuroimmune activation, brain changes, and neurodevelopment deficits in the offspring remains unclear. In order to elucidate the short- and long-term biological basis of the developmental outcomes caused by the severe uncontrolled maternal hyperglycemia, we studied apoptosis, neurogenesis, and neuroinflammation pathways in the hippocampus of neonates and young rats born to diabetic dams. Diabetes was induced on gestational day 5 by an injection of streptozotocin. Evaluations of milestones, body growth, and inhibitory avoidance were performed to monitor the offspring development and behavior. Hippocampal modifications were studied through cellular survival by BrdU in the dentate gyrus, expression of apoptosis-regulatory proteins (procaspase 3, caspase 3, and Bcl-2), BDNF, and neuroinflammatory modulation by interleukins, MHC-I, MHC-II, Iba-1, and GFAP proteins. Severe maternal diabetes caused microsomia and neurodevelopmental delay in pups and decrease of Bcl-2, procaspase 3, and caspase 3 in the hippocampus. Moreover, in a later stage of development, it was found an increase of TNF-α and a decrease of procaspase 3, caspase 3, MHC-I, IL-1β, and BDNF in the hippocampus, as well as impairment in cellular survival in the dentate gyrus. This study showed significant short- and long-term commitments on the development, apoptosis, cell survival, and neuroinflammation in the offspring hippocampus induced by severe uncontrolled maternal hyperglycemia. The data reinforce the need for treatment of maternal hyperglycemic states during pregnancy and breast-feeding.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Aberg A, Westbom L (2001) Association between maternal pre-existing or gestational diabetes and health problems in children. Acta Paediatr 90:746–750

    Article  CAS  PubMed  Google Scholar 

  • Beauquis J, Homo-Delarche F, Revsin Y, De Nicola AF, Saravia F (2008) Brain alterations in autoimmune and pharmacological models of diabetes mellitus: focus o hypothalamic-pituitary-adrenocortical axis disturbances. Neuroimmunomodulation 15(1):61–67

    Article  CAS  PubMed  Google Scholar 

  • Bilbo SD, Schwarz JM (2012) The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 33:267–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  • Chacon MA, Boulanger LM (2013) MHC class I protein is expressed by neurons and neural progenitors in mid-gestation mouse brain. Mol Cell Neurosci 52:117–127

    Article  CAS  PubMed  Google Scholar 

  • Chandna AR, Kuhlmann N, Bryce CA, Greba Q, Campanucci VA, Howland JG (2015) Chronic maternal hyperglycemia induced during mid-pregnancy in rats increases rage expression, augments hippocampal excitability, and alters behavior of the offspring. Neuroscience 303:241–260

    Article  CAS  PubMed  Google Scholar 

  • de Senna PN, Bagatini PB, Galland F, Bobermin L, do Nascimento PS, Nardin P, Tramontina AC, Gonçalves CA, Achaval M, Xavier LL (2017) Physical exercise reverses spatial memory deficit and induces hippocampal astrocyte plasticity in diabetic rats. Brain Res 1655:242–251

    Article  CAS  PubMed  Google Scholar 

  • DeBoer T, Wewerka S, Bauer PJ, Georgieff MK, Nelson CA (2005) Explicit memory performance in infants of diabetic mothers at 1 year of age. Dev Med Child Neurol 47:525–531

    Article  PubMed  PubMed Central  Google Scholar 

  • Dixon-Salazar TJ, Fourgeaud L, Tyler CM, Poole JR, Park JJ, Boulanger LM (2014) MHC class I limits hippocampal synapse density by inhibiting neuronal insulin receptor signaling. J Neurosci 34(35):11844–11856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elmer BM, McAllister AK (2012) Major histocompatibility complex class I proteins in brain development and plasticity. Trends Neurosci 35:660–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elmore S (2007) Apoptosis: a review of programmed cell death. Toxicol Pathol 35:495–516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feldman AZ, Brown FM (2016) Management of type 1 diabetes in pregnancy. Curr Diab Rep 16:76

    Article  PubMed  PubMed Central  Google Scholar 

  • Gabbay-Benziv R, Baschat AA (2015) Gestational diabetes as one of the “great obstetrical syndromes” e the maternal, placental, and fetal dialog. Best Pract Res Clin Obstet Gynaecol 29:150–155

    Article  PubMed  Google Scholar 

  • Greisen MH, Altar CA, Bolwig TG, Whitehead R, Wörtwein G (2005) Increased adult hippocampal brain-derived neurotrophic factor and normal levels of neurogenesis in maternal separation rats. J Neurosci Res 79:772–778

    Article  CAS  PubMed  Google Scholar 

  • Haghir H, Hami J, Lotfi N, Peyvandi M, Ghasemi S, Hosseini M (2017) Expression of apoptosis-regulatory genes in the hippocampus of rat neonates born to mothers with diabetes. Metab Brain Dis 32:617–628

    Article  CAS  PubMed  Google Scholar 

  • Hami J, Shojae F, Vafaee-Nezhad S, Lotfi N, Kheradmand H, Haghir H (2015) Some of the experimental and clinical aspects of the effects of the maternal diabetes on developing hippocampus. World J Diabetes 6:412–422

    Article  PubMed  PubMed Central  Google Scholar 

  • Hartmann P, Cregan M (2001) Lactogenesis and the effects of insulin-dependent diabetes mellitus and prematurity. J Nutr 131:3016S–3020S

    Article  CAS  PubMed  Google Scholar 

  • Izquierdo LA, Vianna M, Barros DM, Mello e Souza T, Ardenghi P, Sant’Anna MK, Rodrigues C, Medina JH, Izquierdo I (2000) Short- and long-term memory are differentially affected by metabolic inhibitors given into hippocampus and entorhinal Cortex. Neurobiol Learn Mem 73:141–149

    Article  CAS  PubMed  Google Scholar 

  • Kafshgiri SK, Ghafari S, Golalipour MJ (2014) Gestational diabetes induces neuronal loss in dentate gyrus in rat offspring. J Neurol Sci 31:316–324

    Google Scholar 

  • Katche C, Goldin A, Gonzalez C, Bekinschtein P, Medina JH (2012) Maintenance of long-term memory storage is dependent on late posttraining Egr-1 expression. Neurobiol Learn Mem 98:220–227

    Article  CAS  PubMed  Google Scholar 

  • Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553

    Article  CAS  PubMed  Google Scholar 

  • Kim YH, Sung YH, Lee HH, Ko IG, Kim SE, Shin MS, Kim BK (2014) Postnatal treadmill exercise alleviates short-term memory impairment by enhancing cell proliferation and suppressing apoptosis in the hippocampus of rat pups born to diabetic rats. J Exerc Rehabil 10:209–217

    Article  PubMed  PubMed Central  Google Scholar 

  • Kohman RA, Rhodes JS (2013) Neurogenesis, inflammation and behavior. Brain Behav Immun 27:22–32

    Article  CAS  PubMed  Google Scholar 

  • Kruse MS, Rey M, Barutta J, Coirini H (2009) Allopregnanolone effects on astrogliosis induced by hypoxia in organotypic cultures of striatum, hippocampus, and neocortex. Brain research 1303:1–7

    Article  CAS  PubMed  Google Scholar 

  • Kruse MS, Barutta J, Vega MC, Coirini H (2012) Down regulation of the proliferation and apoptotic pathways in the embryonic brain of diabetic rats. Cell Mol Neurobiol 32:1031–1037

    Article  CAS  PubMed  Google Scholar 

  • Kruse MS, Vega MC, Rey M, Coirini H (2014) Sex differences in LXR expression in normal offspring and in rats born to diabetic dams. J Endocrinol 222:53–60

    Article  CAS  PubMed  Google Scholar 

  • Lotfi N, Hami J, Hosseini M, Haghir D, Haghir H (2016) Diabetes during pregnancy enhanced neuronal death in the hippocampus of rat offspring. Int J Dev Neurosci 51:28–35

    Article  CAS  PubMed  Google Scholar 

  • Lucassen PJ, Meerlo P, Naylor AS, van Dam AM, Dayer AG, Fuchs E, Oomen CA, Czéh B (2010) Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action. Eur Neuropsychopharmacol 20(1):1–17

    Article  CAS  PubMed  Google Scholar 

  • Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20:9104–9110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Marcuzzo S, Dutra MF, Stigger F, do Nascimento PS, Ilha J, Kalil-Gaspar PI, Achaval M (2010) Different effects of anoxia and hind-limb immobilization on sensorimotor development and cell numbers in the somatosensory cortex in rats. Brain Dev 32:323–331

    Article  PubMed  Google Scholar 

  • Nagayach A, Patro N, Patro I (2014) Astrocytic and microglial response in experimentally induced diabetic rat brain. Metab Brain Dis 29:747–761

    Article  CAS  PubMed  Google Scholar 

  • Neubauer SH, Ferris AM, Chase CG, Fanelli J, Thompson CA, Lammi-Keefe CJ, Clark RM, Jensen RG, Bendel RB, Green KW (1993) Delayed lactogenesis in women with insulin-dependent diabetes mellitus. Am J Clin Nutr 58:54–60

    Article  CAS  PubMed  Google Scholar 

  • Ornoy A (2005) Growth and neurodevelopmental outcome of children born to mothers with pregestational and gestational diabetes. Pediatr Endocrinol Rev 3:104–113

    PubMed  Google Scholar 

  • Ornoy A (2011) Prenatal origin of obesity and their complications: gestational diabetes, maternal overweight and the paradoxical effects of fetal growth restriction and macrosomia. Reprod Toxicol 32:205–212

    Article  CAS  PubMed  Google Scholar 

  • Ornoy A, Ratzon N, Greenbaum C, Wolf A, Dulitzky M (2001) School-age children born to mothers with pregestational or gestational diabetes exhibit a high rate of inattention and fine and gross motor impairment. J Pediatr Endocrinol Metab 14:681–689

    Article  PubMed  Google Scholar 

  • Ornoy A, Reece EA, Pavlinkova G, Kappen C, Miller RK (2015) Effect of maternal diabetes on the embryo, fetus, and children: congenital anomalies, genetic and epigenetic changes and developmental outcomes. Birth Defects Res C Embryo Today 105:53–72

    Article  CAS  PubMed  Google Scholar 

  • Ostrom KM, Ferris AM (1993) Prolactin concentrations in serum and milk of mothers with and without insulin-dependent diabetes mellitus. Am J Clin Nutr 58:49–53

    Article  CAS  PubMed  Google Scholar 

  • Perna R, Loughan AR, Le J, Tyson K (2015) Gestational diabetes: long-term central nervous system developmental and cognitive sequelae. Appl Neuropsychol Child 4:217–220

    Article  PubMed  Google Scholar 

  • Piazza FV, Pinto GV, Trott G, Marcuzzo S, Gomez R, Fernandes MC (2011) Enriched environment prevents memory deficits in type 1 diabetic rats. Behav Brain Res 217:16–20

    Article  CAS  PubMed  Google Scholar 

  • Piazza FV, Segabinazi E, Centenaro LA, do Nascimento PS, Achaval M, Marcuzzo S (2014) Enriched environment induces beneficial effects on memory deficits and microglial activation in the hippocampus of type 1 diabetic rats. Metab Brain Dis 29:93–104

    Article  CAS  PubMed  Google Scholar 

  • Qiu L, Zhu C, Wang X, Xu F, Eriksson PS, Nilsson M, Cooper-Kuhn CM, Kuhn HG, Blomgren K (2007) Less neurogenesis and inflammation in the immature than in the juvenile brain after cerebral hypoxia-ischemia. J Cereb Blood Flow Metab 27:785–794

    Article  CAS  PubMed  Google Scholar 

  • Ramos-Rodriguez JJ, Sanchez-Sotano D, Doblas-Marquez A, Infante-Garcia C, Lubian-Lopez S, Garcia-Alloza M (2017) Intranasal insulin reverts central pathology and cognitive impairment in diabetic mother offspring. Mol Neurodegener 12(1):57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Reece EA (2012) Diabetes-induced birth defects: what do we know? What can we do? Curr Diab Rep 12:24–32

    Article  CAS  PubMed  Google Scholar 

  • Reece EA, Wu YK, Zhao Z, Dhanasekaran D (2006) Dietary vitamin and lipid therapy rescues aberrant signaling and apoptosis and prevents hyperglycemia induced diabetic embryopathy in rats. Am J Obstet Gynecol 194:580–585

    Article  CAS  PubMed  Google Scholar 

  • Reece EA, Leguizamón G, Wiznitzer A (2009) Gestational diabetes: the need for a common ground. Lancet 373:1789–1797

    Article  PubMed  Google Scholar 

  • Revsin Y, Rekers NV, Louwe MC, Saravia FE, De Nicola AF, de Kloet ER, Oitzl MS (2009) Glucocorticoid receptor blockade normalizes hippocampal alterations and cognitive impairment in streptozotocin-induced type 1 diabetes mice. Neuropsychopharmacology 34:747–758

    Article  CAS  PubMed  Google Scholar 

  • Rizzo TA, Dooley SL, Metzger BE, Cho NH, Ogata ES, Silverman BL (1995) Prenatal and perinatal influences on long-term psychomotor development in offspring of diabetic mothers. Am J Obstet Gynecol 173:1754–1758

    Google Scholar 

  • Rudge MV, Piculo F, Marini G, Damasceno DC, Calderon IM, Barbosa AP (2013) Translational research in gestational diabetes mellitus and mild gestational hyperglycemia: current knowledge and our experience. Arq Bras Endocrinol Metabol 57:497–508

    Article  PubMed  Google Scholar 

  • Sadeghi A, Esfandiary E, Hami J, Khanahmad H, Hejazi Z, Mardani M, Razavi S (2018) The effects of maternal diabetes and insulin treatment on neurogenesis in the developing hippocampus of male rats. J Chem Neuroanat 91:27–34

    Article  CAS  PubMed  Google Scholar 

  • Salazar García M, Reyes Maldonado E, Revilla Monsalve MC, Villavicencio Guzmán L, Reyes López A, Sánchez-Gómez C (2015) Importance of maternal diabetes on the chronological deregulation of the intrauterine development: an experimental study in rat. J Diabetes Res 2015:354265

  • Sells CJ, Robinson NM, Brown Z, Knopp RH (1994) Long-term developmental follow-up of infants of diabetic mothers. J Pediatr 125:S9–S17

    Article  CAS  PubMed  Google Scholar 

  • Silva HJ, Marinho SMO, Silva AETM, Albuquerque CG. Moraes SRA, Manhães de Castro R (2005) Protocol of mensuration to avaliation of indicators of somatic development of Wistar rats. Int J Morphol 23:227–230

    Google Scholar 

  • Stigger F, Lovatel G, Marques M, Bertoldi K, Moysés F, Elsner V, Siqueira IR, Achaval M, Marcuzzo S (2013) Inflammatory response and oxidative stress in developing rat brain and its consequences on motor behavior following maternal administration of LPS and perinatal anoxia. Int J Dev Neurosci 31:820–827

    Article  CAS  PubMed  Google Scholar 

  • Taupin P (2007) Brdu immunohistochemistry for studying adult neurogenesis: paradigms, pitfalls, limitations, and validation. Brain Res Rev 53:198–214

    Article  CAS  PubMed  Google Scholar 

  • Thion MS, Ginhoux F, Garel S (2018) Microglia and early brain development: an intimate journey. Science 362(6411):185–189

    Article  CAS  PubMed  Google Scholar 

  • Van Lieshout RJ, Voruganti LP (2008) Diabetes mellitus during pregnancy and increased risk of schizophrenia in offspring: a review of the evidence and putative mechanisms. J Psychiatry Neurosci 33:395–404

    PubMed  PubMed Central  Google Scholar 

  • Van Assche FA, Holemans K, Aerts L (2001) Long-term consequences for offspring of diabetes during pregnancy. Br Med Bull 60:173–182

    Article  PubMed  Google Scholar 

  • Volpato GT, Damasceno DC, Sinzato YK, Ribeiro VM, Rudge MV, Calderon IM (2015) Oxidative stress status and placental implications in diabetic rats undergoing swimming exercise after embryonic implantation. Reprod Sci 22:602–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vuong B, Odero G, Rozbacher S, Stevenson M, Kereliuk SM, Pereira TJ, Dolinsky VW, Kauppinen TM (2017) Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring. J Neuroinflammation 14:80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xiang AH, Wang X, Martinez MP, Walthall JC, Curry ES, Page K, Buchanan TA, Coleman KJ, Getahun D (2015) Association of maternal diabetes with autism in offspring. JAMA 313:1425–1434

    Article  CAS  PubMed  Google Scholar 

  • Yirmiya R, Goshen I (2011) Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25:181–213

    Article  CAS  PubMed  Google Scholar 

  • Zdrojewicz Z, Pachura E, Pachura P (2016) The thymus: a forgotten, but very important organ. Adv Clin Exp Med 25:369–375

    Article  PubMed  Google Scholar 

  • Zhao J, Weiler HA (2010) Long-term effects of gestational diabetes on offspring health are more pronounced in skeletal growth than body composition and glucose tolerance. Br J Nutr 104:1641–1649

    Article  CAS  PubMed  Google Scholar 

  • Ziv Y, Schwartz M (2008) Immune-based regulation of adult neurogenesis: implications for learning and memory. Brain Behav Immun 22:167–176

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are very grateful to Silvia Barbosa for the technical support. This work was financial supported by the Brazilian funding agencies CNPq, CAPES, and FAPERGS (002097-2552/13-6–1), and by the International Brain Research Organization (IBRO). F.V Piazza was supported by a scholarship from CAPES and Short Stay IBRO fellowship.

Author information

Authors and Affiliations

  1. Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, Porto Alegre, RS, CEP 90050-170, Brazil

    Francele Valente Piazza, Ethiane Segabinazi, André Luís Ferreira de Meireles, Filipe Mega, Christiano de Figueiredo Spindler, Matilde Achaval & Simone Marcuzzo

  2. Laboratório de Histofisiologia Comparada, Departamento de Ciências Morfológicas, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Sarmento Leite 500, sala 142, Porto Alegre, RS, CEP 90050-170, Brazil

    Francele Valente Piazza, Ethiane Segabinazi, André Luís Ferreira de Meireles, Filipe Mega, Christiano de Figueiredo Spindler, Otávio Américo Augustin, Gabriela dos Santos Salvalaggio, Matilde Achaval & Simone Marcuzzo

  3. Laboratorio de Neurobiología, Instituto de Biología y Medicina Experimental, Vuelta de Obligado 2490, C1428ADN, Buenos Aires, Argentina

    Maria Sol Kruse & Héctor Coirini

  4. Departamento de Bioquímica Humana, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 5to Piso, C1121ABG, Buenos Aires, Argentina

    Héctor Coirini

Authors
  1. Francele Valente Piazza
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ethiane Segabinazi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. André Luís Ferreira de Meireles
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Filipe Mega
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christiano de Figueiredo Spindler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Otávio Américo Augustin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gabriela dos Santos Salvalaggio
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Matilde Achaval
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria Sol Kruse
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Héctor Coirini
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Simone Marcuzzo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All the authors listed have participated sufficiently in the study, in the research design, execution, and analyses reported in this manuscript. The responsibility for writing the article rests with FVP, MSK, HC, and SM, but every coauthor had the opportunity to review it and all approved the final version. All the authors have read and followed the ethical standards statement for manuscripts submitted to Cellular and Molecular Neurobiology.

Corresponding author

Correspondence to Francele Valente Piazza.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interest regarding the authorship and/or publication of this article.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 303 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Piazza, F.V., Segabinazi, E., de Meireles, A.L.F. et al. Severe Uncontrolled Maternal Hyperglycemia Induces Microsomia and Neurodevelopment Delay Accompanied by Apoptosis, Cellular Survival, and Neuroinflammatory Deregulation in Rat Offspring Hippocampus. Cell Mol Neurobiol 39, 401–414 (2019). https://doi.org/10.1007/s10571-019-00658-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10571-019-00658-8

Keywords

Search

Navigation