Skip to main content Accessibility help
×
Home

Preterm birth affects GABAA receptor subunit mRNA levels during the foetal-to-neonatal transition in guinea pigs

  • J. C. Shaw (a1) (a2), H. K. Palliser (a1) (a2), D. W. Walker (a3) and J. J. Hirst (a1) (a2)

Abstract

Modulation of gamma-aminobutyric acid A (GABAA) receptor signalling by the neurosteroid allopregnanolone has a major role in late gestation neurodevelopment. The objective of this study was to characterize the mRNA levels of GABAA receptor subunits (α4, α5, α6 and δ) that are key to neurosteroid binding in the brain, following preterm birth. Myelination, measured by the myelin basic protein immunostaining, was used to assess maturity of the preterm brains. Foetal guinea pig brains were obtained at 62 days’ gestational age (GA, preterm) or at term (69 days). Neonates were delivered by caesarean section, at 62 days GA and term, and maintained until tissue collection at 24 h of age. Subunit mRNA levels were quantified by RT-PCR in the hippocampus and cerebellum of foetal and neonatal brains. Levels of the α6 and δ subunits were markedly lower in the cerebellum of preterm guinea pigs compared with term animals. Importantly, there was an increase in mRNA levels of these subunits during the foetal-to-neonatal transition at term, which was not seen following preterm birth. Myelination was lower in preterm neonatal brains, consistent with marked immaturity. Salivary cortisol concentrations, measured by EIA, were also higher for the preterm neonates, suggesting greater stress. We conclude that there is an adaptive increase in the levels of mRNA of the key GABAA receptor subunits involved in neurosteroid action after term birth, which may compensate for declining allopregnanolone levels. The lower levels of these subunits in preterm neonates may heighten the adverse effect of the premature decline in neurosteroid exposure.

Copyright

Corresponding author

*Address for correspondence: J. C. Shaw, Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Callaghan, NSW 2308, Australia. (Email julia.shaw@uon.edu.au)

References

Hide All
1. Goldenberg, RL, Culhane, J, Iams, J, Romero, R. Epidemiology and causes of preterm birth. Lancet. 2008; 371, 7584.
2. Mathews, T, Menacker, F, MacDorman, MF. Infant mortality statistics from the 2002 period linked birth/infant death data set. Natl Vital Stat Rep. 2004; 53, 132.
3. Ananth, CV, Vintzileos, AM. Epidemiology of preterm birth and its clinical subtypes. J Matern Fetal Neonatal Med. 2006; 19, 773782.
4. Beck, S, Wojdyla, D, Say, L, et al. The worldwide incidence of preterm birth: a systematic review of maternal mortality and morbidity. Bull World Health Organ. 2010; 88, 3138.
5. Cheong, JL, Doyle, LW. Increasing rates of prematurity and epidemiology of late preterm birth. J Paediatr Child Health. 2012; 48, 784788.
6. Chyi, LJ, Lee, HC, Hintz, SR, Gould, JB, Sutcliffe, TL. School outcomes of late preterm infants: special needs and challenges for infants born at 32 to 36 weeks gestation. J Pediatr. 2008; 153, 2531.
7. Moster, D, Lie, RT, Markestad, T. Long-term medical and social consequences of preterm birth. N Engl J Med. 2008; 359, 262273.
8. van Baar, AL, Vermaas, J, Knots, E, de Kleine, MJ, Soons, P. Functioning at school age of moderately preterm children born at 32 to 36 weeks’ gestational age. Pediatrics. 2009; 124, 251257.
9. Rees, S, Harding, R, Walker, D. An adverse intrauterine environment: implications for injury and altered development of the brain. Int J Dev Neurosci. 2008; 26, 311.
10. Rivkin, MJ. Hypoxic-ischemic brain injury in the term newborn. Neuropathology, clinical aspects, and neuroimaging. Clin Perinatol. 1997; 24, 607625.
11. de Graaf-Peters, VB, Hadders-Algra, M. Ontogeny of the human central nervous system: what is happening when? Early Hum Dev. 2006; 82, 257266.
12. Rice, D, Barone, S Jr. Critical periods of vulnerability for the developing nervous system: evidence from humans and animal models. Environ Health Perspect. 2000; 108, 511533.
13. Rees, S, Inder, T. Fetal and neonatal origins of altered brain development. Early Hum Dev. 2005; 81, 753761.
14. Kelleher, MA, Palliser, HK, Hirst, JJ. Neurosteroid replacement therapy in the preterm neonate. In The 38th Annual Meeting Fetal and Neonatal Physiological Society. 2011. Australia.
15. Nicol, M, Hirst, J, Walker, D. Effect of pregnane steroids on electrocortical activity and somatosensory evoked potentials in fetal sheep. Neurosci Lett. 1998; 253, 111114.
16. Nguyen, PN, Billiards, SS, Walker, DW, Hirst, JJ. Changes in 5 alpha-pregnane steroids and neurosteroidogenic enzyme expression in fetal sheep with umbilicoplacental embolization. Pediatr Res. 2003; 54, 840847.
17. Nosarti, C, Al‐Asady, MH, Frangou, S, et al. Adolescents who were born very preterm have decreased brain volumes. Brain. 2002; 125, 16161623.
18. Yawno, T, Yan, E, Walker, D, Hirst, J. Inhibition of neurosteroid synthesis increases asphyxia-induced brain injury in the late gestation fetal sheep. Neuroscience. 2007; 146, 17261733.
19. Hirst, JJ, Palliser, HK, Yates, DM, Yawno, T, Walker, DW. Neurosteroids in the fetus and neonate: potential protective role in compromised pregnancies. Neurochem Int. 2008; 52, 602610.
20. Kelleher, MA, Hirst, JJ, Palliser, HK. Changes in neuroactive steroid concentrations after preterm delivery in the Guinea pig. Reprod Sci. 2013; 20, 13651375.
21. Belelli, D, Lambert, JJ. Neurosteroids: endogenous regulators of the GABAA receptor. Nat Rev Neurosci. 2005; 6, 565575.
22. Crossley, KJ, Nitsos, I, Walker, DW, et al. Steroid-sensitive GABAA receptors in the fetal sheep brain. Neuropharmacology. 2003; 45, 461472.
23. Crossley, KJ, Walker, DW, Beart, PM, Hirst, JJ. Characterisation of GABAA receptors in fetal, neonatal and adult ovine brain: region and age related changes and the effects of allopregnanolone. Neuropharmacology. 2000; 39, 15141522.
24. Nicol, MB, Hirst, JJ, Walker, DW. Effect of finasteride on behavioural arousal and somatosensory evoked potentials in fetal sheep. Neurosci Lett. 2001; 306, 1316.
25. Coleman, H, Hirst, JJ, Parkington, HC. The GABAA excitatory-to-inhibitory switch in the hippocampus of perinatal Guinea-pigs. In The 40th Annual Meeting Fetal and Neonatal Physiological Society. 2013. Chile.
26. Mirmiran, M. The function of fetal/neonatal rapid eye movement sleep. Behav Brain Res. 1995; 69, 1322.
27. Kelleher, MA, Palliser, HK, Walker, DW, Hirst, JJ. Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on foetal Guinea pig brain development. J Endocrinol. 2011; 208, 301309.
28. Gulinello, M, Gong, Q, Smith, S. Progesterone withdrawal increases the α4 subunit of the GABAA receptor in male rats in association with anxiety and altered pharmacology – a comparison with female rats. Neuropharmacology. 2002; 43, 701714.
29. Burgard, EC, Tietz, EI, Neelands, TR, Macdonald, RL. Properties of recombinant gamma-aminobutyric acid A receptor isoforms containing the alpha 5 subunit subtype. Mol Pharmacol. 1996; 50, 119127.
30. Belelli, D, Harrison, NL, Maguire, J, et al. Extrasynaptic GABAA receptors: form, pharmacology, and function. J Neurosci. 2009; 29, 1275712763.
31. Maguire, J, Mody, I. Neurosteroid synthesis-mediated regulation of GABA(A) receptors: relevance to the ovarian cycle and stress. J Neurosci. 2007; 27, 21552162.
32. Jacobson-Pick, S, Audet, MC, McQuaid, RJ, Kalvapalle, R, Anisman, H. Stressor exposure of male and female juvenile mice influences later responses to stressors: modulation of GABAA receptor subunit mRNA expression. Neuroscience. 2012; 215, 114126.
33. Serra, M, Pisu, MG, Littera, M, et al. Social isolation-induced decreases in both the abundance of neuroactive steroids and GABA(A) receptor function in rat brain. J Neurochem. 2000; 75, 732740.
34. McKendry, A, Palliser, H, Yates, D, Walker, D, Hirst, J. The effect of betamethasone treatment on neuroactive steroid synthesis in a foetal Guinea pig model of growth restriction. J Neuroendocrinol. 2009; 22, 166174.
35. Bennett, GA, Palliser, HK, Saxby, B, Walker, DW, Hirst, JJ. Effects of prenatal stress on fetal neurodevelopment and responses to maternal neurosteroid treatment in Guinea pigs. Dev Neurosci. 2013; 35, 416426.
36. Mihalek, RM, Banerjee, PK, Korpi, ER, et al. Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci. 1999; 96, 1290512910.
37. Spigelman, I, Li, Z, Banerjee, PK, et al. Behavior and physiology of mice lacking the GABAA-receptor delta subunit. Epilepsia. 2002; Suppl. 5, 38.
38. Spigelman, I, Li, Z, Liang, J, et al. Reduced inhibition and sensitivity to neurosteroids in hippocampus of mice lacking the GABA(A) receptor delta subunit. J Neurophysiol. 2003; 90, 903910.
39. Spittle, AJ, Cheong, J, Doyle, LW, et al. Neonatal white matter abnormality predicts childhood motor impairment in very preterm children. Dev Med Child Neurol. 2011; 53, 10001006.
40. Allin, M, Matsumoto, H, Santhouse, AM, et al. Cognitive and motor function and the size of the cerebellum in adolescents born very pre-term. Brain. 2001; 124, 6066.
41. Pitcher, JB, Schneider, LA, Burns, NR, et al. Reduced corticomotor excitability and motor skills development in children born preterm. J Physiol. 2012; 590, 58275844.
42. Payne, HL, Connelly, WM, Ives, JH, et al. GABAA alpha6-containing receptors are selectively compromised in cerebellar granule cells of the ataxic mouse, stargazer. J Biol Chem. 2007; 282, 2913029143.
43. Stoodley, CJ. The cerebellum and cognition: evidence from functional imaging studies. Cerebellum. 2012; 11, 352365.
44. Buckner, RL. The cerebellum and cognitive function: 25 years of insight from anatomy and neuroimaging. Neuron. 2013; 80, 807815.
45. Timmann, D, Drepper, J, Frings, M, et al. The human cerebellum contributes to motor, emotional and cognitive associative learning. A review. Cortex. 2010; 46, 845857.
46. Kajantie, E, Phillips, DI, Andersson, S, et al. Size at birth, gestational age and cortisol secretion in adult life: foetal programming of both hyper- and hypocortisolism? Clin Endocrinol (Oxf). 2002; 57, 635641.
47. Potijk, MR, de Winter, AF, Bos, AF, Kerstjens, JM, Reijneveld, SA. Higher rates of behavioural and emotional problems at preschool age in children born moderately preterm. Arch Dis Child. 2012; 97, 112117.
48. Loe, IM, Lee, ES, Luna, B, Feldman, HM. Behavior problems of 9-16 year old preterm children: biological, sociodemographic, and intellectual contributions. Early Hum Dev. 2011; 87, 247252.
49. Sarkar, J, Wakefield, S, MacKenzie, G, Moss, SJ, Maguire, J. Neurosteroidogenesis is required for the physiological response to stress: role of neurosteroid-sensitive GABAA receptors. J Neurosci. 2011; 31, 1819818210.
50. Herman, JP, Mueller, NK, Figueiredo, H. Role of GABA and glutamate circuitry in hypothalamo-pituitary-adrenocortical stress integration. Ann N Y Acad Sci. 2004; 1018, 3545.
51. Limperopoulos, C, Bassan, H, Gauvreau, K, et al. Does cerebellar injury in premature infants contribute to the high prevalence of long-term cognitive, learning, and behavioral disability in survivors? Pediatrics. 2007; 120, 584593.
52. Ghoumari, AM, Ibanez, C, El-Etr, M, et al. Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J Neurochem. 2003; 86, 848859.
53. Liao, G, Cheung, S, Galeano, J, et al. Allopregnanolone treatment delays cholesterol accumulation and reduces autophagic/lysosomal dysfunction and inflammation in Npc1-/- mouse brain. Brain Res. 2009; 1270, 140151.
54. Luchetti, S, Huitinga, I, Swaab, DF. Neurosteroid and GABA-A receptor alterations in Alzheimer’s disease, Parkinson’s disease and multiple sclerosis. Neuroscience. 2011; 191, 621.

Keywords

Preterm birth affects GABAA receptor subunit mRNA levels during the foetal-to-neonatal transition in guinea pigs

  • J. C. Shaw (a1) (a2), H. K. Palliser (a1) (a2), D. W. Walker (a3) and J. J. Hirst (a1) (a2)

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed