Neonatal seizures are associated with redistribution and loss of GABAA α-subunits in the hypoxic-ischaemic pig

Miller, Stephanie M., Sullivan, Susan M., Ireland, Zoe, Chand, Kirat K., Colditz, Paul B. and Bjorkman, S. Tracey (2016) Neonatal seizures are associated with redistribution and loss of GABAA α-subunits in the hypoxic-ischaemic pig. Journal of Neurochemistry, 139 3: 1-14. doi:10.1111/jnc.13746


Author Miller, Stephanie M.
Sullivan, Susan M.
Ireland, Zoe
Chand, Kirat K.
Colditz, Paul B.
Bjorkman, S. Tracey
Title Neonatal seizures are associated with redistribution and loss of GABAA α-subunits in the hypoxic-ischaemic pig
Formatted title
Neonatal seizures are associated with redistribution and loss of GABAA α-subunits in the hypoxic-ischaemic pig
Journal name Journal of Neurochemistry   Check publisher's open access policy
ISSN 1471-4159
0022-3042
Publication date 2016-09-01
Year available 2016
Sub-type Article (original research)
DOI 10.1111/jnc.13746
Open Access Status Not yet assessed
Volume 139
Issue 3
Start page 1
End page 14
Total pages 14
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing
Language eng
Subject 1303 Biochemistry
2804 Cellular and Molecular Neuroscience
Abstract Seizures are a common manifestation of hypoxic-ischaemic brain injury in the neonate. In status epilepticus models alterations to GABAR subunit expression have been suggested to contribute to (i) abnormal development of the GABAergic system, (ii) why seizures become self-sustaining and (iii) the development of pharmacoresistance. Detailed investigation of GABAR subunit protein expression after neonatal hypoxia-ischaemia (HI) is currently insufficient. Using our pig model of HI and subsequent spontaneous neonatal seizures, we investigated changes in protein expression of the three predominant α-subunits of the GABAR; α, α and α. Anaesthetized, ventilated newborn pigs (< 24 h old) were subjected to 30 min HI and subsequently recovered to 24 or 72 h. Amplitude-integrated electroencephalography was used to monitor brain activity and identify seizure activity. Brain tissue was collected post-mortem and GABAR α-subunit protein expression was analysed using western blot and immunohistochemistry. GABAR α and α protein expression was significantly reduced in animals that developed seizures after HI; HI animals that did not develop seizures did not exhibit the same reductions. Immunohistochemistry revealed decreased α and α expression, and α redistribution from the cell membrane to the cytosol, in the hippocampus of seizure animals. Multivariate analyses, controlling for HI severity and neuronal injury, revealed that seizures were independently associated with significant GABAR α reduction. This is the first study to show loss and redistribution of GABAR α-subunits in a neonatal brain experiencing seizures. Our findings are similar to those reported in models of SE and in chronic epilepsy. (Figure presented.).
Formatted abstract
Seizures are a common manifestation of hypoxic-ischaemic brain injury in the neonate. In status epilepticus models alterations to GABAAR subunit expression have been suggested to contribute to (i) abnormal development of the GABAergic system, (ii) why seizures become self-sustaining and (iii) the development of pharmacoresistance. Detailed investigation of GABAAR subunit protein expression after neonatal hypoxia-ischaemia (HI) is currently insufficient. Using our pig model of HI and subsequent spontaneous neonatal seizures, we investigated changes in protein expression of the three predominant α-subunits of the GABAAR; α1, α2 and α3. Anaesthetized, ventilated newborn pigs (< 24 h old) were subjected to 30 min HI and subsequently recovered to 24 or 72 h. Amplitude-integrated electroencephalography was used to monitor brain activity and identify seizure activity. Brain tissue was collected post-mortem and GABAAR α-subunit protein expression was analysed using western blot and immunohistochemistry. GABAAR α1 and α3 protein expression was significantly reduced in animals that developed seizures after HI; HI animals that did not develop seizures did not exhibit the same reductions. Immunohistochemistry revealed decreased α1 and α3 expression, and α1 redistribution from the cell membrane to the cytosol, in the hippocampus of seizure animals. Multivariate analyses, controlling for HI severity and neuronal injury, revealed that seizures were independently associated with significant GABAAR α3 reduction. This is the first study to show loss and redistribution of GABAAR α-subunits in a neonatal brain experiencing seizures. Our findings are similar to those reported in models of SE and in chronic epilepsy.
Keyword Anticonvulsants
Brain injury
GABAA receptor subunits
Hypoxia
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 569826
Institutional Status UQ
Additional Notes Published online 1 September 2016. Article in Press

Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
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