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The α7 and β2 nicotinic acetylcholine receptor subunits regulate apoptosis in the infant hippocampus, and in sudden infant death syndrome (SIDS)

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Abstract

Apoptosis is increased in the hippocampus of infants who died of sudden infant death syndrome (SIDS), yet it is not known via which mechanism this has occurred. Following existing support for a role of the α7 and β2 nicotinic acetylcholine receptor (nAChR) subunits in apoptotic regulation, we aimed to determine whether these subunits are altered in the SIDS hippocampus and if they are correlated with cell death markers of active caspase-3 (Casp-3) and TUNEL. Further analyses were run according to the presence of major SIDS risk factors related to hypoxia (bed-sharing and prone sleeping), infection (presence of an upper respiratory tract infection (URTI)), cigarette smoke exposure and gender. Immunohistochemical expression of the markers was studied in 4 regions of the hippocampus (Cornu Ammonis (CA)1, CA2, CA3, CA4) and subiculum amongst 52 infants (aged 1–7 months) who died suddenly and unexpectedly (SUDI) and for whom the cause of death was explained (eSUDI; n = 9), or not and characterised as SIDS I (n = 8) and SIDS II (n = 35) according to the San Diego diagnostic criteria. Results showed that SIDS II infants had widespread increases in TUNEL compared with eSUDI and SIDS I infants, as well as increased α7 and Casp-3 in CA2 compared to eSUDI infants, although these changes were predominant amongst infants who did not bed-share. Cigarette smoke exposure had minimal effects on the markers, while an URTI was associated with changes in all markers (after accounting for bed-sharing). Our findings support the role of nAChRs in regulating apoptosis in the SIDS hippocampus, and highlight the need for separate analysis according to risk factors.

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Abbreviations

ACh:

Acetylcholine

CA:

Cornu Ammonis

Casp-3:

Caspase 3

ChAT:

Choline acetyltransferase

eSUDI:

Explained sudden unexpected death in infancy

HF:

Hippocampal formation

IHC:

Immunohistochemistry

IHH:

Intermittent hypercapnic hypoxia

nAChR:

Nicotinic acetylcholine receptor

SIDS:

Sudden infant death syndrome

SUDI:

Sudden unexpected death in infancy

TUNEL:

Terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP nick end labelling

uSUDI:

Unexplained sudden unexpected death in infancy

URTI:

Upper respiratory tract infection

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Acknowledgements

The tissue used in this study was obtained from the NSW Forensic and Analytical Science Service.

Funding

This study was funded by philanthropy; The Miranda Belshaw Foundation, Australia, and The SIDS Stampede, Australia.

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Author notes

  1. LLM Luijerink and A Vivekanandarajah are equal first co-authors.

Authors and Affiliations

  1. Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Medical Foundation Building K25, Sydney, NSW, 2006, Australia

    L. L. M. Luijerink, A. Vivekanandarajah, K. A. Waters & R. Machaalani

  2. The Children’s Hospital at Westmead, Westmead, NSW, 2146, Australia

    K. A. Waters & R. Machaalani

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  1. L. L. M. Luijerink
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  2. A. Vivekanandarajah
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Correspondence to R. Machaalani.

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Ethical approval was from the NSW health RPAH zone (Protocol No 3593, X13-0038 and HREC/13/RPAH/54) and University of Sydney (Approval No. 3013/235) Ethics committees.

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Luijerink, L.L.M., Vivekanandarajah, A., Waters, K.A. et al. The α7 and β2 nicotinic acetylcholine receptor subunits regulate apoptosis in the infant hippocampus, and in sudden infant death syndrome (SIDS). Apoptosis 25, 574–589 (2020). https://doi.org/10.1007/s10495-020-01618-0

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