Nicotinic Receptor Abnormalities in the Cerebellar Cortex of Sudden Unexplained Fetal and Infant Death Victims-Possible Correlation With Maternal Smoking

Abstract

Nicotinic acetylcholine receptors (nAChRs) are cationic channels of the neuronal cell membrane, differentially expressed in the central nervous system which, when activated by endogenous acetylcholine or exogenous nicotine, are able to enhance cholinergic transmission. The aim of this study was to investigate in human perinatal age the immunohistochemical expression of the α7-nAChR subtype, given its involvement in neuronal differentiation and its significant vulnerability to the toxic effects of nicotine. Thirty fetuses (with a gestational age between 25 and 40 weeks) and 35 infants (1-6 months old), suddenly died of known (controls) and unknown causes (unexplained deaths), with smoking and nonsmoking mothers, were included in this study. A negative or low immunoexpression of α7-nAChRs, indicative of their inactivation, was observed in the granular layers of the cerebellar cortex in 66% of the sudden unexplained perinatal deaths and 11% of the controls. A high correlation was also observed between these findings and maternal smoking. Apart from the well-known adverse effects of nicotine exposure during pregnancy, it may also cause significant alterations in cerebellar cholinergic transmission in areas of the brain involved in vital functions. These events may give us insights into the pathogenetic mechanisms leading to sudden unexplained fetal and infant death.

Keywords: acetylcholine; cerebellar cortex; neuropathology; nicotine; nicotinic acetylcholine receptors; sudden infant death syndrome; sudden intrauterine unexplained death syndrome.

Figure 1.

Four-layered structure of the cerebellar cortex. (a) SIDS case 4 month old; (b) age-matched control case. From left to right: external granular layer (EGL), molecular layer (ML), Purkinje cell layer (PCL), and internal granular layer (IGL). In (a) higher thickness of the EGL than that expected in relation to age. Klüver-Barrera stain—Magnification 20×.

Figure 2.

Morphological alterations of the PC layer. (a) To the left: shrunken PC morphology without a discernable nucleus in a SIDS case (2 month old); to the right: normal morphology of a Purkinje cell in an age-matched control case. (b) To the left: extensive loss of PCs in a SIUDS case (40 gestational weeks); to the right: normal PC layer in an age-matched fetus of the control group. Klüver-Barrera stain—Magnification (a) 100 × ; (b) 20×.

Figure 3.

Immunohistochemistry for α7-nicotinic receptor subunit in the granule cells of the IGL of the cerebellar cortex. (a) High immunopositivity (“Class 3” of nAChR-index) of a control case (3 month old). (b) Immunonegativity (“Class 0” of nAChR-Index) in a SIUDS case (39 gestational weeks). Magnification 100×.

Figure 4.

Evidence for significant correlation between SIUDS and SIDS, no or weak nAChR immunoexpression and maternal smoking. Histogram shows the comparison of numbers of cases belonging to the different nAChR-index classes related to maternal smoking. Interestingly, SIUDS and SIDS display a significantly increased number of cases included in Classes 0 and 1 with a smoking mother, compared with controls (p < .01). SIUDS = sudden intrauterine unexplained death syndrome.