Abnormal postnatal ontogeny of the locus coeruleus in the epileptic mutant mouse quaking

The tonic-clonic convulsions of the quaking mutant mice have been shown to be associated with the hyperplasia of the nucleus locus coeruleus, the origin of most brain noradrenergic neurons. In the present study, the postnatal ontogeny of the locus coeruleus has been studied by tyrosine hydroxylase immunolabeling in the mutant mice quaking and their controls at postnatal days 1, 30 and 90. In the control mice, the number of immunoreactive neuronal cell bodies increased significantly in the rostral half of the locus coeruleus between birth and postnatal day 30, while it decreased significantly in the caudal half between birth and adulthood. Thus, during postnatal maturation, the distribution of locus coeruleus neurons was shifted in the rostral direction. In the quaking mutant mice, while the increase of immunolabeling between birth and postnatal day 30 was observed in the rostral half of the locus coeruleus, no diminution could be found in the caudal half between birth and adulthood. As a result, the rostral shift of tyrosine hydroxylase immunoreactivity was not observed. Consequently, in adult mice, the caudal part of the mutants locus coeruleus appeared to contain significantly more neurons than the corresponding region in the controls. These results indicate that the hyperplasia of the locus coeruleus of the quaking mice that we had previously reported results from an alteration of the postnatal maturation of this nucleus. This developmental abnormality might be a primary determinant of the inherited epilepsy of the quaking mutant mice.