Loss of dopaminergic neurons and resulting behavioural deficits in mouse model of Angelman syndrome.

E6 associated protein is an E3 ubiquitin ligase encoded by the gene Ube3a. Deletion or loss of function of the maternally inherited allele of Ube3a leads to Angelman syndrome. In the present study, we show that maternal loss of Ube3a (Ube3a(m-/p+)) in the mouse model leads to motor deficits that could be attributed to the dysfunction of the nigrostriatal pathway. The number of tyrosine hydroxylase positive neurons in the substantia nigra was significantly reduced in Ube3a(m-/p+) mice as compared to the wild type counterparts. The Ube3a(m-/p+) mice performed poorly in behavioural paradigms sensitive to nigrostriatal dysfunction. Even though the tyrosine hydroxylase staining was apparently the same in the striatum of both genotypes, the presynaptic and postsynaptic proteins were significantly reduced in Ube3a(m-/p+) mice. These findings suggest that the abnormality in the nigrostriatal pathway along with the cerebellum produces the observed motor dysfunctions in Ube3a(m-/p+) mice.