Perinatal Copper Deficiency Alters Rat Cerebellar Purkinje Cell Size and Distribution

Abstract

Copper is required for activity of several key enzymes and for optimal mammalian development, especially within the central nervous system. Copper-deficient (CuD) animals are visibly ataxic, and previous studies in rats have demonstrated impaired motor function through behavioral experiments consistent with altered cerebellar development. Perinatal copper deficiency was produced in Holtzman rat dams by restricting dietary copper during the last two thirds of gestation and lactation. Male offspring were evaluated at postnatal day 25. Compared to cerebella from copper-adequate pups, the CuD pups had larger Purkinje cell (PC) size and irregularities in the Purkinje cell monolayer. These results suggest that the ataxic behavioral phenotype of CuD rats may result from disrupted inhibitory pathways in the cerebellum. A similar PC phenotype is seen in Menkes disease and in mottled mouse mutants with genetic copper deficiency, suggesting that copper deficiency and not just specific loss of ATP7A function is responsible.

Hypocupremia: A Possible Association with Late Cortical Cerebellar Atrophy

“…4,21 Perinatal copper deficient rats demonstrated irregularities in the Purkinje cell monolayer in the cerebellum cortex compared to rats with adequate copper. 22 To our knowledge, hypocupremia and its effects on the cerebellum have not been studied in detail in humans. It is possible that hypocupremia in our patient caused changes in the Purkinje cell layer and cortical atrophy.…”

Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis

“…Cerebellar Purkinje neurons are highly sensitive to copper deficiency during development (Lyons and Prohaska, 2009). In the human brain, ATP7A and ATP7B are co-expressed in Purkinje neurons (Davies et al, 2013), and in the mouse brain, for a postnatal period of up to 2 weeks (Barnes et al, 2005).…”