Phenylbutyrate administration reduces changes in the cerebellar Purkinje cells population in PDC-deficient mice

Abstract

In humans, pyruvate dehydrogenase complex (PDC) deficiency impairs brain energy metabolism by reducing the availability of the functional acetyl‑CoA pool. This "hypometabolic defect" results in congenital lactic acidosis and abnormalities of brain morphology and function, ranging from mild ataxia to profound psychomotor retardation. Our previous study showed reduction in total cell number and dendritic arbors in the cerebellar Purkinje cells in systemic PDC‑deficient mice. Phenylbutyrate has been shown to increase PDC activity in cultured fibroblasts from PDC‑deficient patients. Hence, we investigated the effects of postnatal (days 2‑35) phenylbutyrate administration on the cerebellar Purkinje cell population in PDC‑deficient female mice. Histological analyses of different regions of cerebellar cortex from the brain‑specific PDC‑deficient saline‑injected mice revealed statistically significant reduction in the Purkinje cell density and increased cell size of the individual Purkinje cell soma compared to control PDC‑normal, saline‑injected group. Administration of phenylbutyrate to control mice did not cause significant changes in the Purkinje cell density and cell size in the studied regions. In contrast, administration of phenylbutyrate variably lessened the ill effects of PDC deficiency on Purkinje cell populations in different areas of the cerebellum. Our results lend further support for the possible use of phenylbutyrate as a potential treatment for PDC deficiency.