Poster Topical Area: Neurobiology

Location: Hall D

Poster Board Number: 728

P16-026 - Brain Development in PDC-Deficient Mice: Improvement with Phenylbutyrate Treatment

Monday, Jun 11
8:00 AM – 3:00 PM

Pyruvate Dehydrogenase (PDH) Complex (PDC) plays a crucial role in the oxidation of glucose and is inactivated through phosphorylation by PDH kinases and activated by PDH phosphatases. In humans, deficiency of PDC resulting from PDH mutations causes abnormal brain morphology and function. Beneficial effect of phenylbutyrate (PB), an inhibitor of PDH kinases, on residual 'active' PDC activity was shown in skin fibroblast cells from PDC-deficient patients.

Objectives: In the present study we investigated the effect of Pdha1 knock-out on mouse brain cerebellum development which plays key role in controlling sensory-motor processing. Our analyses focused on Purkinje cells (PC) which receive excitatory inputs from the granule cells parallel fibers and inhibitory inputs from the climbing fibers from the inferior olive. We investigated: (1) cerebellar PC population (cell density and sizes) and (2) potential therapeutic effect of PB on the PC population.


Methods: Control female mice and experimental Pdha1-knockout female mice were injected daily with saline or PB in saline (250 mg/kg body weight) starting from postnatal day 2 (P2) up to P35. At P35 mice were perfused and the brains sections were counterstained with Cresyl violet for morphometric studies. Images taken by AxioScan system were used for the reconstruction parts of the cerebellum (vermis: anterior, central, posterior and nodular zones and hemisphere: Crus1, Crus2, simple lobule and paramedian lobule)) and for counting the PC densities and their average size. GraphPrism software was used for statistical analyses.


Results: Saline treated Pdha1 knock-out mice had significantly reduced density of PC accompanied by an increase in the PC size (cell cross-sectional area). Administration of PB to control mice did not affect PC density or the cell size in any of the cerebellar regions examined. In contrast, in Pdha1-knockout mice, PB increased the PC density in several cerebellar regions and reduced the average size of the PC.


Conclusions: The administration of PB to Pdha1-knockout mice, significantly reduced the severity of the negative effects of PDC deficiency (loss of PC and PC hyperplasia) in mouse cerebellum.




Funding Source:

(Supported in part by NIH grant R21NS093264 and funds from Medical University of Gdansk)

CoAuthors: Ilona Klejbor – Medical University of Gdansk, Poland; Saleh Mahmood – University at Buffalo; Natalia Melka – Medical University of Gdansk, Poland; Adriana Ebertowska – Medical University of Gdansk, Poland; Stawomir Wojcik – Medical University of Gdansk, Poland; Janusz Morys – Medical University of Gdansk, Poland; Ewa Stachowiak – University at Buffalo; Michal Stachowiak – University at Buffalo

Mulchand S. Patel

SUNY Distinguished Professor
University at Buffalo, The State University of New York
Buffalo, New York