PI of the laboratory: Prof. Luc Pellerin
Regulation of MCT4 expression in mouse cultured cortical astrocytes by the neuronal signal nitric oxide (NO)
Description of Project:
Introduction: Several neurological diseases (e.g. Alzheimer’s and Parkinson’s diseases) exhibit deficits in neuroenergetics. Astrocytes play a critical role in neuroenergetics by supplying neurons with the energy substrate lactate as a function of the level of synaptic activity. The transport of lactate across the plasma membrane is mediated by a family of carriers known as monocarboxylate transporters (MCTs). Astrocytes express both MCT1 and MCT4 in vivo. However, cultured astrocytes only exhibit MCT1 expression.
Question / Aim of the work: It is suspected that MCT4 expression in astrocytes is under the control of neuronal signals. Nitric oxide (NO) represents an ideal candidate known to be released by active neurons that could trigger transcriptional activation. The main goal of this project will be to explore in cultured cells the role of NO as the main neuronal signal that induces MCT4 expression in astrocytes and the molecular mechanisms involved.
Techniques / methods applied: Primary cultures of mouse cortical astrocytes and neurons will be used to investigate the regulation of MCT4 expression. mRNA levels will be evaluated by quantitative real-time RT-PCR. Protein expression levels will be determined by immunohistochemistry and Western blot. Knockdown approaches using siRNAs and overexpression via transfection will be used to analyze the implication of various key proteins in the mechanism that allows NO to induce MCT4 expression.
Expected outcome: This project will contribute to the demonstration that neurons control their energy substrate supply by altering the expression of a critical transporter in astrocytes. It will complement similar studies performed in our laboratory showing a parallel regulation of the expression of another monocarboxylate transporter in neurons to ensure adequate lactate supply.
L. Pellerin (2008) Brain energetics (thought needs food). Curr Opin Clin Nutr Metab Care 11:701-705.
K. Pierre and L. Pellerin (2005) Monocarboxylate transporters in the central nervous system: distribution, regulation and function.
Link to the group web site