The effect of a cellular prion protein (PrP ^c ) deficiency on neuroenergetics was primarily analyzed via surveying the expression of genes specifically involved in lactate/pyruvate metabolism, such as monocarboxylate transporters (MCT1, MCT2, MCT4). The aim of the present study was to elucidate a potential involvement of PrP ^c in the regulation of energy metabolism in different brain regions. By using quantitative real-time polymerase chain reaction (qRT-PCR), we observed a marked reduction in MCT1 mRNA expression in the cortex of symptomatic Zürich I Prnp ^-/- mice, as compared to their wild-type (WT) counterparts. MCT1 downregulation in the cortex was accompanied with significantly decreased expression of the MCT1 functional interplayer, the Na ⁺ /K ⁺ ATPase α2 subunit. Conversely, the MCT1 mRNA level was significantly raised in the cerebellum of Prnp ^-/- vs. WT control group, without a substantial change in the Na ⁺ /K ⁺ ATPase α2 subunit expression. To validate the observed mRNA findings, we confirmed the observed change in MCT1 mRNA expression level in the cortex at the protein level. MCT4, highly expressed in tissues that rely on glycolysis as an energy source, exhibited a significant reduction in the hippocampus of Prnp ^-/- vs. WT mice. The present study demonstrates that a lack of PrP ^c leads to altered MCT1 and MCT4 mRNA/protein expression in different brain regions of Prnp ^-/- vs. WT mice. Our findings provide evidence that PrP ^c might affect the monocarboxylate intercellular transport, which needs to be confirmed in further studies.