Abnormal group I metabotropic glutamate receptor expression and signaling in the frontal cortex in Pick disease

Group I metabotropic glutamate receptors (mGluR1) regulate synaptic transmission through the stimulation of phospholipase C beta(1) (PLC beta(1)) and then by the activation of protein kinase C (PKC). Considering these properties, it is conceivable that major cortical functional deficits may be attributed to abnormal mGluR processing and signaling. The present work examines mGluRI expression and signaling in the frontal cortex (area 8) of 3 cases with Pick disease (PiD), a neurodegenerative disease with abnormal phospho-tau accumulation, in comparison with 3 age-matched controls by means of glutamate binding assays, enzymatic activity, gel electrophoresis and Western blotting, solubility and immunoprecipitation assays, and confocal microscopy. Reduced expression levels of PLC beta(1) and reduced PLCPI activity have been found in PiD. The expression levels of the nonrelated phospholipase PLC gamma, a substrate of tyrosine kinase, are also reduced in PiD. This is accompanied by a marked decrease in the expression of cPKC alpha and increased expression of the inner band (76 kDa) of the nPKC delta doublet at the expense of a decrease of the phosphorylated (active) form (78 kDa). In contrast, L-[H-3]glutamate-specific binding to mGluRs is augmented in PiD cases, mainly because of the higher mGluR1 and mGluR(5) expression levels detected. No modifications in PLC beta(1) solubility have been observed in PiD and no interactions between PLC beta(1) and tau have been demonstrated in diseased and control cases. Moreover, double-labeling immunofluorescence and confocal microscopy have shown no colocalization of phospho-tau (AT8 antibody) and PLC beta(1) in phospho-tau inclusions, including Pick bodies. These results demontrate for the first time abnormal mGluR signaling in the cerebral cortex in PiD and selective vulnerability of phospholipases and PKC to PiD.