beta-Amyloid peptides impair PKC-dependent functions of metabotropic glutamate receptors in prefrontal cortical neurons.

The metabotropic glutamate receptors (mGluRs) have been implicated in cognition, memory, and some neurodegenerative disorders, including the Alzheimer's disease (AD). To understand how the dysfunction of mGluRs contributes to the pathophysiology of AD, we examined the beta-amyloid peptide (Abeta)-induced alterations in the physiological functions of mGluRs in prefrontal cortical pyramidal neurons. Two potential targets of mGluR signaling involved in cognition, the GABAergic system and the N-methyl-d-aspartate (NMDA) receptor, were examined. Activation of group I mGluRs with (S)-3,5-dihydroxyphenylglycine (DHPG) significantly increased the spontaneous inhibitory postsynaptic current (sIPSC) amplitude, and this effect was protein kinase C (PKC) sensitive. Treatment with Abeta abolished the DHPG-induced enhancement of sIPSC amplitude. On the other hand, activation of group II mGluRs with (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC) significantly increased the NMDA receptor (NMDAR)-mediated currents via a PKC-dependent mechanism, and Abeta treatment also diminished the APDC-induced potentiation of NMDAR currents. In Abeta-treated slices, both DHPG and APDC failed to activate PKC. These results indicate that the mGluR regulation of GABA transmission and NMDAR currents is impaired by Abeta treatment probably due to the Abeta-mediated interference of mGluR activation of PKC. This study provides a framework within which the role of mGluRs in normal cognitive functions and AD can be better understood.