The functional roles of metabotropic glutamate receptors in prefrontal cortex and the implications in Alzheimer's disease

The metabotropic glutamate receptors (mGluRs) mediate their effects through secondary effector messengers and therefore are linked to a large repertoire of chemical and electrical signaling mechanisms. The modulatory effects of mGluRs on neuronal excitability, synaptic plasticity and neurotransmission have placed them among the key players in cognition, memory and goal-oriented behavior---mental processes subserved by the prefrontal cortex (PFC). Two potential targets of mGluRs-mediated signaling essential for cognitive processes and memory are the NMDA receptor and the GABAergic system. To expand our understanding of the physiological functions of mGluRs, we studied their regulation of NMDA receptor function and GABAergic transmission in prefrontal (PFC) cortical pyramidal neurons. We found that (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (APDC), a highly selective and potent group II mGluRs agonist, reversibly enhanced NMDAR-mediated currents in acutely dissociated PFC neurons. Selective group II but not group I mGluRs antagonists, blocked APDC-induced increase of NMDAR currents. The APDC effect on NMDAR currents was independent of Mg 2+ block or membrane potential and targeted both NR2A- and NR2B-subunit containing NMDARs. While changing protein kinase A levels did not alter the response to APDC, inhibition of protein kinase C (PKC) or dialysis with Ca 2+ chelating agent largely inhibited the mGluR 2/3 effect on NMDAR currents. Furthermore, inhibition of protein tyrosine kinase, cyclin-dependent kinase 5, Ca2+/calmodulin-dependent kinase II or phospohatase calcineurin failed to alter the mGluR 2/3 effect.; In addition, we found that activation of the mGluR 1/5 with (s)-3, 5-dihydroxyphenylglycine (DHPG), a selective group I agonist, but not that of mGluR 2/3 with (2S, 2'R, 3 R)-2-(2', 3'-dicarboxycyclopropyl) glycine (DCG IV), a potent group II agonist, significantly increased the amplitude and frequency of spontaneous inhibitory postsynaptic current (sIPSCs). DHPG's effect on sIPSC amplitude was blocked with mGluR 5, but not mGluR 1 specific antagonist, and it was abolished with PKC, but not p38 or p42/44 inhibitors.; Glutamate receptor functions essential for normal synaptic processes underlying memory and cognition are severely altered by neurodegeneration arising from the Amyloid beta (Abeta)-driven synaptotoxicity. The Abeta-mediated synaptic dysfunction is believed to be responsible for the early cognitive and memory impairments manifested in Alzhemer's disease (AD). The mechanistic details of how Abeta induces changes at the synapse level remain, however, unclear. To elucidate how Abeta impacts the physiological functions of mGluRs in PFC, we examined the Abeta-induced changes in the regulatory processes mediated by mGluRs. Intriguingly, we observed that exposure of PFC slice to Abeta peptides abolished both APDC- and DHPG-induced effects on NMDAR currents and sIPSC amplitude, respectively. (Abstract shortened by UMI.)...