Glutamate plays a dominant role in neurotransmission at number of synapses in the mammalian main olfactory bulb (MOB). Work from our laboratory as well as by others over the last 5 years has demonstrated that (1) sensory transmission from olfactory nerve (ON) terminals to mitral/tufted cells (M/TCs) and juxtaglomerular cells, and (2) transmission from MiTCs to granule cells (GCs), is mediated by glutamate acting at AMPA and NMDA receptors. Additionally, glutamate released by M!TCs can activate AMPA and NMDA receptors on other MrrCs, providing a source of autoexcitation that enhances responses to ON input. Receptor localization studies suggest that another class of glutamate receptors, metabotropic glutamate receptors (mGluRs), are densely expressed at several glutamatergic synapses in the MOB. In paiticular, the density of mGluRs on MTFCs and GCs are higher than most other regions of the brain. However, the role(s) of mGluRs in synaptic processing in the MOB are unknown. The goal of the present proposal is to close this gap. Preliminary data show that the operation of the MOB network, and the excitability of MCs and GCs, are potently modulated by activation and inactivation of mGluRs. Direct activation of mGluRs on MCs increases their excitability, and in turn, increases their excitatory drive on GCs. Activation of mGluRs also directly increases GC excitability and GABA release. Inactivation of mGluRs, by contrast, potently attenuates MC - GC excitatory transmission. Based on these results and other preliminary data, we hypothesize that activation of mGluRs by synaptically-released glutamate positively modulates lateral inhibition and increases contrast in the MOB network. In agreement with this hypothesis, preliminary studies using optical imaging of voltage-sensitive dyes show that mGluR antagonists dramatically decrease the amplitude, spatial spread and duration of postsynaptic activity in the external plexiform layer evoked by focal glomerular stimulation. This suggests that endogenous activation of mGluRs amplifies lateral inhibition. This hypothesis will be tested at the cellular and circuit levels using patch clamp electrophysiology and functional imaging approaches in mammalian MOB slices from rats, as well as slices from mice with targeted gene deletions of the major mGluRs expressed by MCs and GCs. The overarching goal of this proposal is to elucidate the roles of mGluRs in the operation of the MOB network and odor coding.