It is now well established that the primary afferent fibers use glutamate as a principal fast excitatory transmitter in the superficial dorsal horn (SDH) of the spinal cord, the first modulatory site in the relay of sensory information from the peripheral receptors to the brain. Glutamate acts through two broad classes of receptors, ion-channel-linked (ionotropic) receptors (AMPA/kainate and NMDA receptors) and metabotropic receptors (mGluRs), which couple via G-proteins to the intracellular second messenger cascades. Group I mGluRs (mGluR1 and 5 subtypes) are expressed by neurons in the SDH, but their roles in synaptic function, and contribution to spinal somatosensory transmission and synaptic plasticity, have yet to be elucidated. The recent development of ligands that bind specifically to these receptors, and availability of mutant mice lacking mGluR1 or mGluR5 receptors, has provided means of characterizing the important roles they may play in tuning of fast and slow excitatory synaptic transmission, including the induction of long-term changes in synaptic efficacy, as suggested by our recent preliminary evidence. Two major objectives in the proposal are: 1) to study involvement of Group I mGluRs via ICAN (non-selective Ca2+-dependent cation channels) in the generation of primary afferent-evoked slow excitatory synaptic potential (sEPSP) in the SDH region; and 2) to study regulation of AMPA and NMDA receptor-mediated sensory transmission by activation of Group I mGluRs. A combination of intracellular and whole-cell patch-clamp recordings, Ca2+ imaging, and pharmacological techniques will be employed to study the involvement of Group I mGluR activation in synaptic transmission and plasticity in SDH neurons within spinal cord slices prepared from young rats and mutant mice lacking mGlu1 or 5 receptors. Delineating the physiological roles of the Group I mGluRs in the SDH region, and cellular and molecular mechanisms underlying their actions, is an important step toward understanding of implications of glutamate-mediated transmission in the spinal cord DH synaptic function, but in particular for synaptic plasticity and nociception.
