Group I metabotropic glutamate receptors elicit epileptiform discharges in the hippocampus through PLCβ1 signaling

Activation of metabotropic glutamate receptors (mGIuRs) produces multiple effects in cortical neurons, resulting in the emergence of network activities including epileptiform discharges. The cellular mechanisms underlying such network responses are largely unknown. We examined the properties of group I mGIuR-mediated cellular responses in CA3 neurons and attempted to determine their role in the generation of the network activities. Group I mGIuR stimulation causes depolarization of hippocampal neurons. This depolarization is primarily mediated by two sets of conductance change: the opening of a voltage-dependent cationic conductance (mediating I_mGIuR(V)) and the closing of a voltage-independent (background) K⁺ conductance. I_mGIuR(V) was no longer elicited by group I mGIuR agonists in the presence of U73122, a phospholipase C (PLC) blocker. Also, the current could not be activated in hippocampal CA3 neurons from PLCβ1 knock-out mice. In contrast, suppression of PLC signaling did not affect the group I mGIuR-mediated suppression of background K⁺ conductance. Thus, the suppression of the background K⁺ conductance occurred upstream to PLC activation, whereas the generation of I_mGIuR(V) occurred downstream to PLC activation. Group I mGIuR agonists normally elicited rhythmic single cell and population burst responses in the CA3 neurons. In the absence of an I_mGIuR(V) response, CA3 neurons in slices prepared from PLCβ1-/-mutant mice could no longer generate these responses. The results suggest that I_mGIuR(V) expression in CA3 hippocampal neuron is PLCβ1 -dependent and that I_mGIuR(V) plays a necessary role in the generation of rhythmic single cell bursts and synchronized epileptiform discharges in the CA3 region of the hippocampus.