MODULATION OF EXCITATORY SYNAPTIC TRANSMISSION BY LOW CONCENTRATIONS OF GLUTAMATE IN CULTURED RAT HIPPOCAMPAL-NEURONS

1. The effects of low micromolar concentrations of glutamate on fast e xcitatory synaptic responses were studied in microcultures of postnata l rat hippocampal neurons using whole-cell patch clamp recordings. 2. Glutamate depressed the lpha-amino-3-hydroxy-5-methyl-4-isoxazolepropi onic acid (AMPA) receptor component of excitatory autaptic currents (E ACs) with an EC(50) of 3.8 mu M. 3. Both pre- and postsynaptic effects contributed to the depression of AMPA receptor mediated EACs. Cycloth iazide and wheatgerm agglutinin, agents which inhibit AMPA receptor de sensitization, partially reversed the depression produced by glutamate , as did pertussis toxin, an agent that blocks presynaptic inhibition mediated by metabotropic glutamate receptors. 4. In neurons in which b oth the AMPA and N-methyl-D-aspartate (NMDA) receptor components of EA Cs were examined, low concentrations of glutamate depressed the NMDA c omponent of EACs to a greater extent. The EC(50) for inhibiting the NM DA component was 1.3 mu M. 5. Calcium-dependent desensitization of pos tsynaptic NDA receptors contributed to the depression of NMDA receptor -mediated synaptic responses. Both depolarization of postsynaptic neur ons to +70 mV to decrease Ca2+ influx via NMDA channels and inclusion of high concentrations of a calcium chelator in recording pipettes dec reased the depression of NMDA receptor-mediated EACs. 6. Threo-3-hydro xy-aspartate (THA), an inhibitor of glutamate transport, depressed EAC s by about 10% and increased the degree of depression produced by 2.5 mu M glutamate, suggesting that glutamate transport in microcultures h elps to control ambient glutamate levels. 7. Because the normal extrac ellular concentration of glutamate is about 1 mu M, these results sugg est that the ambient glutamate level is an important determinant of sy naptic efficacy. Relatively small changes in extracellular glutamate c an alter fast excitatory synaptic transmission by both presynaptic and postsynaptic mechanisms.