ACTION-POTENTIAL BROADENING INDUCED BY LITHIUM MAY CAUSE A PRESYNAPTIC ENHANCEMENT OF EXCITATORY SYNAPTIC TRANSMISSION IN NEONATAL RAT HIPPOCAMPUS

Lithium enhances excitatory synaptic transmission in CA1 pyramidal cel ls, but the mechanisms remain unclear. The present study demonstrates that lithium enhances the N-methyl-D-aspartate (NMDA) and alpha-amino- 3-hydroxy-5-methyl-isoxazole propionic acid (AMPA) receptor-mediated c omponents of the excitatory postsynaptic current (EPSC). Lithium decre ased the magnitude of paired-pulse facilitation and presented an inver se correlation between the lithium-induced enhancement of synaptic tra nsmission and initial paired-pulse facilitation, which is consistent w ith a presynaptic mode of action. The enhancement of synaptic strength is likely to act, at least in part, by increasing the amplitude of th e presynaptic Ca2+ transient. One mechanism which could account for th is change of the presynaptic Ca2+ transient is an increase in the dura tion of the action potential. We investigated action potential in hipp ocampal pyramidal neurons and found that lithium (0.5-6 mM) increased the half-amplitude duration and reduced the rate of repolarization, wh ereas the rate of depolarization remained similar. To find out whether the lithium synaptic effects might be explained by spike broadening, we investigated the field recording of the excitatory postsynaptic pot ential (EPSP) in hippocampal slices and found three lines of evidence. First, the prolongation of the presynaptic action potential with 4-am inopyridine and tetraethylammonium blocked or reduced the synaptic eff ects of lithium. Second, the lithium-induced synaptic enhancement was modulated when presynaptic Ca2+ influx was varied by changing the exte rnal Ca2+ concentration. Finally, both effects, the synaptic transmiss ion increment and the action potential broadening, were independent of inositol depletion. These results suggest that lithium enhances synap tic transmission in the hippocampus via a presynaptic site of action: the mechanism underlying the potentiating effect may be attributable t o an increased Ca2+ influx consequent to the broadening effect of lith ium on the action potential.