ABSTRACT
Lithium is an effective mood stabilizer but its use is associated with many side effects. Electrophysiological recordings of miniature excitatory postsynaptic currents (mEPSCs) mediated by glutamate receptor AMPA-subtype (AMPARs) in hippocampal pyramidal neurons revealed that CLi (therapeutic concentration of 1 mM lithium, from days in vitro 4–10) decreased the mean amplitude and mean rectification index (RI) of AMPAR mEPSCs. Lowered mean RI indicate that contribution of Ca2+-permeable AMPARs in synaptic events is higher in CLi neurons (supported by experiments sensitive to Ca2+-permeable AMPAR modulation). Co-inhibiting PKA, GSK-3β and glutamate reuptake was necessary to bring about changes in AMPAR mEPSCs similar to that seen in CLi neurons. FM1-43 experiments revealed that recycling pool size was affected in CLi cultures. Results from minimum loading, chlorpromazine treatment and hyperosmotic treatment experiments indicate that endocytosis in CLi is affected while not much difference is seen in modes of exocytosis. CLi cultures did not show the high KCl associated presynaptic potentiation observed in control cultures. This study, by calling attention to long-term lithium-exposure-induced synaptic changes, might have implications in understanding the side effects such as CNS complications occurring in perinatally exposed babies and cognitive dulling seen in patients on lithium treatment.
ABSTRACT
The effects of Zn2+ on spontaneous glutamate and GABA release were tested in mechanically dissociated rat CA3 pyramidal neurons which retained functional presynaptic nerve terminals. The spontaneous miniature excitatory and inhibitory postsynaptic currents (mEPSCs and mIPSCs, respectively) were pharmacologically isolated and recorded using whole-cell patch clamp technique under voltage-clamp conditions. Zn2+ at a lower concentration (30 micrometer) increased GABAergic mIPSC frequency without affecting mIPSC amplitude, but it decreased both mIPSC frequency and amplitude at higher concentrations (> or =300 micrometer). In contrast, Zn2+ (3 to 100 micrometer) did not affect glutamatergic mEPSCs, although it slightly decreased both mIPSC frequency and amplitude at 300 micrometer concentration. Facilitatory effect of Zn2+ on GABAergic mIPSC frequency was occluded either in Ca2+ -free external solution or in the presence of 100 micrometer 4-aminopyridine, a non-selective K+ channel blocker. The results suggest that Zn2+ at lower concentrations depolarizes GABAergic nerve terminals by blocking K+ channels and increases the probability of spontaneous GABA release. This Zn2+ -mediated modulation of spontaneous GABAergic transmission is likely to play an important role in the regulation of neuronal excitability within the hippocampal CA3 area.