Giant and Opposite Lithium Isotope Effects on Rat Hippocampus Synaptic Activity Revealed by Multi-Electrode Array Electrophysiology

Lithium (Li) has been a frontline medication for the treatment of bipolar disorder for decades, but its mechanism of action remains poorly understood 1,2 . While clinically prescribed Li salts consist of a mixture of two stable isotopes, 6 Li and 7 Li, the neurobiological effects of each isotope are only beginning to receive attention. Recent theoretical proposals have suggested that the Li isotopes may exert unique effects in the brain, stemming from quantum phenomena linked to their distinct nuclear spin properties 3-5 . However, aside from earlier observations of isotope-dependent variations in animal behavior 6,7 , direct experimental evidence is lacking. We used multi-electrode array electrophysiology to probe field excitatory post-synaptic potentials (fEPSPs) in rat brain slices and demonstrated that 6 Li and 7 Li have large and opposite effects on synaptic transmission and lead to smaller, but still distinct, differences in synaptic plasticity, particularly, paired-pulse facilitation and the early stages of long-term potentiation. Our results provide direct experimental evidence that Li isotopes exert remarkably different neurological effects, while avoiding many of the interpretive challenges associated with behavioural studies. These findings lay the groundwork for future investigations of quantum phenomena in neuronal activity and promote the idea that Li isotopes are pharmacologically distinct agents.