• lithium
• electrophysiology
• imaging
• animal model

Lithium salts have been for decades a first-line treatment for neuropsychiatric disorders, such us Bipolar Disorder (BD); furthermore, in the last few years lithium has been considered also a valuable candidate for treatment of traumatic brain injury and various neurodegenerative conditions. However, how this monocation could yield such profound therapeutic effects remains unclear. The therapeutic action of lithium is particularly complex and mainly related to its interaction with other cations, such us Na+ and Mg2+, in various signaling proteins and cofactors, promoting various effects on gene expression, neurotransmitter signaling, receptor-mediated signaling, signal transduction processes, circadian regulation and ion transport. In this study, starting from preliminary data of in vivo imaging of intracellular chloride concentration, we show that systemic administration of lithium lowers intracellular chloride concentration [Cl-]i in neocortical pyramidal cells. As a consequence, the lithium-mediated lowering of [Cl-]i could increase the strength of GABA-mediated inhibition on pyramidal neurons. Conversely, we show that lithium withdrawal causes a higher level of excitability and an increased susceptibility to epileptogenesis. Further experiments will be conducted in this direction to demonstrate whether and how lithium withdrawal causes an increase in [Cl-]i, possibly leading to a switch towards a depolarizing effect of GABA.