Synapse-specific accumulation of lithium in intracellular microdomains: a model for uncoupling coincidence detection in the brain.

Lithium's therapeutic specificity for the treatment of bipolar disorder may be attributable in part to an ability to target sites where there are high levels of synaptic activity. We show that glutamate receptors expressed in oocytes are highly permeable to lithium. Mathematical simulations of Li+ diffusion in mature dendritic spines suggest that in the presence of 1 mM extracellular lithium one synaptic current can increase Li+ concentration in the spine head by 4 mM with a decay time constant of about 15-20 ms. Two or more current spikes will produce oscillations between 6 and 8 mM or potentially higher. These results predict that the local intracellular lithium in dendritic spines can rise to high enough levels to uncouple second messenger mechanisms of coincidence detection.