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 disorde r may be attributable in part to an ability to target sites where ther e are high levels of synaptic activity. We show that glutamate recepto rs expressed in oocytes are highly permeable to lithium. Mathematical simulations of Li+ diffusion in mature dendritic spines suggest that i n 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 o scillations between 6 and 8 mM or potentially higher. These results pr edict that the local intracellular lithium in dendritic spines can ris e to high enough levels to uncouple second messenger mechanisms of coi ncidence detection. (C) 1998 WiIey-Liss, Inc.