Chronic lithium salt treatment reduces CRE/CREB-directed gene transcription and counter-balance its up-regulation by chronic psychosocial stress in transgenic reporter gene mice

Lithium salts (Li) are clinically relevant treatments for bipolar affective disorder. The onset of their mood stabilizing action occurs after a lag period of up to several months and is not yet understood. It is generally assumed that chronic treatment with Li induces a neuronal adaptation by changing the pattern of expressed genes. Thus, various transcriptions factors could be involved in the action of Li. CREB (cAMP-responsive element binding protein) is a transcription factor, which has been implicated with important brain functions and action of psychogenic agents. CREB is phosphorylated after activation of cAMP- and Ca2+-depending signal cascades and binds as dimer to a cAMP-responsive element (CRE). In order to investigate the action of lithium salts on CRE/CREB-directed gene transcription in vivo, transgenic mice were generated, which express the luciferase reporter gene under the control of four copies of the CRE from the somatostatin gene promoter (CRE-Luc-mice). As Li exert their therapeutic action not under healthy but psychopathic conditions, chronic psychosocial stress was applied to CRE-Luc-mice using a sensory contact model, where two males were housed in a partitioned cage. Luciferase acitivity reflecting CREB activity was quantified after chronic treatment with Li (7,5 mmol/kg/d) for 21d, chronic stress (25d) and chronic stress plus Li treatment in homogenates of various brain regions including bulbus olfactorious, cerebellum, pons, hippocampus, hypothalamus, colliculi and frontal cortex. Chronic treatment with Li for 21d inhibited luciferase activity in hippocampus, cortex and striatum to 60–70%. Chronic psychosocial stress led to an increase of luciferase activity to 200–250% all over the brain. This increase was reduced to control levels under concurrent treatment with Li. This suggests that chronic psychosocial stress and chronic treatment with Li have opposite effects on CRE/CREB-directed gene expression and that Li possibly counter-balance the stress response. Thus, the therapeutic effect of lithium salts may be explained partially by modulating the activity of the transcription factor CREB.