As discussed, there has been a growing appreciation that any relevant bio- chemical model of lithium’s actions must account for the observation that its prophylactic efficacy generally requires weeks to develop (F. K. Goodwin and Jamison 1990b; Jope and Williams 1994; Manji and Lenox 1994); biochemi- cal changes requiring such prolonged administration of a drug suggest alter- ations at the genomic level. In this context, it is noteworthy that increasing evidence suggests that lithium affects gene expression, possibly via PKC- induced alterations in nuclear transcription regulatory factors responsible for modulating the expression of specific genes (Bohmann 1990; Hunter and Karin 1992). Several studies have demonstrated that lithium alters the ex- pression of the early response gene c-fos in different cell systems including the brain through a PKC-mediated mechanism (reviewed in Manji and Lenox 1994). For example, preincubation of cultured PC12 cells (a rat pheochromocytoma cell line) with lithium for 16 hours markedly potentiates
fos expression in response to the muscarinic agonist carbachol. Lithium pre-
treatment in these cells also potentiates fos expression in response to phorbol esters, which directly activates PKC and thus bypasses PI turnover (Divish et al. 1991; Kalasapudi et al. 1990). Moreover, lithium’s effects show a selectiv- ity for the PKC signal transduction pathway and do not appear to be a result of a nonspecific alteration in mRNA stability, because the fos expression in re- sponse to AC activation is unaffected under identical conditions (Divish et al. 1991; Kalasapudi et al. 1990). Paralleling the results observed in cell culture, a single intraperitoneal injection of lithium results in an augmentation of pilocarpine-induced fos gene expression in rat brain, which can be antagonized by the M1 muscarinic antagonist pirenzepine (E. D. Weiner et al. 1991). These lithium-induced effects on the expression of fos mRNA, generally thought to represent a “master switch” to turn on a “second wave” of specific neuronal genes of functional importance, offer a mechanism for affecting long-term events in the brain. In this regard, incubation of cerebellar granule cells with 1.5 mM lithium has been shown to result in biphasic effects on the
levels of both fos mRNA and muscarinic M3receptor mRNA, consistent with the previously noted short-term versus long-term effects of lithium on PKC-mediated responses (Gao et al. 1993). Long-term “therapeutic” in vivo administration of lithium also significantly changes the expression of a num- ber of genes in rat brain, several of which are known neuromodulatory pep- tide hormones (prodynorphin, preprotachykinin) and their receptors (glucocorticoid type II), and are known to contain PKC-responsive elements (neuropeptide Y) (Kislauskis and Dobner 1990; Pfeiffer et al. 1991; Sivam et al. 1988, 1989; Weiner et al. 1991). In view of lithium’s proposed actions on synaptic function and signal transducing systems, it is also noteworthy that
long-term lithium administration (3–4 weeks) has been reported to alter the expression of various components of second messenger generating systems in-
cluding Gαi1, Gαi2, and GαsmRNA and AC type I and type II mRNA in rat
brain (Colin et al. 1991; Li et al. 1991).
It has been demonstrated recently that lithium, at therapeutically relevant concentrations, regulates AP-1 DNA binding activity in vitro (G. Chen et al. 1997, 1999; Jope, in press; Ozaki and Chuang 1997; Yuan et al. 1998). A lu- ciferase reporter gene system known to be regulated by AP-1 has been used to confirm that these effects on AP-1 DNA binding activity do, in fact, trans- late into changes at the gene expression level in vitro (G. Chen et al. 1999; Yuan et al. 1998). Lithium exposure results in a time- and concentration- dependent increase in the expression of a luciferase reporter gene driven by an SV40 promoter/enhancer that contains transcription regulatory factors (TREs) (G. Chen et al. 1997, 1999; Yuan et al. 1998). Furthermore, muta- tions in the TRE sites of the reporter gene promoter markedly attenuated these effects. These data indicate that lithium may stimulate gene expression (at least in part) through the AP-1 transcription factor pathway, and these ef- fects may play an important role in its long-term clinical actions. However, to ascribe any potential therapeutic relevance to the above biochemical find- ings, it is obviously necessary to show that they do, in fact, also occur in criti- cal regions of the central nervous system in vivo. We have therefore investigated the effects of chronic lithium on AP-1 DNA binding activity in rat frontal cortex and hippocampus. Similar to what has been seen in rat and human cells in vitro, lithium markedly increased the DNA binding activity of the AP-1 family of transcription factors (Manji and Lenox, in press). It is of interest that valproate has had similar effects on AP-1 DNA binding activity both in vitro and in vivo. In view of the key roles of these nuclear transcrip- tion regulatory factors in long-term neuronal plasticity and cellular respon- siveness, and the potential to regulate patterns of gene expression in critical neuronal circuits (Boyle et al. 1991; Lin et al. 1993), these effects may play a
major role in lithium’s and valproate’s long-term beneficial effects.
The demonstration of the long-term modulation of the genetic expression of critical proteins involved in the regulation of synaptic and transmembrane signaling in the brain is of considerable heuristic importance and offers new strategies for unraveling the complex physiological effects of long-term lith- ium treatment in the prophylaxis of recurrent episodes of affective illness in patients with bipolar disorder.