NFAT/Fas signaling mediates the neuronal apoptosis and motor side effects of GSK-3 inhibition in a mouse model of lithium therapy

Abstract

Use of lithium, the mainstay for treatment of bipolar disorder, is limited by its frequent neurological side effects and its risk for overdose-induced toxicity. Recently, lithium has also been proposed as a treatment for Alzheimer disease and other neurodegenerative conditions, but clinical trials have been hampered by its prominent side effects in the elderly. The mechanisms underlying both the positive and negative effects of lithium are not fully known. Lithium inhibits glycogen synthase kinase-3 (GSK-3) in vivo, and we recently reported neuronal apoptosis and motor deficits in dominant-negative GSK-3-transgenic mice. We hypothesized that therapeutic levels of lithium could also induce neuronal loss through GSK-3 inhibition. Here we report induction of neuronal apoptosis in various brain regions and the presence of motor deficits in mice treated chronically with lithium. We found that GSK-3 inhibition increased translocation of nuclear factor of activated T cells c3/4 (NFATc3/4) transcription factors to the nucleus, leading to increased Fas ligand (FasL) levels and Fas activation. Lithium-induced apoptosis and motor deficits were absent when NFAT nuclear translocation was prevented by cyclosporin A administration and in Fas-deficient lpr mice. The results of these studies suggest a mechanism for lithium-induced neuronal and motor toxicity. These findings may enable the development of combined therapies that diminish the toxicities of lithium and possibly other GSK-3 inhibitors and extend their potential to the treatment of Alzheimer disease and other neurodegenerative conditions.

Lithium suppression of tau induces brain iron accumulation and neurodegeneration

“…66,77,88,11,15 Unexpectedly, we found that lithium treatment at doses inducing blood levels well below the human therapeutic range caused cognitive impairment and brain atrophy in mice after 3 weeks (Figures 4j-l). It has been shown previously that lithium treatment at therapeutic doses can cause cortical neuronal apoptosis, 17 and this may explain our findings. Although lithium treatment was previously reported to correct the smaller hippocampal volumes in patients with bipolar disorder, 85 there is also evidence that long-term lithium treatment is associated with cognitive impairment 86, 87, 88, 89 and brain atrophy.…”

“…This is probably because the tau-knockout mice in youth have the benefit of upregulated compensatory responses from other microtubule-associated proteins 45 in contrast to the more acute suppression of tau expression by lithium treatment. Our findings add to the evidence that lithium at therapeutic (and eventually even at subtherapeutic) chronic doses can cause neurodegeneration, 17 and provide a possible mechanism for adverse neurological effects in susceptible individuals.…”

“…Although a previous study demonstrated the neurotoxic potential of lithium in mice treated with a dose considered to be within the therapeutic range (2.55 g kg −1 in food), 17 lithium has been more extensively investigated for a host of neuroprotective properties in various neurological and psychiatric models including cerebral ischemia/reperfusion injury 18 and other neurotoxic insults. 19 A recent study 19 of adolescents at ultrahigh risk for psychosis 20 found that low-dose lithium treatment over 4 months lowered hippocampal T 2 relaxation time (T 2 *), and this was taken to signify neurochemical improvements that could underlie potential neuroprotective benefits of low-dose lithium as an approach to prevent the onset of psychosis.…”

Control of neuronal apoptosis by reciprocal regulation of NFATc3 and Trim17

“…Notably, the nuclear factor of activated T cell (NFAT) transcription factors have an important role in the development of the nervous system 7,8 and in the control of the survival/death fate of neurons. [9][10][11][12][13][14] The NFAT family comprises four calcium/calcineurindependent transcription factors that are encoded by four closely related genes. [15][16][17] NFAT proteins are expressed in most mammalian tissues, with the different members of the family being present in distinct but overlapping sets of cell types.…”

“…Both NFATc3 and NFATc4 have been shown to have either proapoptotic or antiapoptotic effects, depending on the physiologic and cellular context. [9][10][11][12][13][14][20][21][22] However, the mechanisms that regulate their activity in response to apoptotic stimuli and the target genes that mediate their differential effects on neuronal apoptosis are mostly unknown.…”