The Utility of Tuberless Models of Tuberous Sclerosis

To the Editors: I commend Drs. Holmes, Stafstrom, and the Tuberous Sclerosis Study Group on their comprehensive review of both clinical and basic aspects of Tuberous Sclerosis Complex (TSC) (Holmes et al., 2007). I would just like to comment on a particular key issue related to the utility of animal models for investigating the neurological manifestations of TSC. The review points out that existing rodent models of TSC, including the Eker rat and two conditional knockout mouse models, Tsc1GFAPCKO and Tsc1SynapsinCKO mice (Mizuguchi et al., 2000; Uhlmann et al., 2002; Meikle et al., 2007; Wang et al., 2007), do not exhibit cortical tubers (with the exception of a single Eker rat reported in the literature). Based primarily on this lack of tubers, the authors conclude that the relevance of these animal models to human TSC remains to be established and appropriately advise caution in extrapolating the animal data to humans. In a similar vein, during an Investigator’s Workshop on animal models at the 2006 American Epilepsy Society meeting, an even stronger view was expressed by some participants, implying that the existence of tubers is a required feature of an animal model of TSC in order to have clinical or human relevance. Although animal models clearly have a number of limitations and can never completely recapitulate all aspects of human disease, I would nevertheless like to emphasize that valuable, clinically applicable information can potentially still be derived from almost any reduced system or model. In fact, the direct clinical relevance of “tuberfree” animal models to human TSC is already evident in several examples of TSC research mentioned in the review. First, one of the most exciting recent findings is that the TSC genes regulate the Akt/mammalian target of rapamycin (mTOR) signaling pathway, an observation originally made primarily in Drosophila (Gao et al., 2002; Potter et al., 2002) and later confirmed in human TSC (El-Hashemite et al, 2002; Baybis et al., 2004). Remarkably, this initial discovery from a tuberless insect model has already led to very promising clinical TSC trials with mTOR inhibitors (Franz et al., 2006). Second, abnormalities in astrocyte glutamate transporters initially found in the Tsc1GFAPCKO mice (Wong et al., 2003) have subsequently been demonstrated in preliminary studies of human TSC tissue (Wu et al., 2005) and may have direct relevance and therapeutic implications for epileptogenesis in TSC. In addition, a number of other molecular markers show very similar patterns of expression in astrocytes from Tsc1GFAPCKO mice and human tubers (Maldonado et al., 2003; Ess et al., 2004). Third, increases in intrinsic neuronal excitability and seizures have just recently been reported in Tsc1SynapsinCKO mice, as well as a human case of TSC, in the absence of tubers (Meikle et al., 2007; Wang et al., 2007), which, along with the Tsc1GFAPCKO mice, suggest that tubers may not be necessary for epileptogenesis in TSC. Further reductionist approaches in “tuber-free” systems, such as knock-down of the TSC genes in neuronal cultures (Tavazoie et al., 2005), may turn out to be most useful in determining the molecular mechanisms of altered neuronal structure and function on the single-cell level and potentially revealing novel, rational therapeutic targets for the neurological symptoms of TSC. Thus, while it is always wise to interpret animal data with caution and it is possible that fundamental differences in cortical organization (e. g., the normally lissencephalic brains of rodents) may hinder the development of animal models of TSC with bonafide tubers, much of the information derived from animal models has already had and should continue to have direct clinical and scientific applications for human TSC, even in the absence of tubers.