27 June 2008. Rapamycin is best known as a tumor suppressant, so it may come as a surprise to hear that it can also suppress learning deficits. In the June 22 Nature Medicine online, researchers led by Alcino Silva at the University of California, Los Angeles, reported that the drug can treat symptoms in mouse models of tuberous sclerosis. This rare inherited disease, caused by mutation in either of two genes, Tsc1 or Tsc2, is associated with mental retardation, autism, and epilepsy. Affected patients, even if they have an average IQ, often have neuropsychological problems, including deficits in long-term and working memory. Though the disease is rooted in neurodevelopmental problems, Silva sees the ability to reverse the symptoms as having a broader impact, being relevant to adult disease such as Alzheimer’s. “We are finally getting to a point where we are starting to understand what happens in the brain when individuals learn and remember. I think that information will have a wide impact on a number of areas, including disorders of learning and memory, and it may be very relevant to Alzheimer’s,” said Silva in an interview with ARF.
The exact pathology behind tuberous sclerosis has yet to be determined. This prompted Silva and colleagues to investigate the effect of Tsc2 deficiency in mice. Tsc2, also known as tuberin, is a GTPase activating protein that regulates the G protein Rheb, an activator of mTOR (mammalian target of rapamycin). The mTOR signaling pathway turns on local protein synthesis, a requirement for synaptic plasticity.
In keeping with tuberin’s role in tempering the mTOR pathway, first author Dan Ehninger and colleagues found that phosphorylation of the S6 ribosomal protein, a target of mTOR signaling, was enhanced in Tsc2+/- heterozygotes. The mutant animals were also deficient in several hippocampal-dependent learning and memory paradigms, including spatial memory, contextual fear conditioning, and working memory. The molecular basis for these deficits appears to be perturbed, late-phase long-term potentiation (LTP), which is enhanced in the animals. Ehninger and colleagues found that late-phase LTP (L-LTP) was induced at a much lower stimulatory threshold in Tsc2+/- mice. What appears to happen in these mice is that L-LTP is induced under conditions that would normally elicit only early-phase LTP. “One may think that going into this long-term memory mode under conditions when you should only go into the short-term memory mode is good, but it turns out that when we are learning something we often initially learn things that are wrong. So if we stabilize and store information that can potentially be wrong, that information actually gets in the way of us learning things that are useful,” said Silva. He believes that these Tsc2+/- mice go so easily into long-term memory mode that they end up storing a lot of noise, which keeps them from learning what is important and doing well in the learning path tests they are given.
If the learning and memory deficits are simply due to enhanced L-LTP, then inhibiting the mTOR pathway might help to ameliorate the symptoms. That is just what Ehninger and colleagues found. When they gave the mice the mTOR inhibitor rapamycin before the learning regimens were started, the animals performed just as well as wild-type controls in tests of spatial memory and fear conditioning. In keeping with the idea that the learning deficits result from enhanced L-LTP driven by mTOR signaling, they also found that S6 phosphorylation was normal in rapamycin-treated mice, and that proper LTP induction was restored.
There are some links between mTOR and neurodegenerative diseases, but Silva said it is not clear how these relate to tuberous sclerosis. For example, rapamycin may help in Huntington disease by upregulating autophagy, which is attenuated by mTOR signaling (see ARF related news story). Recent work suggests that autophagy is downregulated in AD as well (see ARF related news story). In the case of Parkinson disease, rare inherited forms are associated with mutations in Pink1, or PTEN-induced putative kinase1. PTEN is an upstream regulator of the mTOR pathway.
Rapamycin has been used as an immunosuppressant for some time, but Silva says there is no literature citing any cognitive effects, perhaps not surprisingly, since patients undergoing transplantation would have to be put through cognitive testing. In collaboration with Petrus de Vries at the University of Cambridge, U.K., Silva hopes to test the drug in tuberous sclerosis patients.—Tom Fagan.
Ehninger D, Han S, Shilyansky C, Zhou Y, Li W, Kwiatkowski DJ, Ramesh V, Silva AJ. Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Nature Medicine. 2008 June 22; advanced online publication. Abstract