May 2013

This study used the logic that cells that are resistant to stroke, such as the neurons in the CA3 region of the hippocampus; and cells that can be preconditioned by ischemic stress, such as those in the CA1 region of hippocampus, might share a factor that could be upregulated to prevent cell death. The investigators used both the in vivo rat model of global forebrain ischemia and an in vitro oxygen glucose deprivation system in embryonic rat hippocampal cultures to determine what the nature of the factor might be. They found that hamartin is selectively induced in the resistant CA3 neurons after global ischemia, and while not changed in CA1 after ischemia, it was upregulated after ischemic preconditioning, which protected the vulnerable cells. When the investigators targeted TSC1 with shRNA viral vectors both in vitro and in vivo, they found an increased cell death in the CA3 neurons. The cell death was manifested behaviorally by increased locomotor activity in an open field test and decreased habituation in a task that relies on hippocampal functioning. They also investigated the mechanism underlying hamartin’s role in protection. Hamartin and its partner tuberin suppress mTORC1 via inhibition of the GTPase Rheb. mTORC1 inhibits productive autophagy which is an essential process that degrades protein aggregates and damaged organelles. When hamartin is suppressed, so is productive autophagy. Since productive autophagy has been implicated in the beneficial effects of ischemic preconditioning, its induction seems critical to protection. With these new data, hamartin and the mTOR pathway could be novel targets for neuroprotection after ischemia (Nat Med 2013;19:315–317).