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Previous attempts to identify neuroprotective targets by studying the ischemic cascade and devising ways to suppress it have failed to translate to efficacious therapies for acute ischemic stroke. We hypothesized that studying the molecular determinants of endogenous neuroprotection in two well-established paradigms, the resistance of CA3 hippocampal neurons to global ischemia and the tolerance conferred by ischemic preconditioning (IPC), would reveal new neuroprotective targets. We found that the product of the tuberous sclerosis complex 1 gene (TSC1), hamartin, is selectively induced by ischemia in hippocampal CA3 neurons. In CA1 neurons, hamartin was unaffected by ischemia but was upregulated by IPC preceding ischemia, which protects the otherwise vulnerable CA1 cells. Suppression of hamartin expression with TSC1 shRNA viral vectors both in vitro and in vivo increased the vulnerability of neurons to cell death following oxygen glucose deprivation (OGD) and ischemia. In vivo, suppression of TSC1 expression increased locomotor activity and decreased habituation in a hippocampal-dependent task. Overexpression of hamartin increased resistance to OGD by inducing productive autophagy through an mTORC1-dependent mechanism.

Original publication

DOI

10.1038/nm.3097

Type

Journal article

Journal

Nat Med

Publication Date

03/2013

Volume

19

Pages

351 - 357

Keywords

Adenine, Animals, Anoxia, Autophagy, CA1 Region, Hippocampal, CA3 Region, Hippocampal, Cells, Cultured, Hypoxia-Ischemia, Brain, Ischemic Preconditioning, Male, Multiprotein Complexes, Neuroprotective Agents, Prosencephalon, Proteins, RNA Interference, RNA, Small Interfering, Rats, Rats, Wistar, Sirolimus, TOR Serine-Threonine Kinases, Tumor Suppressor Proteins