title: Forebrain depletion of Rheb GTPase elicits spatial memory deficits in mice.
abstract: The precise molecular and cellular events responsible for age-dependent cognitive dysfunctions remain unclear. We report that Rheb (ras homolog enriched in brain) GTPase, an activator of mammalian target of rapamycin (mTOR), regulates memory functions in mice. Conditional depletion of Rheb selectively in the forebrain of mice obtained from crossing Rhebf/fand CamKIICreresults in spontaneous signs of age-related memory loss, that is, spatial memory deficits (T-maze, Morris water maze) without affecting locomotor (open-field test), anxiety-like (elevated plus maze), or contextual fear conditioning functions. Partial depletion of Rheb in forebrain was sufficient to elicit memory defects with little effect on the neuronal size, cortical thickness, or mammalian target of rapamycin activity. Rheb depletion, however, increased the levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein elevated in aging and Alzheimer's disease. Overall, our study demonstrates that forebrain Rheb promotes aging-associated cognitive defects. Thus, molecular understanding of Rheb pathway in brain may provide new therapeutic targets for aging and/or Alzheimer's disease-associated memory deficits.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Neelam
authors.initials: N
authors.lastname: Shahani
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Wen-Chin
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Megan
authors.initials: M
authors.lastname: Varnum
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: Damon T
authors.initials: DT
authors.lastname: Page
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA. Electronic address: ssubrama@scripps.edu.
authors.forename: Srinivasa
authors.initials: S
authors.lastname: Subramaniam
mesh_terms: D000375:Aging / Q000378:metabolism / Q000523:psychology*; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000523:psychology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000209:etiology; D008569:Memory Disorders / Q000209:etiology*; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D020559:Monomeric GTP-Binding Proteins / Q000172:deficiency* / Q000502:physiology*; D009479:Neuropeptides / Q000172:deficiency* / Q000502:physiology*; D016548:Prosencephalon / Q000201:enzymology*; D000076205:Ras Homolog Enriched in Brain Protein; D020123:Sirolimus / Q000378:metabolism; D065852:Spatial Memory
chemical_list: D009479:Neuropeptides; D000076205:Ras Homolog Enriched in Brain Protein; C490213:Rheb protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D020559:Monomeric GTP-Binding Proteins; D020123:Sirolimus
keywords: Alzheimer's disease; BACE1; Forebrain; Rheb; Spatial memory