An important aspect of brain aging is the increased glutamate (Glu) release and accumulation in theextracellular space of neurons. Age-associated increases in extracellular Glu occur because of partial loss ofactivity of Glu transporters. Essentially all neurons in the central nervous system (CNS) are exposed toelevated extracellular Glu, yet not all brain regions suffer equally. The sensitivity of certain neurons to thetoxic effects of Glu produced through Ca2+- and oxidative stress-mediated processes, increases with age.The reasons for differential vulnerability of certain neurons to Glu are still not known. Also, no animal modelof age-associated increases in Glu release in CNS is available to determine how excess Glu produces itseffect on aging neurons. We have generated transgenic (Tg) mice that have extra copies of the gene for Gludehydrogenase 1 (GLUD1), a mitochondrial enzyme considered to be a rate-limiting, step in the biosynthesisof Glu as a transmitter. The GLUD1 transgene, introduced under the control of a neuron-specific promoter, isexpressed only in neurons. GLUD1 mice have higher levels of depolarization-induced Glu release than wildtype (wt) and suffer losses in specific neuronal populations. GLUD1 mice also have a shortened life spanwithout exhibiting severe neurological dysfunction. The hypothesis being tested is that excess extracellularGlu in aging brain initiates events that lead to altered metabolic states in CNS, damage to select populationsof neurons, an imbalance between damage and recovery, metabolic stress in peripheral tissues, anddecreased longevity. Short-term objectives are: a) To quantify changes in longevity and protein/ DNAoxidation in brain and other tissues of hyper-glutamatergic and wt mice; b) To determine changes inmetabolism, gene expression, and morphology of vulnerable and resistant neurons; and c) To characterize asignaling protein complex involved in active neurite remodeling and define how Glu hyperactivity and agingaffect this complex. The long-term objectives are to understand the molecular and cellular processes thatlink increased Glu activity in CNS to age-dependent changes in neuronal structure and function, but withoutneurological disease, and to identify potential targets for therapeutic intervention. To test the hypothesis, wedeveloped the following specific aims: 1) Assess longevity and protein and DNA oxidation levels in brainand other tissues of wt and Tg mice during aging; 2) Determine the effects of neuronal GLUD1overexpression and of aging on structural, metabolic and gene expression changes in vulnerable andresistant neurons; and 3) Determine the age-dependent changes in expression, composition and activity of aCa2+-sensitive, dendrite-growth controlling complex in GLUD1 and wt mice. These studies make use of anovel animal model of age-associated hyperglutamatergic states to probe mechanisms of differentialneuronal vulnerability and novel molecular mechanisms of neuronal recovery from stress.
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