Variable degrees of memory loss occur during aging, even in otherwise healthy people. Attempts to counteract age-related memory loss (ARML) will benefit from knowledge of the brain mechanisms involved. Many proteins vary in function according to the extent to which phosphate groups are added by kinases or removed by phosphatases. Imbalance in these enzymatic activities can disrupt intracellular signaling pathways necessary to mediate changes in gene expression and cellular function that are required for learning and memory to occur. Protein phosphatase (PP) 2A is the primary enzyme acting on the extracellular receptor kinase (ERK) class of mitogen-activated protein kinases (MAPK). The type 5 metabotropic glutamate neurotransmitter receptor (mGluR5) forms a complex with active PP2A along the neuronal plasma membrane. This complex dissociates when glutamate binds to mGluR5 receptors, inactivating PP2A and allowing the accumulation of the activated, phosphorylated forms of ERK (pERKs). These stimulate levels of nuclear phosphoproteins, such as Elk-1, to form DNA-binding complexes that activate the expression of several genes. Interruption of this signal transduction cascade impairs learning and memory. Reduction in the number of functional mGluR5 receptors, and pERK activity, during aging suggest that ARML may represent a failure of integrated neuronal synaptic transmission to generate a threshold level of intracellular pERK necessary for the expression of memory-related genes. To bypass the lost receptors and boost pERK levels, we propose using a gene delivery technique to overexpress I1PP2A, a natural protein inhibitor of PP2A. A vector based on adeno-associated virus (AAV) will be used for bilateral hippocampal injections in 26-month rats exhibiting an age-related impairment in learning and memory performance. Acquisition and retention of hippocampal-dependent and independent maze tasks will be re-evaluated 4 weeks after I1PP2A or control gene transfer. Hippocampal tissue harvested after gene transfer and behavioral reassessment will be used for histological evaluation of transgene expression. We hypothesize that treatment with I1PP2A will normalize age-impairment. Further, we predict that the improvement in learning and memory will correspond with decreased PP2A activity, increased levels of pERK, and upregulation of downstream targets pElk-1, pCREB, c-fos, zif/268 and arc. PUBLIC HEALTH RELEVANCE: Many people experience a decrease in memory function as they age. The proposed project will test how disruption of one biochemical signaling system in the brain might account for a reduced ability for aged rats to learn or remember. The results could lead to new pharmacological targets for treating age-related memory dysfunction.