FK506-Binding Protein 12.6/1b, a Negative Regulator of [Ca 2+ ], Rescues Memory and Restores Genomic Regulation in the Hippocampus of Aging Rats

Hippocampal overexpression of FK506-binding protein 12.6/1b ( ), a negative regulator of ryanodine receptor Ca release, reverses aging-induced memory impairment and neuronal Ca dysregulation. Here, we tested the hypothesis that also can protect downstream transcriptional networks from aging-induced dysregulation. We gave hippocampal microinjections of -expressing viral vector to male rats at either 13 months of age (long-term, LT) or 19 months of age (short-term, ST) and tested memory performance in the Morris water maze at 21 months of age. Aged rats treated ST or LT with substantially outperformed age-matched vector controls and performed similarly to each other and young controls (YCs). Transcriptional profiling in the same animals identified 2342 genes with hippocampal expression that was upregulated/downregulated in aged controls (ACs) compared with YCs (the aging effect). Of these aging-dependent genes, 876 (37%) also showed altered expression in aged -treated rats compared with ACs, with restoring expression of essentially all such genes (872/876, 99.5%) in the direction opposite the aging effect and closer to levels in YCs. This inverse relationship between the aging and effects suggests that the aging effects arise from deficiency. Functional category analysis revealed that genes downregulated with aging and restored by were associated predominantly with diverse brain structure categories, including cytoskeleton, membrane channels, and extracellular region. Conversely, genes upregulated with aging but not restored by associated primarily with glial-neuroinflammatory, ribosomal, and lysosomal categories. Immunohistochemistry confirmed aging-induced rarefaction and -mediated restoration of neuronal microtubular structure. Therefore, a previously unrecognized genomic network modulating diverse brain structural processes is dysregulated by aging and restored by overexpression. Previously, we found that hippocampal overexpression of FK506-binding protein 12.6/1b ( ), a negative regulator of intracellular Ca responses, reverses both aging-related Ca dysregulation and cognitive impairment. Here, we tested whether hippocampal overexpression also counteracts aging changes in gene transcriptional networks. In addition to reducing memory deficits in aged rats, selectively counteracted aging-induced expression changes in 37% of aging-dependent genes, with cytoskeletal and extracellular structure categories highly associated with the -rescued genes. Our result