Molecular Mechanisms of Environmental Enrichment: Impairments in Akt/GSK3b, Neurotrophin-3 and CREB Signaling

YUAN-SHIH HU; NANCY LONG; GUSTAVO PIGINO; SCOTT T. BRADY; ORLY LAZAROV

PLOS ONE

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2013

1932-6203

Experience of mice in a complex environment enhances neurogenesis and synaptic plasticity in the hippocampus of wildtype and transgenic mice harboring familial Alzheimer?s disease (FAD)-linked APPswe/PS1DE9. In FAD mice, this experiencealso reduces levels of tau hyperphosphorylation and oligomeric b-amyloid. Although environmental enrichment hassignificant effects on brain plasticity and neuropathology, the molecular mechanisms underlying these effects are unknown.Here we show that environmental enrichment upregulates the Akt pathway, leading to the downregulation of glycogensynthase kinase 3b (GSK3b), in wild type but not FAD mice. Several neurotrophic signaling pathways are activated in thehippocampus of both wild type and FAD mice, including brain derived neurotrophic factor (BDNF) and nerve growth factor(NGF), and this increase is accompanied by the upregulation of the BDNF receptor, tyrosine kinase B (TrkB). Interestingly,neurotrophin-3 (NT-3) is upregulated in the brains of wild type mice but not FAD mice, while insulin growth factor-1 (IGF-1)is upregulated exclusively in the brains of FAD mice. Upregulation of neurotrophins is accompanied by the increase of NMethyl-D-aspartic acid (NMDA) receptors in the hippocampus following environmental enrichment. Most importantly, weobserved a significant increase in levels of cAMP response element- binding (CREB) transcripts in the hippocampus of wildtype and FAD mice following environmental enrichment. However, CREB phosphorylation, a critical step for the initiation oflearning and memory-required gene transcription, takes place in the hippocampus of wild type but not of FAD mice. Theseresults suggest that experience of wild type mice in a complex environmental upregulates critical signaling that play amajor role in learning and memory in the hippocampus. However, in FAD mice, some of these pathways are impaired andcannot be rescued by environmental enrichment.