Post on 07-Jul-2015
description
Environmental novelty potently prevents impairment ofhippocampal synaptic plasticity by Aβ oligomers
via a β2-adrenergic signaling pathway
Shaomin Li*, Ming Jin*, Dainan Yang,Ting Yang, Thomas Koeglsperger, Hongjun Fu
and Dennis Selkoe
Neuron - March 6, 2013
Center for Neurologic DiseasesBrigham and Women’s Hospital
Harvard Medical School
Expose young mice for 4 weeks (2-6 wk old) to a complex environment ofnovel objects they can explore from 9:00 – 5:00. Change the “toys” each day.
Golgi staining of hippocampus: dendritic spine area, lengthand volume -- but not density – are increased by exposure to EE
Standard housing Enriched environment
EE exposure enhances hippocampal LTP
EE training prevents LTP inhibition by synthetic Aß S26C dimers,and importantly, by Aß dimers isolated directly from AD cortex
Exposure to EE enhances levels of ß2-AR but notß1-AR, DR1, DR2 and other monoamine receptors
EE rescue of Aβ-impaired LTP is β-adrenergic dependent
Membrane
TR
DR2
DR1
b1AR
b2AR
Soluble Aß oligomers induce a time-dependent decrease in ß2-AR levelsin hippocampal membranes -- selectively among monoamine receptors
Prolonged oral administration of a b-adrenergicantagonist prevents EE from rescuing the Aß inhibition of LTP
Prolonged oral administration of the b-adrenergic agonistisoproternol to SH mice mimics the benefit of EE on LTP
Two months of EE in mid-adulthood producessimilar benefit as one month of EE in juvenile mice
Novelty vs. exercise in enhancing hippocampal LTP
Prolonged exposure to novelty contributes more to preventionof Aβ-impaired LTP than does prolonged exercise alone
Use It or Lose It?
Exposing healthy, wild-type mice to a novel environment producesseveral benefits for hippocampal structure and function
These benefits make the EE mice substantially resistant to the acutesynaptic toxicity of soluble Ab oligomers isolated from AD cortex
Among numerous signaling cascades augmented by EE, a b2-adrenergicpathway shows more enhancement than other monoamine receptors
Accordingly, we can mimic the EE resistance to Aß oligomers byprolonged feeding of a b-adrenergic agonist (isoproterenol) to SH mice
Prolonged exposure to a novel environment promotes resistanceto Ab oligomers more effectively than does prolonged exercise
The benefits of EE exposure can be observed not just injuvenile mice but also in middle-aged mice if done longer