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