A saturation hypothesis to explain both enhanced and impaired learning with enhanced plasticity.

Td Barbara Nguyen-Vu,Carla J Shatz,Surya Ganguli,Hanmi Lee,Grace Q Zhao,Rhea R Kimpo,Jennifer L Raymond,Subhaneil Lahiri

doi:10.7554/elife.20147

Abstract

Across many studies, animals with enhanced synaptic plasticity exhibit either enhanced or impaired learning, raising a conceptual puzzle: how enhanced plasticity can yield opposite learning outcomes? Here, we show that the recent history of experience can determine whether mice with enhanced plasticity exhibit enhanced or impaired learning in response to the same training. Mice with enhanced cerebellar LTD, due to double knockout (DKO) of MHCI H2-Kb/H2-Db (KbDb-/-), exhibited oculomotor learning deficits. However, the same mice exhibited enhanced learning after appropriate pre-training. Theoretical analysis revealed that synapses with history-dependent learning rules could recapitulate the data, and suggested that saturation may be a key factor limiting the ability of enhanced plasticity to enhance learning. Optogenetic stimulation designed to saturate LTD produced the same impairment in WT as observed in DKO mice. Overall, our results suggest that the recent history of activity and the threshold for synaptic plasticity conspire to effect divergent learning outcomes.

Highlights

The prospect that learning might be enhanced by enhancing synaptic plasticity has captured the imagination of many, fueled by reports of super cognition in transgenic mice with enhanced synaptic plasticity (McConnell et al 2009; Tang et al, 1999; Lee and Silva, 2009; Huh et al, 2000; Ito, 2002)
We tested the ability of double knockout (DKO) mice to adaptively modify their vestibulo-ocular reflex (VOR)
Previous work has suggested that LTD contributes selectively to VOR learning when training to increase the amplitude of the VOR is done using high-frequency (!1 Hz) visual-vestibular stimuli, and much less so, if at all, when VOR learning is tested with other training paradigms (Boyden et al, 2006; Hansel et al, 2006; Titley et al, 2010; Schonewille et al, 2011; Aiba et al, 1994; Shibuki et al, 1996; Endo et al, 2009; Feil et al, 2003; Lee et al, 2009; Li et al, 1995; Miyata et al, 2001)

Summary

Introduction

The prospect that learning might be enhanced by enhancing synaptic plasticity has captured the imagination of many, fueled by reports of super cognition in transgenic mice with enhanced synaptic plasticity (McConnell et al 2009; Tang et al, 1999; Lee and Silva, 2009; Huh et al, 2000; Ito, 2002). Rapid progress in our understanding of plasticity at the synaptic level is providing targets for drug development and other molecular strategies for enhancing synaptic plasticity (Lee and Silva, 2009) Optimism for this approach has been tempered by the observation that the enhancement of synaptic plasticity can, in some cases, impair learning (Migaud et al, 1998; Uetani et al, 2000; Hayashi et al, 2004; Cox et al, 2003). There have been no experimental tests of why enhanced synaptic

Methods

Results

Conclusion