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

Across many studies, genetically modified animals with enhanced synaptic plasticity exhibit either enhanced or impaired learning, raising a fundamental conceptual puzzle: how can the enhancement of plasticity yield these 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 genetic knockout (DKO) of Class-I major histocompatibility molecules H2-Kb and H2-Db (KbDb-/-), exhibited oculomotor learning deficits. However, the same mice exhibited enhanced oculomotor learning after the appropriate pre-training. Theoretical analysis revealed that complex synapses with history-dependent learning rules could recapitulate our experimental results, and suggested that saturation may be a key factor limiting the ability of enhanced plasticity to support enhanced learning. Consistent with this, optogenetic stimulation designed to saturate cerebellar LTD produced the same, specific learning impairment in wildtype mice that was observed in DKO mice without such stimulation. Overall, our results suggest that the recent history of activity in a circuit and the threshold for synaptic plasticity conspire to effect divergent learning outcomes. [ABSTRACT FROM AUTHOR]