★ Two forms of startle plasticity independently predict cognitive performance in mice. ★ Prepulse inhibition at low prepulse positively correlates with working memory scores. ★ Strong overall startle habituation is associated with superior memory retention. ★ The predictive value of prepulse inhibition warrants further investigation.
Prepulse inhibition (PPI) of the acoustic startle reflex refers to the attenuation of the startle response to an intense pulse stimulus when it is shortly preceded by a weak non-startling prepulse stimulus. It is a well-established high-throughput translational measure of pre-attentive sensory gating, and its impairment is detected in several neuropsychiatric diseases including schizophrenia. It has been hypothesized that PPI might be associated with, or predictive of, cognitive deficiency in such diseases, and therefore provide an efficient assay for screening drugs with potential pro-cognitive efficacy. Free from any predetermined disease model, the present study evaluated in a homogeneous cohort of inbred C57BL/6 mice the presence of a statistical link between PPI expression and cognitive performance. Performance indices in a spatial reference memory test and a working memory test conducted in the Morris water maze, and contextual fear conditioning were correlated against pre-existing baseline PPI expression. A specific correlative link between working memory and PPI induced by weak (but not strong) prepulse was revealed. In addition, a correlation between habituation of the startle reflex and reference memory was identified for the first time: a stronger overt habituation effect was associated with superior spatial search accuracy. The PPI paradigm thus provides two independent predictors of dissociable cognitive traits in normal C57BL/6 mice; and they might serve as potential markers for high-throughput evaluation of potential cognitive enhancers, especially in the context of schizophrenia where deficits in startle habituation and PPI co-exist.