Not a deficit, just different - Prepulse inhibition disruptions in autism depend on startle stimulus intensities

Abstract

Sensory processing disruptions are a core symptom of autism spectrum disorder (ASD) and other neurological disorders. The acoustic startle response and prepulse inhibition (PPI) are common metrics used to assess disruptions in sensory processing and sensorimotor gating in clinical studies and animal models. However, often there are inconsistent findings on ASD-related PPI deficits across different studies. Here, we used a novel method for assessing changes in startle and PPI in rodents, using the Cntnap2 knockout (KO) rat model for neurodevelopmental disorder/ASD that has consistently shown PPI disruptions in past studies. We discovered that not only sex and prepulse intensity but also the intensity of the startle stimulus, profoundly impacts whether PPI deficits are evident in the Cntnap2 KO rat or not. We show that rats do not universally exhibit a PPI deficit, instead impaired PPI is contingent on specific testing conditions. Notably, at lower startle stimulus intensities, Cntnap2 KO rats not only demonstrated intact PPI but also exhibited evidence of enhanced PPI compared to their wildtype counterparts. This finding emphasizes the importance of considering specific testing conditions when evaluating startle and PPI in the context of ASD and other neuropsychiatric conditions and might explain some of the inconsistencies between different studies.

Significance Statement The present study extends traditional approaches to evaluating sensory processing using startle and PPI by showing that startle and PPI disruptions are contingent upon specific testing parameters. Compared to conventional PPI testing where only prepulse levels and interstimulus intervals might vary, we here show that animals consistently reported to have PPI deficits do not have a general sensorimotor gating deficit, but intact, and potentially even enhanced, PPI at lower startle intensities. This has a widespread impact on PPI testing and the interpretation of PPI results, given the broad use in animal models of various neurodevelopmental conditions, alongside the translational relevance to clinical settings.