Genetic Perturbation of TIA1 Reveals a Physiological Role in Fear Memory

Abstract

Summary: TIA1 is a prion-related RNA-binding protein whose capacity to form various types of intracellular aggregates has been implicated in neurodegenerative disease. However, its role in normal brain function is poorly understood. Here, we show that TIA1 bidirectionally modulates stress-dependent synaptic plasticity in the hippocampus, a brain region involved in fear memory and olfactory discrimination learning. At the behavioral level, conditioned odor avoidance is potentiated by TIA1 deletion, whereas overexpression of TIA1 in the ventral hippocampus inhibits both contextual fear memory and avoidance. However, the latter genetic manipulations have little impact on other hippocampus-dependent tasks. Transcriptional profiling indicates that TIA1 presides over a large network of immune system genes with modulatory roles in synaptic plasticity and long-term memory. Our results uncover a physiological and partly sex-dependent function for TIA1 in fear memory and may provide molecular insight into stress-related psychiatric conditions, such as post-traumatic stress disorder (PTSD) and anxiety. : Rayman et al. show that TIA1 regulates avoidance behavior and fear memory in a partly sex-dependent manner in mice and controls a vast network of immune system genes with overlapping roles in synaptic plasticity and behavior. These findings may be relevant to fear-related psychopathologies, such as PTSD and anxiety. Keywords: TIA1, avoidance behavior, fear memory, contextual fear conditioning, stress, ventral hippocampus, long-term potentiation, glucocorticoids, gene-environment interaction, sex differences