A novel mouse genetic model for post-traumatic stress disorder

Abstract

Rationale/statement of the problem : Post-traumatic stress disorder (PTSD) arises from the interaction of genetic and environmental factors. Thus, a better understanding of the molecular etiology of PTSD would be greatly facilitated by the development of animal models that explore gene×environment interaction in the context of traumatic stress. To this end, we have identified a new mouse genetic model for stress vulnerability that may provide novel insight into the neurobiology of PTSD. Our studies focus on mice that are deficient for TIA-1, a prion-related RNA binding protein that regulates the expression of multiple target genes in the mammalian brain. Methods : TIA-1 KO mice and wild-type littermates are generated from TIA-1 heterozygous crosses. All behavioral (fear conditioning, open field, elevated-plus maze, forced-swim test) and electrophysiological (hippocampal field recordings) experiments are conducted in accordance with standard protocols. Results : Under baseline conditions, TIA-1 KO mice are indistinguishable from wild-type controls in all behavioral and neuroendocrinological measures evaluated thus far. However, several weeks after exposure to contextual fear conditioning, TIA-1 KO mice demonstrate increased anxiety and despair-like behavior, as well as abnormal glucocorticoid production. Moreover, these phenotypes are observed predominantly in female animals. Electrophysiological studies reveal aberrant synaptic plasticity in the ventral hippocampus of knockout animals in response to corticosterone treatment, consistent with a critical role for TIA-1 in normal emotional memory formation in the hippocampus during stress. Finally, molecular data suggest that TIA-1 may regulate alternative splicing of the glucocorticoid receptor, which is known to be important for both hypothalamic–pituitary–adrenal (HPA) axis function and hippocampal synaptic plasticity during stress. Conclusion : TIA-1 KO mice recapitulate several key features of chronic PTSD observed in humans. Thus, our studies demonstrate that TIA-1-deficient mice represent a useful model in the study of gene×environment interaction during traumatic stress, and may contribute to our knowledge of the molecular basis of PTSD. Finally, because individuals with PTSD are also susceptible to substance abuse, we, therefore, discuss the utility of TIA-1 knockout mice in the study of PTSD and comorbid substance use disorders.

Keywords

• genetic model
• PTSD
• mice
• substance use
• anxiety