A Birst of LINE‐1 and IAP Retrotransposon Expression in the Mouse Brain Following Acute Behavioral Stress

Abstract

Retrotransposons belong to mobile genetic elements that account for up to ~40% of the human genome and are propagated by being transcribed into RNA, then reverse-transcribed into DNA and inserted into a new site in the genome. Physiological regulation and possible effects of such retrotranspositions in cells of an adult organism are largely unknown. In the mouse genome LINE-1 (L1) and intracisternal A particle (IAP) are among functional and the most transpositionally active retrotransposons, capable of self-copying and insertion into DNA. Recent findings indicate that L1 is active in neuronal precursor cells during differentiation, and its de novo insertions can change expression of neuron-specific genes and cause somatic mosaicism in the adult brain. Furthermore, clinical studies have identified increased L1 expression and copy numbers in the brain of patients with psychiatric disorders. However, there has been limited understanding whether such retrotranspositions happen in the adult brain, when and how they occur, and what is their role in the CNS function. In our experiments we test the hypothesis that retrotranspositions can be activated in the brain by behavioral and particularly cognitive stimuli and that this process can influence adaptive neural plasticity. In previous experiments we showed an increase in L1 DNA copy number in hippocampus, frontal cortex and cerebellum of the mouse brain, but not in the muscular and testicular tissues after a prolonged stress. In this study we tested whether an acute stress can lead to L1 and IAP mRNA expression changes in the mouse brain. We used male C57Bl/6 mice at the age of 5 months. To assess the effect of acute stress, the animals were subjected to immobilization for 30 minutes or 2 hours. The frontal cortex and hippocampus were taken for qPCR studies. Compared to naive home cage controls, mice that underwent 30 min immobilization had significantly increased mRNA levels of L1 and IAP in frontal cortex and L1 in hippocampus. After 2 hours of immobilization IAP mRNA levels were significantly increased in both frontal cortex and hippocampus compare to control group. Therefore, L1 expression is up-regulated prior to IAP expression, perhaps, due to the differences in the transcription regulation of these two elements. Thus, we have shown that expression of both L1 and IAP is rapidly induced in several brain regions by behavioral stress. Since our previous data demonstrated a stress-induced increase of L1 and IAP DNA copy number in the same brain structures, together it points to a full retrotransposition event. We further suggest that reverse transcription involved in L1 and IAP retrotransposition by behavioral stimuli may also contribute to long-term plasticity and memory formation in the nervous system.