Modulation of long interspersed nuclear element-1 in the mouse hippocampus during maturation

Abstract

Background: Retrotransposition of long interspersed nuclear element-1 (L1-RTP) is proposed to contribute to central nervous system (CNS) plasticity by inducing mosaicism of neuronal cells. Clinical studies have identified increased L1 copy numbers in the brains of patients with psychiatric disorders. These observations implicate that L1-RTP is important for neurogenesis and that its deregulation represents a risk factor for mental disorders. However, no supportive evidence is available for understanding the importance of L1-RTP in CNS function. Findings: To explore the physiological role of L1-RTP in CNS, we examined the L1 copy number during maturation. Interestingly, the L1 copy number increased after birth in the mouse hippocampus, but not the frontal lobe, with maximal copy numbers found in 8-week-old mice. This age-dependent L1 increase was abolished by administration of a reverse-transcriptase inhibitor, stavudine (d4T), which showed no toxic effects. Notably, the age-dependent L1 increase was attenuated by post-weaning social isolation (SI) stress, a well-known intervention for inducing psychiatric disorders in mice, or deletion of the NR2A gene that encodes a subunit of the glutamate receptor. Moreover, the negative effects of SI stress on L1-RTP were partially restored by environmental enrichment with voluntary running, but not by fluoxetine, a commonly used antipsychiatric drug. Finally, behavioral experiments revealed that learning memory was defective in d4T-treated mice, which was similarly observed in mice raised under SI stress. Conclusion: We detected the modulation of L1-RTP in the hippocampus during maturation of the CNS. In a recent study, we demonstrated that stimulants such as methamphetamine and cocaine were active in the induction of L1-RTP in neuronal cells, and previous studies have shown that NR2A-deficient mice are susceptible to mental abnormality. Herein, our data support the notion that the age-dependent modulation of L1-RTP is involved in genome differentiation in the hippocampus, and that modulation defects are linked to the development of psychiatric disorders.

Long INterspersed element‐1 mobility as a sensor of environmental stresses

“…Ueno et al . (Ueno et al ., ) investigated the effect of post‐weaning social isolation (SI) stress on L1 activity in mice at different ages. SI is a commonly used rodent model of environmental early life stress and consists of deprivation of social interactions by housing rat or mouse pups in individual cages from the first day of weaning from the dam.…”

“…The same analyses were carried out on mice exposed to environmental enrichment consisting in cage with a Fast‐Trac Amber running disc and Red Mouse Igloo (K3327) for voluntary running (the average running distance was 23.28 km/day). Interestingly, environmental enrichment restored the SI‐induced down modulation of the L1 copy numbers (Ueno et al ., ).…”

Mouse retrotransposons: sequence structure, evolutionary age, genomic distribution and function

“…The L1 family is deeply involved in biological phenomena, with or without retrotranspositional activity. For instance, their transcription is involved in developmental programs (Muotri et al, 2005;Fadloun et al, 2013;Blythe et al, 2021), X-chromosome inactivation (Chow et al, 2010) and many diseases (Miki et al, 1992;Morse et al, 1988;Ueno et al, 2016;Song et al, 2021;Takahashi et al, 2022). A correlation between LINE density and regional GC content is observed, as low-GC regions harbor more LINE copies (Fig.…”

Social isolation-induced transcriptomic changes in mouse hippocampus impact the synapse and show convergence with human genetic risk for neurodevelopmental phenotypes

“…The use of rodent models of SI to investigate behaviour is common. Mice exposed to post-weaning SI tend to experience increased anxiety [9][10][11][12][13][14][15][16], increased depressive-like behaviour [11,13], decreased cognitive ability [13,14,[17][18][19], increased aggression [12,20] and decreased sociability [10,21] when compared to group-housed controls. Some of the neurobiology relevant to SI-induced behaviour in rodents has been mapped [22].…”