Developmental Exposure to Psychostimulant Primes Activity‐dependent Gene Induction in Frontal Cortex

Abstract

Perinatal neurodevelopment involves extensive formation of neural connections and onset of activity-dependent gene expression for synaptic function and plasticity. Exposure to psychostimulants at this stage imposes significant risks for developing cognitive and affective disorders later in life. However, how developmental exposure to psychostimulants may induce long lasting molecular changes relevant to neural circuit function remains incompletely understood. In this study, we investigated the impacts of psychostimulant amphetamine on the activity-dependent induction of synaptic adaptor molecule Arc in the frontal cortex of neonatal mice. We found that transient exposure to amphetamine not only amplifies activity-dependent Arc mRNA expression immediately, but also potentiates subsequent induction of Arc mRNA in the absence of amphetamine. This priming effect is associated with a rapid and persistent increase of histone mono-methylation (H3K4me1), a marker for transcriptionally permissive chromatin, at the Arc locus, but not any long-lasting change in the phosphorylation of upstream transcription factor CREB. Furthermore, the increase of H3K4me1 at the Arc locus requires dopamine receptor signaling, and the priming of Arc expression correlates with the dopaminergic innervation pattern in the frontal cortex. Together, our results demonstrate that developmental exposure to psychostimulant amphetamine induces long-lasting chromatin changes and primes activity-dependent Arc gene induction. These findings reveal the molecular targets of psychostimulant during perinatal development that may contribute to long-term psychiatric risks.

Synaptic Formation, Neural Circuits and Neurodevelopmental Disorders Controlled by Signaling, Translation, and Epigenetic Regulation

“…In that study, Arc (an immediate early gene that responds to neuronal activation) was used as a reporter to show the priming effect of amphetamine for rapid and persistent enhancement of histone monomethylation (H3K4me1). The results suggest that developmental exposure to psychostimulants induces long‐lasting changes to chromatin, which can still enhance neuronal responses at later stages even in the absence of psychostimulants, and also suggests how early exposure to psychoactive and addictive drugs increase the risk of psychiatric disorders (Ye et al ., ).…”

“…Epigenetic regulation is likely to be involved in such long-lasting effects. Indeed, Ye and colleagues demonstrated that amphetamine treatment enhances neuronal activity in response to immediate stimulation, as well as subsequent stimulation without amphetamine treatment (Ye et al, 2018). In that study, Arc (an immediate early gene that responds to neuronal activation) was used as a reporter to show the priming effect of amphetamine for rapid and persistent enhancement of histone monomethylation (H3K4me1).…”

A sex difference in mouse dopaminergic projections from the midbrain to basolateral amygdala

“…Images were processed using a custom-written MATLAB (MathWorks) script with three subfunctions-one for detecting axons in the red channel of BLA images, one for detecting boutons in the green channel of BLA images, and one for detecting cells in both the red and green channels of VTA images. The axon detection function used Hessian filters to highlight line-like structures in the photomicrographs [56][57][58], and the filtered images were thresholded at 5 standard deviations (10× Olympus images) or 7 SD (25× Zeiss images) above image background in accordance with visual inspection. The detected line segments were then skeletonized to one pixel-width, so total pixel output would represent axon length.…”