ROLE OF MTOR-REGULATED AUTOPHAGY IN SPINE PRUNING DEFECTS AND MEMORY IMPAIRMENTS INDUCED BY BINGE-LIKE ETHANOL TREATMENT IN ADOLESCENT MICE

Introduction: Adolescence is a critical period for brain maturation, characterized by significant remodeling and changes in synaptic plasticity and neural connectivity. Synaptic pruning, the selective elimination of synapses, is essential for neurocircuitry refinement. Autophagy, regulated by the mammalian target of rapamycin (mTOR), plays a key role in synaptic development and plasticity. Alcohol abuse during adolescence can induce neuroinflammation, synaptic and myelin alterations, neural damage, and behavioral impairments. Given mTOR's involvement in both autophagy and synaptic plasticity, this study aims to evaluate whether binge ethanol treatment during adolescence induces synaptic and cognitive dysfunctions and if mTOR inhibition with rapamycin can restore these effects.

Key Findings: The study utilized C57BL/6 adolescent mice, administering ethanol to mimic binge drinking. Binge ethanol treatment altered the density and morphology of dendritic spines, leading to learning and memory impairments, and changes in transcription factor CREB phosphorylation and miRNAs levels. Rapamycin administration prior to ethanol exposure restored the synaptic and cognitive deficits, supporting the critical role of mTOR/autophagy dysfunction in these alterations.

Innovative Tools: Researchers employed a variety of methods to analyze the effects of ethanol and rapamycin on synaptic plasticity and cognitive functions. Behavioral assessments included the Hebb-Williams maze, novel object recognition, and passive avoidance tests. Biochemical analyses focused on mTOR phosphorylation, dendritic spine morphology, CREB phosphorylation, and miRNA expression. Confocal imaging and Western blotting provided detailed insights into the molecular mechanisms underlying the observed behavioral changes.

Behavioral Assessments: Ethanol-treated mice displayed significant memory and learning impairments in the Hebb-Williams maze, novel object recognition, and passive avoidance tests. These cognitive deficits were characterized by increased time to reach goals, reduced discrimination index, and shorter latency in avoidance tasks. Rapamycin treatment restored performance across these tasks, indicating its potential to mitigate ethanol-induced cognitive dysfunctions.

Biochemical Analysis: Ethanol exposure led to increased mTOR phosphorylation, altered spine density and morphology, decreased CREB phosphorylation, and elevated levels of pro-inflammatory miRNAs (miR-155-5p, miR-96-5p, miR-182-5p). Rapamycin administration reversed these biochemical changes, normalizing mTOR activity, spine morphology, CREB phosphorylation, and miRNA expression. This suggests that rapamycin's protective effects are mediated through the modulation of mTOR-regulated autophagy and inflammatory pathways.

Conclusions: This study demonstrates that binge-like ethanol treatment during adolescence disrupts synaptic pruning and cognitive functions through mTOR-regulated autophagy dysfunction. Rapamycin effectively restores these deficits, highlighting its therapeutic potential for treating alcohol-induced neurodevelopmental disorders. Further research is needed to explore rapamycin's long-term safety and efficacy in human subjects, particularly adolescents.

Join the Discussion: We invite you to share your thoughts on the potential of mTOR inhibitors like rapamycin as therapeutic agents for addressing alcohol-induced cognitive impairments during adolescence. How might these findings influence future treatment protocols for substance abuse? What additional mechanisms might be involved in mTOR-regulated autophagy and synaptic plasticity? Join the conversation in the comments section below and share your insights and ideas.

Credit:

Image: Here

Original Research: The original research, "Role of mTOR-regulated autophagy in spine pruning defects and memory impairments induced by binge-like ethanol treatment in adolescent mice," can be found on PubMed here.