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The human VGLUT3-pT8I mutation elicits uneven striatal DA signaling, food or drug maladaptive consumption in male mice

Medicine and Health

The human VGLUT3-pT8I mutation elicits uneven striatal DA signaling, food or drug maladaptive consumption in male mice

M. Favier, E. M. Garcia, et al.

This groundbreaking research by Mathieu Favier and colleagues delves into the role of VGLUT3 in cholinergic striatal interneurons, exploring its impact on addiction and eating disorders. Discover how the VGLUT3-p.T8I variant leads to altered dopaminergic transmission and how enhancing acetylcholine could reverse self-starvation behaviors. A must-listen for anyone interested in the neurochemical underpinnings of substance use and food habits!

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Playback language: English
Introduction
Persistent habitual behaviors and compulsion are common features of substance use disorders (SUDs) and eating disorders (EDs). The dorsal striatum is crucial for the transition from reward-guided behaviors to automatic habitual behaviors and, ultimately, compulsion. Cholinergic striatal interneurons (ChIs) play a pivotal role in both normal and pathological states. ChIs, expressing both vesicular acetylcholine transporter (VAChT) and VGLUT3, regulate the striatal network using both acetylcholine (ACh) and glutamate. VGLUT3-dependent glutamate enhances ACh vesicular accumulation and cholinergic tone. In mice, silencing ACh release from ChIs facilitates habit formation and vulnerability to maladaptive eating, while VGLUT3 ablation increases anxiety and sensitivity to cocaine. ACh from ChIs stimulates dopamine (DA) efflux, while glutamate inhibits it, a dual regulation observed in the nucleus accumbens and dorsomedial striatum (DMS) but not the dorsolateral striatum (DLS). Sakae et al. reported increased rare VGLUT3 variants in SUD patients, including the heterozygous *SLC17A8* p.T8I missense mutation. This study investigates the molecular, cellular, and behavioral consequences of the VGLUT3-p.T8I variant using a knock-in mouse line (*VGLUT3<sup>T8I/T8I</sup>*).
Literature Review
The literature review section extensively cites prior research on the roles of ChIs, VGLUT3, and DA signaling in habit formation, SUDs, and EDs. Studies on VAChT deletion in ChIs, showing facilitation of habit formation and maladaptive eating, are highlighted. Conversely, VGLUT3 ablation studies are presented, demonstrating increased anxiety and cocaine sensitivity. The dual and opposing effects of ACh and glutamate co-transmission on DA release in specific striatal regions (DMS and DLS) are discussed. Finally, previous findings on the increased frequency of VGLUT3 variants, particularly p.T8I, in SUD patients are reviewed, suggesting a potential link between VGLUT3 genetic variations and these disorders.
Methodology
The study employed both human genetic analysis and animal models. Human genetic analysis involved screening for *SLC17A8* gene mutations in two independent samples: an eating disorders (EDs) sample and a substance use disorders (SUDs) sample. The EDs sample included healthy controls and patients with anorexia nervosa, bulimia nervosa, and EDNOS. The SUDs sample comprised outpatients with SUDs. Extensive phenotyping was conducted using structured assessment instruments. DNA was extracted from blood samples, and genotyping was performed. Ancestry was determined by self-report or genotyping. Animal studies used a knock-in mouse line (*VGLUT3<sup>T8I/T8I</sup>*) expressing the p.T8I mutation. Molecular and cellular investigations involved immunofluorescence, immunoautoradiography, STED microscopy, and electrophysiological recordings. Behavioral experiments assessed locomotor activity, anxiety, cocaine self-administration, habit formation, binge-like sucrose overconsumption, and activity-based anorexia (ABA). Statistical analyses included t-tests, ANOVAs, and other appropriate methods.
Key Findings
Genetic analysis replicated the finding of the VGLUT3-p.T8I variant in new patient samples, with a higher frequency in patients of African descent. In *VGLUT3<sup>T8I/T8I</sup>* male mice, the p.T8I mutation did not affect VGLUT3 expression, glutamate vesicular accumulation, or glutamate release. However, it blunted vesicular synergy, decreasing striatal ACh release and DA release in the DMS but not the DLS. Behaviorally, this uneven DA transmission facilitated habit formation, increased cocaine-seeking relapse, and promoted maladaptive eating in binge-like sucrose overconsumption and ABA models. Importantly, donepezil, an acetylcholinesterase inhibitor, reversed the self-starvation phenotype in *VGLUT3<sup>T8I/T8I</sup>* mice. These results suggest that the p.T8I mutation increases vulnerability to SUDs and EDs, with unbalanced dopaminergic transmission in the dorsal striatum as a potential common mechanism.
Discussion
The study's findings support the causal link between the VGLUT3-p.T8I variant and increased vulnerability to both SUDs and EDs. The observed reduction in vesicular synergy and subsequent decrease in ACh and DA signaling in the DMS, but not DLS, provide a potential mechanism underlying the behavioral phenotypes. The asymmetric pattern of DA signaling in the dorsal striatum likely promotes DLS/putamen activity and habit formation. The study highlights the importance of ChIs and ACh/glutamate co-transmission in the balance between goal-directed behaviors and habits. The results are discussed in the context of similar findings in other rodent models with altered α5nAChR function. The possibility that imbalanced striatal DA transmission is a common mechanism across various psychiatric disorders with a compulsive component is proposed. The potential repositioning of donepezil as a treatment for EDs based on the observed reversal of self-starvation in the mouse model is suggested.
Conclusion
The study demonstrates that the VGLUT3-p.T8I mutation leads to an imbalance in striatal dopamine signaling, increasing susceptibility to both SUDs and EDs. The mouse model recapitulates key pathological features of these disorders, offering a valuable tool for future research. Increasing cholinergic tone, potentially using donepezil, may offer a therapeutic avenue for these disorders. Future research should focus on elucidating the precise molecular mechanisms of vesicular synergy and investigating the generalizability of these findings to other genetic variants and patient populations. Clinical trials exploring the efficacy and safety of donepezil in ED patients are warranted.
Limitations
The study primarily focused on male mice, and further investigation is needed to assess the effects of the p.T8I variant in females. The human genetic analysis involved relatively small sample sizes, particularly for specific subgroups, requiring further validation in larger cohorts. While the mouse model provides valuable insights, extrapolating the findings directly to humans requires caution, considering the complexity of human genetics and environmental factors. The observed higher frequency of p.T8I in patients with African ancestry may be linked to both genetic and environmental factors and deserves further investigation.
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