Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated...

Area of Science:

• Neuroscience
• Genetics
• Pharmacology

Background:

• The serotonin transporter (SERT, SLC6A4) is crucial for treating neurobehavioral disorders like anxiety, depression, and OCD.
• Naturally occurring genetic variations in SERT influence its function and are linked to various disorders.

Purpose of the Study:

• To investigate the impact of SERT genetic polymorphisms on phenotypes using mouse models.
• To identify specific anatomical, biochemical, and behavioral traits affected by SERT variation.

Main Methods:

• Utilized recombinant inbred (RI) mouse lines (BXD) with distinct SERT haplotypes (GK vs. ER).
• Conducted ex vivo synaptosomal and in vitro heterologous expression studies to assess SERT function.
• Employed experimental and in silico approaches, including SERT knockout mice, for comprehensive analysis.

Main Results:

• Identified reduced 5-HT uptake associated with the GK SERT variant.
• Linked SERT variation to phenotypes affecting alcohol consumption and dopamine signaling.
• Demonstrated SERT-dependent 5-HT signaling as a key regulator of midbrain iron homeostasis, influencing dopamine phenotypes.

Conclusions:

• SERT genetic variation significantly impacts multiple system-level phenotypes.
• SERT's role in iron homeostasis is a critical link to dopamine regulation.
• Integrated approaches using RI lines effectively elucidate the functional consequences of gene variation.