Slc17a6, also known as Vglut2, is a gene encoding vesicular glutamate transporter 2. It is crucial for transporting glutamate into synaptic vesicles, enabling glutamatergic neurotransmission, which is involved in various neural activities [1,2,3,6,7]. Glutamatergic neurotransmission is a key pathway in the nervous system, playing a vital role in synaptic transmission and plasticity, thus having overall biological importance for neural function. Genetic models, such as those in nematodes and mice, are valuable for studying its functions [1].

In mice, conditional knockout (cKO) of Slc17a6/Vglut2 specifically in the subthalamic nucleus leads to reduced postsynaptic activity, cell loss, and structural disorganization in this region. This is followed by increased motor activity and decreased sugar consumption, demonstrating its role in motor and reward-related behaviors [5]. Also, knocking out CPEB2 in VGLUT2-expressing glutamatergic neurons impairs hippocampus-dependent memory consolidation in mice, and presynaptic-specific ablation of Cpeb2 in VGLUT2-dominated afferents attenuates protein-synthesis-dependent long-term potentiation (LTP). Blocking activity-induced axonal Slc17a6 translation diminishes the releasable pool of VGLUT2-containing synaptic vesicles, suggesting Slc17a6's importance in presynaptic plasticity and memory-related processes [7].

In conclusion, Slc17a6 is essential for glutamatergic neurotransmission, influencing neural activities like synaptic plasticity, motor function, and reward-related behaviors. Mouse models, especially KO/CKO models, have revealed its role in conditions potentially related to Parkinson's disease, as indicated by sex-specific PD-associated methylation changes in SLC17A6 in cortical neurons [4], and in memory-related disorders through its impact on presynaptic plasticity. These models contribute significantly to understanding the functions of Slc17a6 in normal and disease-related biological processes.

References:

1. Serrano-Saiz, Esther, Vogt, Merly C, Levy, Sagi, Grant, Barth D, Hobert, Oliver. 2019. SLC17A6/7/8 Vesicular Glutamate Transporter Homologs in Nematodes. In Genetics, 214, 163-178. doi:10.1534/genetics.119.302855. https://pubmed.ncbi.nlm.nih.gov/31776169/

2. Azcorra, Maite, Gaertner, Zachary, Davidson, Connor, Awatramani, Rajeshwar, Dombeck, Daniel A. 2023. Unique functional responses differentially map onto genetic subtypes of dopamine neurons. In Nature neuroscience, 26, 1762-1774. doi:10.1038/s41593-023-01401-9. https://pubmed.ncbi.nlm.nih.gov/37537242/

3. de Jong, Johannes W, Afjei, Seyedeh Atiyeh, Pollak Dorocic, Iskra, Deisseroth, Karl, Lammel, Stephan. 2018. A Neural Circuit Mechanism for Encoding Aversive Stimuli in the Mesolimbic Dopamine System. In Neuron, 101, 133-151.e7. doi:10.1016/j.neuron.2018.11.005. https://pubmed.ncbi.nlm.nih.gov/30503173/

4. Kochmanski, Joseph, Kuhn, Nathan C, Bernstein, Alison I. 2022. Parkinson's disease-associated, sex-specific changes in DNA methylation at PARK7 (DJ-1), SLC17A6 (VGLUT2), PTPRN2 (IA-2β), and NR4A2 (NURR1) in cortical neurons. In NPJ Parkinson's disease, 8, 120. doi:10.1038/s41531-022-00355-2. https://pubmed.ncbi.nlm.nih.gov/36151217/

5. Schweizer, Nadine, Viereckel, Thomas, Smith-Anttila, Casey J A, Dumas, Sylvie, Wallén-Mackenzie, Åsa. 2016. Reduced Vglut2/Slc17a6 Gene Expression Levels throughout the Mouse Subthalamic Nucleus Cause Cell Loss and Structural Disorganization Followed by Increased Motor Activity and Decreased Sugar Consumption. In eNeuro, 3, . doi:. https://pubmed.ncbi.nlm.nih.gov/27699212/

6. Gasparini, Silvia, Howland, Jacob M, Thatcher, Andrew J, Geerling, Joel C. 2020. Central afferents to the nucleus of the solitary tract in rats and mice. In The Journal of comparative neurology, 528, 2708-2728. doi:10.1002/cne.24927. https://pubmed.ncbi.nlm.nih.gov/32307700/

7. Lu, Wen-Hsin, Chang, Tzu-Tung, Chang, Yao-Ming, Hwang, Ming-Jing, Huang, Yi-Shuian. 2024. CPEB2-activated axonal translation of VGLUT2 mRNA promotes glutamatergic transmission and presynaptic plasticity. In Journal of biomedical science, 31, 69. doi:10.1186/s12929-024-01061-2. https://pubmed.ncbi.nlm.nih.gov/38992696/