{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSLC17A8 encodes vesicular glutamate transporter 3 (VGLUT3), a protein essential for the proton gradient–dependent uptake of glutamate into synaptic vesicles, thereby enabling quantal release of the major excitatory neurotransmitter. Although its sequence shares considerable homology with VGLUT1 and VGLUT2, VGLUT3 exhibits a distinct and more restricted distribution that underlies unique aspects of glutamatergic signaling in both the central and peripheral nervous systems."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the auditory system, VGLUT3 is selectively expressed in the inner hair cells of the cochlea where it is responsible for the vesicular loading of glutamate, a critical step for auditory coding and synaptic transmission. Mutations in SLC17A8—including missense, splicing, and other pathogenic variants—lead to a significant reduction in VGLUT3 expression or disrupted transporter function, resulting in progressive high‐frequency nonsyndromic hearing loss (DFNA25) and auditory neuropathy. Animal models have demonstrated that loss or dysfunction of VGLUT3 culminates in impaired glutamate uptake and subsequent defects in synaptic integrity and neuronal survival within the inner ear."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond the auditory pathway, VGLUT3 is expressed in discrete populations of central neurons—most notably in cholinergic interneurons of the nucleus accumbens and striatal circuits—where it orchestrates the co-release of glutamate alongside other neurotransmitters. Disruption of VGLUT3 in these networks has been shown to enhance dopamine release, alter synaptic plasticity, and influence behaviors related to reward, addiction, and motor control. Such findings, together with evidence of its interplay with metabotropic glutamate receptor 5 (mGluR5), suggest that VGLUT3 is a key regulator of basal ganglia function and may contribute to the pathophysiology of movement disorders and neuropsychiatric conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its roles in neural transmission and synaptic regulation, VGLUT3 displays a tightly controlled and region-specific expression pattern during development, as exemplified by its transient distribution in the myenteric plexus of the small intestine. This developmental regulation further emphasizes the complexity of glutamatergic neurotransmission orchestrated by VGLUT3 across multiple organ systems."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shigeo Takamori, Pari Malherbe, Clemens Broger, et al. 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