Slc32a1, also known as the vesicular inhibitory amino acid cotransporter (VGAT), is a gene that encodes the only protein identified to date that loads gamma-aminobutyric acid (GABA) and glycine into synaptic vesicles, thus playing a crucial role in inhibitory neurotransmission. GABAergic neurotransmission is essential for regulating neuronal excitability in the nervous system [2].

Missense variants in Slc32a1 have been associated with genetic epilepsy with febrile seizures plus (GEFS+) and idiopathic generalized epilepsy (IGE). These variants are predicted to alter GABA transport into synaptic vesicles, leading to altered neuronal inhibition [1]. De novo missense variants in Slc32a1 can also cause a developmental and epileptic encephalopathy. In silico modeling and functional analyses in a murine neuronal cell culture model showed that some variants reduce quantal size, consistent with impaired filling of synaptic vesicles with GABA, while another variant increases presynaptic release probability, leading to more severe synaptic depression during high-frequency stimulation [2]. Conditional deletion of MOR-encoding Oprm1 in Vgat+ (Slc32a1-expressing) neurons abolished morphine-induced itch, suggesting that spinal inhibitory interneurons expressing Slc32a1 are involved in the itch-related disinhibition mechanism [3].

In conclusion, Slc32a1 is essential for proper inhibitory neurotransmission by facilitating the loading of GABA into synaptic vesicles. Studies using mouse models, especially those with gene variants or conditional knockouts related to Slc32a1, have revealed its significance in epilepsy and encephalopathy, as well as in the context of morphine-induced itch. These findings contribute to understanding the underlying mechanisms of these neurological and pain-related conditions.

References:

1. Heron, Sarah E, Regan, Brigid M, Harris, Rebekah V, Gécz, Jozef, Berkovic, Samuel F. 2021. Association of SLC32A1 Missense Variants With Genetic Epilepsy With Febrile Seizures Plus. In Neurology, 96, e2251-e2260. doi:10.1212/WNL.0000000000011855. https://pubmed.ncbi.nlm.nih.gov/34038384/

2. Platzer, Konrad, Sticht, Heinrich, Bupp, Caleb, Abou Jamra, Rami, Wojcik, Sonja M. 2022. De Novo Missense Variants in SLC32A1 Cause a Developmental and Epileptic Encephalopathy Due to Impaired GABAergic Neurotransmission. In Annals of neurology, 92, 958-973. doi:10.1002/ana.26485. https://pubmed.ncbi.nlm.nih.gov/36073542/

3. Wang, Zilong, Jiang, Changyu, Yao, Hongyu, Huh, Yul, Ji, Ru-Rong. . Central opioid receptors mediate morphine-induced itch and chronic itch via disinhibition. In Brain : a journal of neurology, 144, 665-681. doi:10.1093/brain/awaa430. https://pubmed.ncbi.nlm.nih.gov/33367648/