γ-Aminobutyric Acid Transporter Mutation GAT1 (S295L) Substantially Impairs Neurogenesis in Dentate Gyrus DOI Creative Commons
Weitong Liu, Yang Yuan,

Y Liu

и другие.

Brain Sciences, Год журнала: 2025, Номер 15(4), С. 393 - 393

Опубликована: Апрель 13, 2025

Background: GABAergic signaling plays a crucial role in modulating neuronal proliferation, migration, and the formation of neural network connections. The termination GABA transmission primarily occurs through action transporter 1 (GAT1), encoded by SLC6A1 gene. Multiple mutations have been implicated neurodevelopmental disorders, but their effects on nervous system are unclear. Methods: We estimated expression pattern GAT1 (S295L) protein using Slc6a1S295L/S295L mouse model via RT-PCR, Western blotting, confocal immunofluorescence. effect hippocampal neurogenesis was investigated marker staining (Sox2, Tbr2, NeuroD1, DCX, NeuN) BrdU label experiments. dendritic complexity mapped Sholl analysis. RNA-Seq utilized to explore pathways molecules associated with disorders. Results: detected remarkable decline quantity type-2b intermediate progenitor cells, neuroblasts, immature neurons dentate gyrus (DG) mice at 4 weeks. These abnormalities were exacerbated adulthood, as evidenced compromised length height well neurons. Immunofluorescence showed abnormal aggregation RNA-seq analysis identified neurodevelopment, neurological homeostasis, neuronutrition. neurotrophin Bdnf decreased all ages mice. Conclusions: Our data provide new evidence that causes impaired DG. mutation not only disrupts homeostasis also impairs neurotrophic support necessary for normal development, which may be one factors contributing neurogenesis.

Язык: Английский

Gene-replacement therapy in neurodevelopmental disorders: progress and challenges DOI Creative Commons
Holger Lerche, Ulrike B. S. Hedrich, Thomas V. Wuttke

и другие.

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(3)

Опубликована: Фев. 2, 2025

Heterozygous loss-of-function variants in the SLC6A1 gene, encoding GAT1, which is main GABA transporter brain, lead to a broad spectrum of neuropsychiatric and neurodevelopmental disorders including epilepsy, developmental delay, intellectual disability, autism. Gene-replacement strategies involving adeno-associated viruses (AAV) require delivery genes specific types neurons or areas likely during certain time points. In this issue JCI, Guo colleagues from Gray lab evaluated two promoters, three injection modalities, various timing for replacement GAT1 via AAV type 9 heterozygous homozygous knockout mouse models. Intrathecal administration vectors containing either promoter at postnatal day 5 achieved high expression was best tolerated approach. Notably, gene-replacement therapy failed later disease stages, suggesting importance early gene reconstitution confirming metabolism brain development.

Язык: Английский

Процитировано

1
γ-Aminobutyric Acid Transporter Mutation GAT1 (S295L) Substantially Impairs Neurogenesis in Dentate Gyrus DOI Creative Commons
Weitong Liu, Yang Yuan,

Y Liu

и другие.

Brain Sciences, Год журнала: 2025, Номер 15(4), С. 393 - 393

Опубликована: Апрель 13, 2025

Background: GABAergic signaling plays a crucial role in modulating neuronal proliferation, migration, and the formation of neural network connections. The termination GABA transmission primarily occurs through action transporter 1 (GAT1), encoded by SLC6A1 gene. Multiple mutations have been implicated neurodevelopmental disorders, but their effects on nervous system are unclear. Methods: We estimated expression pattern GAT1 (S295L) protein using Slc6a1S295L/S295L mouse model via RT-PCR, Western blotting, confocal immunofluorescence. effect hippocampal neurogenesis was investigated marker staining (Sox2, Tbr2, NeuroD1, DCX, NeuN) BrdU label experiments. dendritic complexity mapped Sholl analysis. RNA-Seq utilized to explore pathways molecules associated with disorders. Results: detected remarkable decline quantity type-2b intermediate progenitor cells, neuroblasts, immature neurons dentate gyrus (DG) mice at 4 weeks. These abnormalities were exacerbated adulthood, as evidenced compromised length height well neurons. Immunofluorescence showed abnormal aggregation RNA-seq analysis identified neurodevelopment, neurological homeostasis, neuronutrition. neurotrophin Bdnf decreased all ages mice. Conclusions: Our data provide new evidence that causes impaired DG. mutation not only disrupts homeostasis also impairs neurotrophic support necessary for normal development, which may be one factors contributing neurogenesis.

Язык: Английский

Процитировано

0