Arg209Lys and Gln508His missense variants in Rabphilin 3A cause pre- and post-synaptic dysfunctions at excitatory glutamatergic synapses DOI Creative Commons

Marta Barzasi,

Alessio Spinola,

Alex Costa

и другие.

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 13, 2025

The synaptic protein Rabphilin 3A (Rph3A), encoded by the RPH3A gene, is a known binding partner of NMDA receptor (NMDAR) complex, which essential for plasticity and cognitive functions. A recent report demonstrated causal association between missense variants in gene neurodevelopmental disorders, manifesting as either drug-resistant epilepsy with intellectual disability or autism spectrum disorder learning disability. In this study, we used primary hippocampal neurons to analyse effects induced p.(Arg209Lys) p.(Gln508His) variants, located N-terminal disordered region C-terminal C2A domain Rph3A, respectively. We found that both mutants exert on pre- post-synaptic events mediated despite their different positions within Rph3A amino acid sequence. Notably, cases, reduced presynaptic glutamate release led decreased retention NMDARs containing GluN2A subunit, Rph3A. These changes were associated frequency calcium at dendritic spines, indicating an overall significant dysregulation glutamatergic transmission.

Язык: Английский

Arg209Lys and Gln508His missense variants in Rabphilin 3A cause pre- and post-synaptic dysfunctions at excitatory glutamatergic synapses DOI Creative Commons

Marta Barzasi,

Alessio Spinola,

Alex Costa

и другие.

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Март 13, 2025

The synaptic protein Rabphilin 3A (Rph3A), encoded by the RPH3A gene, is a known binding partner of NMDA receptor (NMDAR) complex, which essential for plasticity and cognitive functions. A recent report demonstrated causal association between missense variants in gene neurodevelopmental disorders, manifesting as either drug-resistant epilepsy with intellectual disability or autism spectrum disorder learning disability. In this study, we used primary hippocampal neurons to analyse effects induced p.(Arg209Lys) p.(Gln508His) variants, located N-terminal disordered region C-terminal C2A domain Rph3A, respectively. We found that both mutants exert on pre- post-synaptic events mediated despite their different positions within Rph3A amino acid sequence. Notably, cases, reduced presynaptic glutamate release led decreased retention NMDARs containing GluN2A subunit, Rph3A. These changes were associated frequency calcium at dendritic spines, indicating an overall significant dysregulation glutamatergic transmission.

Язык: Английский

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