GABA transporter 1 is a promising drug target for CUL4B mutation-associated epilepsy.

Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene result in syndromic X-linked intellectual disability (XLID). In addition to intellectual disability, patients with CUL4B mutations exhibit epilepsy. To date, the mechanism underlying epilepsy associated with CUL4B mutation has not been elucidated. Here, we show that male mice with Cul4b deleted in the nervous system are more susceptible to both pentylenetetrazole (PTZ)- and kainic acid (KA)-induced epilepsy and exhibit spontaneous epilepsy without any chemical inducers. We identify the CRL4B complex as an E3 ubiquitin ligase that targets GABA transporter 1 (GAT1). CUL4B deletion in male mice results in GAT1 accumulation and increased GABA reuptake, leading to impaired GABA-mediated inhibitory synaptic transmission. Treating CUL4B-deficient mice with the GAT1 inhibitor tiagabine effectively reverses the increased susceptibility to chemical-induced epilepsy and attenuates spontaneous epilepsy without the use of chemical inducers. We further confirm the role of CUL4B in the regulation of GAT1 levels and GABA uptake in neurons and astrocytes differentiated from induced pluripotent stem cells (iPSCs) derived from patients with CUL4B loss-of-function mutations. Our work reveals a novel mechanism underlying the pathogenesis of epilepsy and identifies a promising drug target for treating CUL4B mutation-associated epilepsy.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2025. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)