Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Psychotic Disorders, Shanghai 201108, China.
King's Lab, Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2023 Jan 10;120:110622. doi: 10.1016/j.pnpbp.2022.110622. Epub 2022 Aug 25.
Deterioration of inhibitory synapse may be an essential neurological basis underlying abnormal social behaviours. Manipulations that regulate GABAergic transmission are associated with improved behavioural phenotypes in sociability. The synaptic protein, Ephrin-B2 (EB2), plays an important role in the maintenance and reconfiguration of inhibitory synapses in the medial prefrontal cortex (mPFC). However, the inhibitory cell-type specific role of EB2 in the pathophysiology and treatment of social deficits remains unknown. As expected, we revealed that tdTomato-expressing cells were only found in GABAergic neurons instead of excitatory neurons in transgenic EB2-vGATCre mice. This result indicated that depletion of EB2 would occur in those neurons, which further contribute to social deficits. In addition, specific over-expression of mPFC EB2 restored the defective social behaviour abnormalities. These results suggest that the effect of EB2 on social deficits is anatomically and cell-type specific. More importantly, the global upregulation of HDAC4 expression was found in EB2-vGATCre mice. Significant subcellular nuclear shuttling of HDAC4 in vGAT+ neurons was examined and quantified, suggesting a role of nuclear HDAC4 in mediating the mechanism underlying EB2 impairment in vGAT+ neurons. Treatment with LMK235 led to a remarkable rescue of social deficits, thus our data revealed a new domain for the potential utility of HDAC targeting agents to treat social deficits. In conclusion, these results not only revealed a novel molecular mechanism underlying the pathophysiology of social deficits, but also suggested a potential intervention avenue for the treatment of social deficits.
抑制性突触的退化可能是异常社交行为的重要神经基础。调节 GABA 能传递的操作与社交能力的行为表型改善有关。突触蛋白 Ephrin-B2（EB2）在中前额叶皮层（mPFC）中抑制性突触的维持和重新配置中发挥重要作用。然而，EB2 在社交缺陷的病理生理学和治疗中的抑制性细胞类型特异性作用仍然未知。不出所料，我们发现在转基因 EB2-vGATCre 小鼠中，表达 tdTomato 的细胞仅存在于 GABA 能神经元中，而不存在于兴奋性神经元中。这一结果表明，EB2 的耗竭将发生在那些神经元中，这进一步导致了社交缺陷。此外，mPFC EB2 的特异性过表达恢复了缺陷的社交行为异常。这些结果表明，EB2 对社交缺陷的影响具有解剖学和细胞类型特异性。更重要的是，在 EB2-vGATCre 小鼠中发现了 HDAC4 表达的全局上调。在 vGAT+神经元中检查和量化了 HDAC4 的显著核内穿梭，表明核内 HDAC4 在介导 EB2 损伤 vGAT+神经元的机制中起作用。用 LMK235 治疗导致社交缺陷显著改善，因此我们的数据揭示了 HDAC 靶向药物治疗社交缺陷的新领域。总之，这些结果不仅揭示了社交缺陷病理生理学的新分子机制，还为社交缺陷的治疗提供了潜在的干预途径。
