Neural Regeneration Research ›› 2024, Vol. 19 ›› Issue (5): 1133-1141.doi: 10.4103/1673-5374.385307

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Forebrain excitatory neuron-specific loss of Brpf1 attenuates excitatory synaptic transmission and impairs spatial and fear memory 

Baicheng Zhao1, #, Hang Zhang1, #, Ying Liu1, #, Gaoyu Zu1, Yuxiao Zhang2, 3, 4, Jiayi Hu1, Shuai Liu2, 3, 4, Linya You1, 5, *   

  1. 1Department of Human Anatomy & Histoembryology, School of Basic Medical Sciences, Fudan University, Shanghai, China; 2Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Affiliated Mental Health Center (ECNU), School of Psychology and Cognitive Science, East China Normal University, Shanghai, China; 3Shanghai Changning Mental Health Center, Shanghai, China; 4NYU-ECNU Institute of Brain and Cognitive Science at NYU Shanghai, Shanghai, China; 5Key Laboratory of Medical Imaging Computing and Computer Assisted Intervention of Shanghai, Shanghai, China
  • Online:2024-05-15 Published:2023-10-31
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81771228 and Shanghai Association of Science and Technology, Nos. 22WZ2501700 and 23WZ2504500 (all to LY). 

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Abstract: Bromodomain and plant homeodomain (PHD) finger containing protein 1 (Brpf1) is an activator and scaffold protein of a multiunit complex that includes other components involving lysine acetyltransferase (KAT) 6A/6B/7. Brpf1, KAT6A, and KAT6B mutations were identified as the causal genes of neurodevelopmental disorders leading to intellectual disability. Our previous work revealed strong and specific expression of Brpf1 in both the postnatal and adult forebrain, especially the hippocampus, which has essential roles in learning and memory. Here, we hypothesized that Brpf1 plays critical roles in the function of forebrain excitatory neurons, and that its deficiency leads to learning and memory deficits. To test this, we knocked out Brpf1 in forebrain excitatory neurons using CaMKIIa-Cre. We found that Brpf1 deficiency reduced the frequency of miniature excitatory postsynaptic currents and downregulated the expression of genes Pcdhgb1, Slc16a7, Robo3, and Rho, which are related to neural development, synapse function, and memory, thereby damaging spatial and fear memory in mice. These findings help explain the mechanisms of intellectual impairment in patients with BRPF1 mutation.

Key words: behavioral test, Brpf1, CAMKIIa-Cre, intellectual disability, miniature excitatory postsynaptic current, mRNA-Seq