Abstract
Patients with monoallelic bromodomain and PHD finger-containing protein 1 (BRPF1) mutations showed intellectual disability. The hippocampus has essential roles in learning and memory. Our previous work indicated that Brpf1 was specifically and strongly expressed in the hippocampus from the perinatal period to adulthood. We hypothesized that mouse Brpf1 plays critical roles in the morphology and function of hippocampal neurons, and its deficiency leads to learning and memory deficits. To test this, we performed immunofluorescence, whole-cell patch clamp, and mRNA-Seq on shBrpf1-infected primary cultured hippocampal neurons to study the effect of Brpf1 knockdown on neuronal morphology, electrophysiological characteristics, and gene regulation. In addition, we performed stereotactic injection into adult mouse hippocampus to knock down Brpf1 in vivo and examined the learning and memory ability by Morris water maze. We found that mild knockdown of Brpf1 reduced mEPSC frequency of cultured hippocampal neurons, before any significant changes of dendritic morphology showed. We also found that Brpf1 mild knockdown in the hippocampus showed a decreasing trend on the spatial learning and memory ability of mice. Finally, mRNA-Seq analyses showed that genes related to learning, memory, and synaptic transmission (such as C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, and Grin2a) were dysregulated upon Brpf1 knockdown. Our results showed that Brpf1 mild knockdown attenuated hippocampal excitatory synaptic transmission and reduced spatial learning and memory ability, which helps explain the symptoms of patients with BRPF1 mutations.
Highlights
Intellectual disability is a prevalent neurodevelopmental disorder, affecting 1–2% of children or young adults
Immunostaining was performed at days in vitro (DIV) 14–15 with anti-MAP2 antibody, and the quantification of dendritic morphology was calculated from three independent experiments using Sholl analysis (O’Neill et al, 2015); totally 32 and 44 neurons in the scramble and shBrpf1 groups were analyzed, respectively (Figure 1A)
The results showed that the average total dendritic length and number of intersections of primary cultured hippocampal neurons did not change significantly upon half reduction of Brpf1 expression (Figures 1C,D)
Summary
Intellectual disability is a prevalent neurodevelopmental disorder, affecting 1–2% of children or young adults. Bromodomain and PHD finger-containing protein 1 (BRPF1) is an important candidate gene with its monoallelic mutations resulting in intellectual disability The cumulative number of patients with BRPF1 mutations has reached 40, and patients were often accompanied with symptoms such as epilepsy, hypotonia, developmental delay, language dysfunction, ptosis, and cerebellar and facial deformities (Mattioli et al, 2017; Yan et al, 2017, 2020; Demeulenaere et al, 2019; Pode-Shakked et al, 2019). In human, BRPF1 is stably expressed in the hippocampus from development to adulthood by BrainSpan Atlas, a transcriptional resource of the developing human brain (Zhao et al, 2019)
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