Abstract
Haploinsufficiency of the bromodomain and PHD finger-containing protein 1 (BRPF1) gene causes intellectual disability (ID), which is characterized by impaired intellectual and cognitive function; however, the neurological basis for ID and the neurological function of BRPF1 dosage in the brain remain unclear. Here, by crossing Emx1-cre mice with Brpf1fl/fl mice, we generated Brpf1 heterozygous mice to model BRPF1-related ID. Brpf1 heterozygotes showed reduced dendritic complexity in both hippocampal granule cells and cortical pyramidal neurons, accompanied by reduced spine density and altered spine and synapse morphology. An in vitro study of Brpf1 haploinsufficiency also demonstrated decreased frequency and amplitude of miniature EPSCs that may subsequently contribute to abnormal behaviors, including decreased anxiety levels and defective learning and memory. Our results demonstrate a critical role for Brpf1 dosage in neuron dendrite arborization, spine morphogenesis and behavior and provide insight into the pathogenesis of BRPF1-related ID.
Highlights
Neurons display highly specialized and polarized morphology with distinct regions optimized for their functional roles (Craig and Banker, 1994; Caceres et al, 2012)
To investigate the impact of Brpf1 haploinsufficiency on behavior in mice, we mainly focused on the role of Brpf1 in the dorsal telencephalon and related behaviors
Emx1-cre medicate recombination occurs as early as E10.5 during the development of the telencephalon, Brpf1 was disrupted in both telencephalic excitatory glutamatergic neurons and astroglias, while GABAergic interneurons arising from the ventral ganglionic eminence were not affected
Summary
Neurons display highly specialized and polarized morphology with distinct regions optimized for their functional roles (Craig and Banker, 1994; Caceres et al, 2012). Previous studies have shown that both cell intrinsic and extrinsic cues, such as secreted signaling molecules (Yacoubian and Lo, 2000), transcription factors (Redmond et al, 2002; Bonini et al, 2011) and postsynaptic density proteins (Charych et al, 2006), contribute to the development of dendritic arborization and spines. Epigenetic modulators, such as histone acetylases (HATs) and histone deacetylases (HDACs), have emerged as regulators of chromatin remodeling that control access to the genes that regulate dendritic growth (Gaub et al, 2010).
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