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Deficiency of intellectual disability-related gene Brpf1 reduced inhibitory neurotransmission in MGE-derived GABAergic interneurons.

ABSTRACT: Intellectual disability is closely related to impaired GABA neurotransmission. Brpf1 was specifically expressed in medial ganglionic eminence (MGE), a developmental niche of GABAergic interneurons, and patients with BRPF1 mutations showed intellectual disability. To test its role in development and function of MGE-derived GABAergic interneurons, we performed immunofluorescence staining, whole-cell patch-clamp, MGE transplantation and mRNA-Seq to understand its effect on neuronal differentiation, dendritic morphology, electrophysiology, migration and gene regulation, using mouse MGE-derived GABAergic interneurons infected with AAV-shBrpf1. The results showed that Brpf1 knockdown had a decreasing trend, although not significant, on the differentiation of GABAergic interneurons into parvalbumin+ interneurons. Moreover, increased firing threshold, decreased number of evoked action potentials, and a reduced amplitude of miniature inhibitory postsynaptic currents were observed before any significant change of MAP2+ dendritic morphology and in vivo migration ability appeared. Finally, mRNA-Seq analysis revealed that genes related to neurodevelopment and synaptic transmission such as Map2k7 were dysregulated. Our results demonstrated a key role of Brpf1 in inhibitory neurotransmission and related gene expression of GABAergic interneurons.

SUBMITTER: Cao J

PROVIDER: S-EPMC8496217 | biostudies-literature |

REPOSITORIES: biostudies-literature

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brpf1 knockdown reduces inhibitory neurotransmission and regulates gene expression of GABAergic interneurons derived from MGE

Project description:Our research is to investigate the role of Brpf1 in the development and function of GABAergic interneurons. To test this, we used mouse primary in vitro cultured GABAergic interneurons derived from medial ganglionic eminence (MGE) and utilized AAV-shBrpf1 virus to knockdown Brpf1. We performed mRNA-seq on the total RNA extracted from the infected neurons .We found that most of the up-regulated genes after Brpf1 knockdown were involved in processes such as protein binding, gene negative transcription, ubiquitination, and inflammation by mRNA-seq. We found that many genes related to neuronal calcium, potassium ion transport and neurotransmitter release changed after Brpf1 was knockdown.Our results demonstrate the key role of Brpf1 in related gene expression of GABAergic interneurons, and provide new lights on the underlying neurobiological mechanisms of BRPF1 mutations that cause mental retardation in children or adolescents.

2021-02-23 | GSE157903 | GEO

Deficiency of intellectual disability-related gene Brpf1 attenuated hippocampal excitatory neurotransmission and impaired learning and memory behavior

Project description: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, 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 knockdown 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 hippocampal knockdown of Brpf1 reduced the learning and memory ability of mice to some extent. Finally, mRNA-Seq analyses showed that genes related to learning, memory, movement and synaptic transmission (such as C1ql1, Gpr17, Htr1d, Glra1, Cxcl10, Grin2a) were dysregulated upon Brpf1 knockdown. Our results showed that Brpf1 mild knockdown attenuated hippocampal excitatory neurotransmission and reduced learning and memory ability, which helps explain the symptoms of patients with BRPF1 mutations.

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brpf1 knockdown reduces inhibitory neurotransmission and regulates gene expression of GABAergic interneurons derived from MGE

Project description:brpf1 knockdown reduces inhibitory neurotransmission and regulates gene expression of GABAergic interneurons derived from MGE

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Epilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission.

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Identification of a Protein Network Driving Neuritogenesis of MGE-Derived GABAergic Interneurons.

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BRPF1-associated intellectual disability, ptosis, and facial dysmorphism in a multiplex family.

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LIM homeodomain transcription factor-dependent specification of bipotential MGE progenitors into cholinergic and GABAergic striatal interneurons.

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Deficiency of Intellectual Disability-Related Gene <i>Brpf1</i> Attenuated Hippocampal Excitatory Synaptic Transmission and Impaired Spatial Learning and Memory Ability.

Project description: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.

| S-EPMC8415984 | biostudies-literature

Deficiency of intellectual disability-related gene Brpf1 attenuated hippocampal excitatory neurotransmission and impaired learning and memory behavior

Project description:Deficiency of intellectual disability-related gene Brpf1 attenuated hippocampal excitatory neurotransmission and impaired learning and memory behavior

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Mutations in the Chromatin Regulator Gene BRPF1 Cause Syndromic Intellectual Disability and Deficient Histone Acetylation.

Project description:Identification of over 500 epigenetic regulators in humans raises an interesting question regarding how chromatin dysregulation contributes to different diseases. Bromodomain and PHD finger-containing protein 1 (BRPF1) is a multivalent chromatin regulator possessing three histone-binding domains, one non-specific DNA-binding module, and several motifs for interacting with and activating three lysine acetyltransferases. Genetic analyses of fish brpf1 and mouse Brpf1 have uncovered an important role in skeletal, hematopoietic, and brain development, but it remains unclear how BRPF1 is linked to human development and disease. Here, we describe an intellectual disability disorder in ten individuals with inherited or de novo monoallelic BRPF1 mutations. Symptoms include infantile hypotonia, global developmental delay, intellectual disability, expressive language impairment, and facial dysmorphisms. Central nervous system and spinal abnormalities are also seen in some individuals. These clinical features overlap with but are not identical to those reported for persons with KAT6A or KAT6B mutations, suggesting that BRPF1 targets these two acetyltransferases and additional partners in humans. Functional assays showed that the resulting BRPF1 variants are pathogenic and impair acetylation of histone H3 at lysine 23, an abundant but poorly characterized epigenetic mark. We also found a similar deficiency in different lines of Brpf1-knockout mice. These data indicate that aberrations in the chromatin regulator gene BRPF1 cause histone H3 acetylation deficiency and a previously unrecognized intellectual disability syndrome.

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