Npas3 deficiency impairs cortical astrogenesis and induces autistic-like behaviors

Li, Yuanyuan; Fan, Tianda; Li, Xianfeng; Liu, Liqiu; Mao, Fengbiao; Li, Yang; Zhang, Miao; Zeng, Cheng; Song, Wei; Pan, Jinrong; Zhou, Shutang; Wang, Hongbing; Wang, Yan; Sun, Zhong Sheng

doi:10.1016/j.celrep.2022.111289

Cited by 8 publications

(4 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Neuronal differentiation-related genes including AGRN ( 53 ), SOX9 ( 54 , 55 ), TLE ( 56 , 57 ), MEST ( 58 ), CLU ( 59 ), NCAM1 ( 60 ), NGFR ( 61 ), NRCAM ( 62 , 63 ), SYT1 ( 64 ), SYT4 ( 65 ), and SYT11 ( 66 ) were also upregulated in both SH-SY5Y and Neuro2A under lactate treatment. Other crucial neural differentiation regulators such as RUNX1T1 ( 67 , 68 ), SPARCL1 ( 69 ), NPAS3 ( 70 ), CEND1 ( 71 ), SYT9 ( 72 ), and SYP ( 73 ) were upregulated only in SH-SY5Y cells. Based on previous reports about the functional contribution in the neural differentiation and the expression specificity of our RNA-seq data, we picked up six neural differentiation-related genes (SRY-box transcription factor 9 ( SOX9 ), transducin-like enhancer of split 2 ( TLE2 ), neuropeptide Y ( NPY ), synaptotagmin 4 ( SYT4 ), RUNX1 partner transcriptional co-repressor 1 ( RUNX1T1 ), and SPARC like 1 ( SPARCL1 ) and analyzed this gene expression in 5, 15, or 30 mM lactate-treated SH-SY5Y cells for 24 h ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Lactate promotes neuronal differentiation of SH-SY5Y cells by lactate-responsive gene sets through NDRG3-dependent and -independent manners

Kusuyama

Osana

et al. 2023

Journal of Biological Chemistry

View full text Add to dashboard Cite

Section: Resultsmentioning

confidence: 99%

Lactate promotes neuronal differentiation of SH-SY5Y cells by lactate-responsive gene sets through NDRG3-dependent and -independent manners

Kusuyama

Osana

et al. 2023

Journal of Biological Chemistry

View full text Add to dashboard Cite

“…Nfia knockout in astrocytes resulted in shortened processes and decreased morphological complexity within the cortex as well as decreased blood–brain-barrier function following white matter injury [ 31 , 39 ]. Npas3 knockdown in astrocytes resulted in decreased synaptic densities in astrocyte-neuron co-cultures and animal models [ 42 ]. Forebrain-specific knockout of Zbtb20 resulted in an increase in GFAP + astrocytes [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Human Alzheimer’s disease reactive astrocytes exhibit a loss of homeostastic gene expression

Dai

Lee

2023

acta neuropathol commun

View full text Add to dashboard Cite

Astrocytes are one of the brain’s major cell types and are responsible for maintaining neuronal homeostasis via regulating the extracellular environment, providing metabolic support, and modulating synaptic activity. In neurodegenerative diseases, such as Alzheimer’s disease, astrocytes can take on a hypertrophic appearance. These reactive astrocytes are canonically associated with increases in cytoskeletal proteins, such as glial fibrillary acidic protein and vimentin. However, the molecular alterations that characterize astrocytes in human disease tissues have not been extensively studied with single cell resolution. Using single nucleus RNA sequencing data from normal, pathologic aging, and Alzheimer’s disease brains, we identified the transcriptomic changes associated with reactive astrocytes. Deep learning-based clustering algorithms denoised expression data for 17,012 genes and clustered 15,529 astrocyte nuclei, identifying protoplasmic, gray matter and fibrous, white matter astrocyte clusters. RNA trajectory analyses revealed a spectrum of reactivity within protoplasmic astrocytes characterized by a modest increase of reactive genes and a marked decrease in homeostatic genes. Amyloid but not tau pathology correlated with astrocyte reactivity. To identify reactivity-associated genes, linear regressions of gene expression versus reactivity were used to identify the top 52 upregulated and 144 downregulated genes. Gene Ontology analysis revealed that upregulated genes were associated with cellular growth, responses to metal ions, inflammation, and proteostasis. Downregulated genes were involved in cellular interactions, neuronal development, ERBB signaling, and synapse regulation. Transcription factors were significantly enriched among the downregulated genes. Using co-immunofluorescence staining of Alzheimer’s disease brain tissues, we confirmed pathologic downregulation of ERBB4 and transcription factor NFIA in reactive astrocytes. Our findings reveal that protoplasmic, gray matter astrocytes in Alzheimer’s disease exist within a spectrum of reactivity that is marked by a strong loss of normal function.

show abstract

“…It is widely reported that there is very rapid development of synapses during the perinatal period. Such synaptogenesis is dysfunctional in both human autism/ASD patients and in autism/ASD animal models [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. Furthermore, synaptogenesis dysfunction is raised by agents causing autism [10,12,14,24,26] and lowered by agents thought to be helpful in autism treatment [18,19,23].…”

Section: Autism/asd Causation Via Disruption Of Synaptogenesis During...mentioning

confidence: 99%

“…Such synaptogenesis is dysfunctional in both human autism/ASD patients and in autism/ASD animal models [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. Furthermore, synaptogenesis dysfunction is raised by agents causing autism [10,12,14,24,26] and lowered by agents thought to be helpful in autism treatment [18,19,23]. Synaptogenesis dysfunction may be a major cause of the changes in connectivity between different regions of the brain in ASDs [27][28][29][30][31].…”

Section: Autism/asd Causation Via Disruption Of Synaptogenesis During...mentioning

confidence: 99%

Central Causation of Autism/ASDs via Excessive [Ca2+]i Impacting Six Mechanisms Controlling Synaptogenesis during the Perinatal Period: The Role of Electromagnetic Fields and Chemicals and the NO/ONOO(-) Cycle, as Well as Specific Mutations

Pall

2024

Brain Sciences

View full text Add to dashboard Cite

The roles of perinatal development, intracellular calcium [Ca2+]i, and synaptogenesis disruption are not novel in the autism/ASD literature. The focus on six mechanisms controlling synaptogenesis, each regulated by [Ca2+]i, and each aberrant in ASDs is novel. The model presented here predicts that autism epidemic causation involves central roles of both electromagnetic fields (EMFs) and chemicals. EMFs act via voltage-gated calcium channel (VGCC) activation and [Ca2+]i elevation. A total of 15 autism-implicated chemical classes each act to produce [Ca2+]i elevation, 12 acting via NMDA receptor activation, and three acting via other mechanisms. The chronic nature of ASDs is explained via NO/ONOO(-) vicious cycle elevation and MeCP2 epigenetic dysfunction. Genetic causation often also involves [Ca2+]i elevation or other impacts on synaptogenesis. The literature examining each of these steps is systematically examined and found to be consistent with predictions. Approaches that may be sed for ASD prevention or treatment are discussed in connection with this special issue: The current situation and prospects for children with ASDs. Such approaches include EMF, chemical avoidance, and using nutrients and other agents to raise the levels of Nrf2. An enriched environment, vitamin D, magnesium, and omega-3s in fish oil may also be helpful.

show abstract

Npas3 deficiency impairs cortical astrogenesis and induces autistic-like behaviors

Cited by 8 publications

References 74 publications

Lactate promotes neuronal differentiation of SH-SY5Y cells by lactate-responsive gene sets through NDRG3-dependent and -independent manners

Lactate promotes neuronal differentiation of SH-SY5Y cells by lactate-responsive gene sets through NDRG3-dependent and -independent manners

Human Alzheimer’s disease reactive astrocytes exhibit a loss of homeostastic gene expression

Central Causation of Autism/ASDs via Excessive [Ca2+]i Impacting Six Mechanisms Controlling Synaptogenesis during the Perinatal Period: The Role of Electromagnetic Fields and Chemicals and the NO/ONOO(-) Cycle, as Well as Specific Mutations

Contact Info

Product

Resources

About