The Subiculum: A Potential Site of Ictogenesis in a Neonatal Seizure Model

Wang, Xin Xin; Li, Yong Hua; Gong, Hai Qing; Liang, Pei Ji; Zhang, Pu-Ming; Qin, Lu

doi:10.3389/fneur.2017.00147

“…Downregulated genes in this cell type were also enriched for known neurodevelopmental disease genes including those 310 associated with autism, developmental delay and epilepsy. Although the subiculum functions as the primary output of the hippocampus and is important for normal hippocampal-related functions, such as learning and memory and stress response, this brain region has also been implicated in pathological conditions, such as the generation and spread of temporal lobe seizures [61][62][63][64][65] . While the location of seizure onset was not reported for most individuals with HNRNPU mutations, two 315 patients reportedly had temporal lobe epilepsy 21,23 .…”

Section: Cell-type-specific Effects Upon Heterozygous Loss Of Hnrnpumentioning

confidence: 99%

Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model ofHNRNPUhaploinsufficiency

Dugger

¹

,

Dhindsa

²

,

Sampaio

³

et al. 2020

Preprint

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Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated 5 neuroanatomical abnormalities, global developmental delay and impaired ultrasonic vocalizations, and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory neurons of the 10 subiculum-a region of the hippocampus implicated in temporal lobe epilepsy. Evaluation of transcriptomic signature reversal as a therapeutic strategy highlighted the potential importance of generating cell-type-specific signatures. Overall, this work provides insight into HNRNPUmediated disease mechanisms, and provides a framework for using single-cell RNA-sequencing to study transcriptional regulators implicated in disease. chromatin organization 17,18 . We and others have reported de novo loss-of-function variants [19][20][21][22][23] and microdeletions 24,25 encompassing HNRNPU in pediatric patients with a severe, and often treatment refractory, developmental and epileptic encephalopathy (DEE) characterized by earlyonset epilepsy, moderate to severe developmental delay, autistic features, structural brain abnormalities, hypotonia, short stature and variable renal and cardiac abnormalities. HnRNP U is 35 essential for mammalian development as lethality results by embryonic day 11.5 in mice carrying homozygous hypomorphic mutations 26 . Furthermore, homozygous pathogenic mutations have yet to be reported in humans 27 . Conditional loss of Hnrnpu in mouse cardiomyocytes was also associated with a lethal dilated cardiomyopathy and widespread transcriptional and splicing 3 dysregulation including known cardiomyopathy disease genes 16 . However, the transcriptomic and 40 physiologic effects of Hnrnpu haploinsufficiency in the brain have yet to be characterized.Here we assess the neurophysiological consequences and face validity of an Hnrnpu mouse disease model using in vivo developmental, morphological, electrophysiological, and behavioral studies. We also perform a comprehensive cell-type-and brain region-specific characterization of reduced Hnrnpu levels on gene expression using scRNAseq. Using these 45 data, we generate cell-type-specific disease expression signatures and identify vulnerable cell types in the mutant mouse brain. We then compare these signatures to publicly-available gene expression signatures of cells treated with small molecules in order to identify compounds that correct disease-associated transcriptomic changes towards a normal state. ...

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“…Downregulated genes in this cell type were also enriched for known neurodevelopmental disease genes including those associated with autism, developmental delay, and epilepsy. Although the subiculum functions as the primary output of the hippocampus and is important for normal hippocampal-related functions such as learning and memory and stress response, this brain region has also been implicated in pathological conditions such as the generation and spread of temporal lobe seizures [72][73][74][75][76]. While the location of seizure onset was not reported for most individuals with HNRNPU mutations, two patients reportedly had temporal lobe epilepsy [26,28].…”

Section: Cell-type-specific Effects Upon Heterozygous Loss Of Hnrnpumentioning

confidence: 99%

Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model of HNRNPU haploinsufficiency

Dugger,

Dhindsa,

Sampaio

et al. 2023

PLoS Genet

3

0

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Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the potential groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated global developmental delay, impaired ultrasonic vocalizations, cognitive dysfunction and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory neurons of the subiculum—a region of the hippocampus implicated in temporal lobe epilepsy. Evaluation of transcriptomic signature reversal as a therapeutic strategy highlights the potential importance of generating cell-type-specific signatures. Overall, this work provides insight into HNRNPU-mediated disease mechanisms and provides a framework for using single-cell RNA-sequencing to study transcriptional regulators implicated in disease.

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