Current Opinion in Neurobiology, Год журнала: 2024, Номер 89, С. 102917 - 102917
Опубликована: Сен. 20, 2024
Язык: Английский
PLoS ONE, Год журнала: 2024, Номер 19(3), С. e0300529 - e0300529
Опубликована: Март 18, 2024
Behavioral thresholds define the lowest stimulus intensities sufficient to elicit a behavioral response. Establishment of baseline during development is critical for proper responses throughout animal’s life. Despite relevance such innate thresholds, molecular mechanisms establishing are not well understood. The acoustic startle response conserved behavior whose threshold established yet subsequently acutely regulated. We have previously identified zebrafish mutant line ( escapist ) that displays decreased or threshold. Here, we identify single base pair substitution on Chromosome 25 located within coding sequence synaptotagmin 7a syt7a gene tightly linked hypersensitivity phenotype. By generating animals in which deleted open reading frame, and subsequent complementation testing with line, demonstrate loss function cause Nonetheless, mutants provide powerful tool decipher overlap between acute developmental regulation thresholds. Extensive analyses reveal establishment impaired, while its remains intact. Moreover, our deficit visual stimuli, but stimuli. Together, this work eliminates as causative phenotype suggests regulate larvae can operate independently from those regulating regulation.
Язык: Английский
Процитировано
2
Frontiers in Molecular Neuroscience, Год журнала: 2024, Номер 17
Опубликована: Июль 10, 2024
Background and aims SYNGAP1-related disorder (SYNGAP1-RD) is a prevalent genetic form of Autism Spectrum Disorder Intellectual Disability (ASD/ID) caused by de novo or inherited mutations in one copy the SYNGAP1 gene. In addition to ASD/ID, associated with comorbid symptoms including treatment-resistant-epilepsy, sleep disturbances, gastrointestinal distress. Mechanistic links between these diverse variants remain obscure, therefore, our goal was generate zebrafish model which this range can be studied. Methods We used CRISPR/Cas9 introduce frameshift syngap1a syngap1b duplicates ( syngap1ab ) validated stable models for Syngap1 loss-of-function. Because extensively spliced, we mapped splice two b genes identified mammalian-like isoforms. then quantified locomotory behaviors larvae under three conditions that normally evoke different arousal states wild-type larvae: aversive, high-arousal acoustic, medium-arousal dark, low-arousal light stimuli. Results show indels produced loss-of-function alleles at RNA protein levels. Our analyses isoforms showed that, as mammals, N- C-termini are spliced. syngap1 α1-like variant maps exclusively Quantifying locomotor mutant hyperactive compared but differing degrees depending on stimulus. Hyperactivity most pronounced low settings, hyperactivity proportional number alleles. Limitations produce relatively subtle phenotypes mammals. For example, while mouse homozygotes die birth, syngap1ab−/− survive adulthood fertile, thus some aspects people SYNGAP1- Related not likely reflected zebrafish. Conclusion data support causal elevated especially environments.
Язык: Английский
Процитировано
1
medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Ноя. 2, 2024
ABSTRACT Individuals with monoallelic pathogenic variants in the histone lysine methyltransferase DOT1L display global developmental delay and varying congenital anomalies. However, impact of loss remains unclear. Here, we present a largely female cohort 11 individuals delays dysmorphic facial features. We found that include missense clustered catalytic domain, frameshift, stop-gain variants. demonstrate specific cause activity therefore sought to define effects decreased function. Using RNA-sequencing cultured neurons single nucleus mouse cortical tissue, partial Dot1l depletion causes sex-specific transcriptional responses disrupts transcription synaptic genes. Further, alters neuron branching expression proteins. Lastly using zebrafish models, behavioral disruptions deficits mice. Overall, how leads neurological dysfunction by demonstrating impacts transcription, morphology, behavior across multiple models systems.
Язык: Английский
Процитировано
1
bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown
Опубликована: Апрель 5, 2024
Abstract Background 22q11.2 Deletion Syndrome (22qDel) is a copy number variant (CNV) associated with psychosis and other neurodevelopmental disorders. Adolescents at clinical high risk for (CHR) have subthreshold symptoms without known genetic factors. Whether common neural substrates underlie these distinct high-risk populations unknown. We compared functional brain measures in 22qDel CHR cohorts mapped results to biological pathways. Methods analyzed two large multi-site resting-state MRI (rs-fMRI): 1) (n=164, 47% female) typically developing (TD) controls (n=134, 56% female); 2) individuals (n=244, 41% TD (n=151, 46% from the North American Prodrome Longitudinal Study-2. computed global connectivity (GBC), local (LC), signal variability (BSV) across cortical regions, testing case-control differences separately. Group difference maps were related published using autocorrelation-preserving permutation. Results BSV, LC, GBC are significantly disrupted (False Discovery Rate q<0.05). Spatial of BSV LC highly correlated each other, unlike GBC. In CHR, only altered versus controls, different spatial pattern 22qDel. map onto gradients, effects strongest regions predicted blood flow metabolism. Conclusion exhibit divergent on fMRI temporal multi-scale connectivity. 22qDel, strong convergent disruptions not seen suggest alterations.
Язык: Английский
Процитировано
0
Biological Psychiatry, Год журнала: 2024, Номер 97(2), С. 178 - 187
Опубликована: Авг. 23, 2024
Язык: Английский
Процитировано
0
Current Opinion in Neurobiology, Год журнала: 2024, Номер 89, С. 102917 - 102917
Опубликована: Сен. 20, 2024
Язык: Английский
Процитировано
0