scholarly journals Abnormal brain development of monoamine oxidase mutant zebrafish and impaired social interaction of heterozygous fish

2021 ◽  
Author(s):  
Diego Baronio ◽  
Yu-Chia Chen ◽  
Pertti Panula
Keyword(s):  
Monoamine Oxidase ◽  
Brain Development ◽  
Genetic Model ◽  
Loss Of Function ◽  
Acoustic Stimuli ◽  
Dopaminergic Systems ◽  
Serotonin Immunoreactivity ◽  
And Behavior ◽  
Abnormal Brain

Monoamine oxidase (MAO) deficiency and imbalanced levels of brain monoamines have been associated with developmental delay, neuropsychiatric disorders and aggressive behavior. Animal models are valuable tools to gain mechanistic insight into outcomes associated with MAO deficiency. Here we report a novel genetic model to study the effects of mao-loss-of-function in zebrafish. Quantitative PCR, in situ hybridization and immunocytochemistry were used to study neurotransmitter systems, and expression of relevant genes for brain development in zebrafish mao mutants. Larval and adult fish behavior was evaluated through different tests. A stronger serotonin immunoreactivity was detected in both mao+/- and mao−/- larvae when compared with mao+/+ siblings. Mao−/- larvae were hypoactive, presented decreased reactions to visual and acoustic stimuli. They also had impaired histaminergic and dopaminergic systems, abnormal expression of developmental markers, and they died within 20 days post-fertilization. Mao+/- fish were viable, grew until adulthood and demonstrated anxiety-like behavior and impaired social interactions when compared with adult mao+/+ siblings. Our results indicate that mao−/- and mao+/- mutants could be promising tools to study the roles of MAO in brain development and behavior.

scholarly journals VER/VEGF receptors regulate AMPA receptor surface levels and glutamatergic behavior

PLoS Genetics ◽  
2021 ◽  
Vol 17 (2) ◽  
pp. e1009375
Author(s):  
Eric S. Luth ◽  
Molly Hodul ◽  
Bethany J. Rennich ◽  
Carmino Riccio ◽  
Julia Hofer ◽  
...  
Keyword(s):  
Cell Surface ◽  
Ampa Receptor ◽  
Intracellular Trafficking ◽  
Genetic Model ◽  
Synaptic Function ◽  
Vegf Receptor ◽  
Loss Of Function ◽  
Glutamate Signaling ◽  
Ampar Trafficking ◽  
And Behavior

Several intracellular trafficking pathways contribute to the regulation of AMPA receptor (AMPAR) levels at synapses and the control of synaptic strength. While much has been learned about these intracellular trafficking pathways, a major challenge is to understand how extracellular factors, such as growth factors, neuropeptides and hormones, impinge on specific AMPAR trafficking pathways to alter synaptic function and behavior. Here, we identify the secreted ligand PVF-1 and its cognate VEGF receptor homologs, VER-1 and VER-4, as regulators of glutamate signaling in C. elegans. Loss of function mutations in ver-1, ver-4, or pvf-1, result in decreased cell surface levels of the AMPAR GLR-1 and defects in glutamatergic behavior. Rescue experiments indicate that PVF-1 is expressed and released from muscle, whereas the VERs function in GLR-1-expressing neurons to regulate surface levels of GLR-1 and glutamatergic behavior. Additionally, ver-4 is unable to rescue glutamatergic behavior in the absence of pvf-1, suggesting that VER function requires endogenous PVF-1. Inducible expression of a pvf-1 rescuing transgene suggests that PVF-1 can function in the mature nervous system to regulate GLR-1 signaling. Genetic double mutant analysis suggests that the VERs act together with the VPS-35/retromer recycling complex to promote cell surface levels of GLR-1. Our data support a genetic model whereby PVF-1/VER signaling acts with retromer to promote recycling and cell surface levels of GLR-1 to control behavior.

scholarly journals The Neurodevelopmental Hypothesis of Huntington’s Disease

2020 ◽  
Vol 9 (3) ◽  
pp. 217-229
Author(s):  
Ellen van der Plas ◽  
Jordan L. Schultz ◽  
Peg C. Nopoulos
Keyword(s):  
At Risk ◽  
Brain Development ◽  
Abnormal Development ◽  
Alternative Theory ◽  
Loss Of Function ◽  
Cellular Mechanisms ◽  
Brain Structure And Function ◽  
And Function ◽  
Neurodevelopmental Hypothesis ◽  
Abnormal Brain

The current dogma of HD pathoetiology posits it is a degenerative disease affecting primarily the striatum, caused by a gain of function (toxicity) of the mutant mHTT that kills neurons. However, a growing body of evidence supports an alternative theory in which loss of function may also influence the pathology.This theory is predicated on the notion that HTT is known to be a vital gene for brain development. mHTT is expressed throughout life and could conceivably have deleterious effects on brain development. The end event in the disease is, of course, neurodegeneration; however the process by which that occurs may be rooted in the pathophysiology of aberrant development. To date, there have been multiple studies evaluating molecular and cellular mechanisms of abnormal development in HD, as well as studies investigating abnormal brain development in HD animal models. However, direct study of how mHTT could affect neurodevelopment in humans has not been approached until recent years. The current review will focus on the most recent findings of a unique study of children at-risk for HD, the Kids-HD study. This study evaluates brain structure and function in children ages 6–18 years old who are at risk for HD (have a parent or grand-parent with HD).

scholarly journals Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Genes ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 470
Author(s):  
Jeremy W. Prokop ◽  
Caleb P. Bupp ◽  
Austin Frisch ◽  
Stephanie M. Bilinovich ◽  
Daniel B. Campbell ◽  
...  
Keyword(s):  
Brain Development ◽  
Neural Progenitor Cells ◽  
Neurodevelopmental Disorder ◽  
Fetal Brain ◽  
Missense Variant ◽  
Neural Progenitor ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Systematic Analysis ◽  
Function Expression

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.

Imaging Normal and Abnormal Brain Development: New Perspectives for Child Psychiatry

2001 ◽  
Vol 35 (3) ◽  
pp. 272-281 ◽  
Author(s):  
Judith L. Rapoport ◽  
Xavier F. Castellanos ◽  
Nitin Gogate ◽  
Kristin Janson ◽  
Shawn Kohler ◽  
...  
Keyword(s):  
Attention Deficit Hyperactivity Disorder ◽  
Brain Development ◽  
Attention Deficit ◽  
Grey Matter ◽  
Brain Volume ◽  
Brain Magnetic Resonance Imaging ◽  
Childhood And Adolescence ◽  
Hyperactivity Disorder ◽  
Developmental Neuroscience ◽  
Abnormal Brain

Objective: The availability of non-invasive brain imaging permits the study of normal and abnormal brain development in childhood and adolescence. This paper summarizes current knowledge of brain abnormalities of two conditions, attention deficit hyperactivity disorder (ADHD) and childhood onset schizophrenia (COS), and illustrates how such findings are bringing clinical and preclinical perspectives closer together. Method: A selected review is presented of the pattern and temporal characteristics of anatomic brain magnetic resonance imaging (MRI) studies in ADHD and COS. These results are discussed in terms of candidate mechanisms suggested by studies in developmental neuroscience. Results: There are consistent, diagnostically specific patterns of brain abnormality for ADHD and COS. Attention deficit hyperactivity disorder is characterized by a slightly smaller (4%) total brain volume (both white and grey matter), less-consistent abnormalities of the basal ganglia and a striking (15%) decrease in posterior inferior cerebellar vermal volume. These changes do not progress with age. In contrast, patients with COS have smaller brain volume due to a 10% decrease in cortical grey volume. Moreover, in COS there is a progressive loss of regional grey volume particularly in frontal and temporal regions during adolescence. Conclusions: In ADHD, the developmental pattern suggests an early non-progressive ‘lesion’ involving neurotrophic factors controlling overall brain growth and selected dopamine circuits. In contrast, in COS, which shows progressive grey matter loss, various candidate processes influencing later synaptic and dendritic pruning are suggested by human post-mortem and developmental animal studies.

scholarly journals A circadian clock in Saccharomyces cerevisiae

2010 ◽  
Vol 107 (5) ◽  
pp. 2043-2047 ◽  
Author(s):  
Zheng Eelderink-Chen ◽  
Gabriella Mazzotta ◽  
Marcel Sturre ◽  
Jasper Bosman ◽  
Till Roenneberg ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Genetic Model ◽  
Circadian Clocks ◽  
Model Systems ◽  
Model Organisms ◽  
Biological Clocks ◽  
Experimental Systems ◽  
Fundamental Biological Process ◽  
Free Running ◽  
And Behavior

Circadian timing is a fundamental biological process, underlying cellular physiology in animals, plants, fungi, and cyanobacteria. Circadian clocks organize gene expression, metabolism, and behavior such that they occur at specific times of day. The biological clocks that orchestrate these daily changes confer a survival advantage and dominate daily behavior, for example, waking us in the morning and helping us to sleep at night. The molecular mechanism of circadian clocks has been sketched out in genetic model systems from prokaryotes to humans, revealing a combination of transcriptional and posttranscriptional pathways, but the clock mechanism is far from solved. Although Saccharomyces cerevisiae is among the most powerful genetic experimental systems and, as such, could greatly contribute to our understanding of cellular timing, it still remains absent from the repertoire of circadian model organisms. Here, we use continuous cultures of yeast, establishing conditions that reveal characteristic clock properties similar to those described in other species. Our results show that metabolism in yeast shows systematic circadian entrainment, responding to cycle length and zeitgeber (stimulus) strength, and a (heavily damped) free running rhythm. Furthermore, the clock is obvious in a standard, haploid, auxotrophic strain, opening the door for rapid progress into cellular clock mechanisms.

scholarly journals Decreased glucorticoid sensitivity as a factor of stressogenic shifts in the activity of monoamine oxidase, lipid peroxidation, and behavior in rats

2003 ◽  
Vol 49 (5) ◽  
pp. 48-51 ◽  
Author(s):  
I. A. Volchegorsky ◽  
V. E. Tseilikman ◽  
D. S. Smirnov ◽  
S. A. Ship ◽  
A. V. Borisenkov
Keyword(s):  
Lipid Peroxidation ◽  
Monoamine Oxidase ◽  
Brain Tissue ◽  
Behavioral Disorders ◽  
Immobilization Stress ◽  
Glucocorticoid Hormones ◽  
And Behavior ◽  
The Brain

Four episodes of immobilization stress cause a decrease in the sensitivity to glucocorticoid hormones, followed by anxiogenic be­havioral disorders, enhanced monoamine oxidase-В (МАО-В) activity and simultaneously increased lipid peroxidation (LPO) in the brain tissue of rats. Concurrently, there is an increase in renal МАО-В activity, as well as renal and hepatic accumulation of LPO products. Administration of kenalog (2 mg/kg), a phar­macological analogue of glucocorticoid hormones, prevents the poststress МАО-В activation and LPO and attenuates anxiogen­ic behavioral disorders in the rats.

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