scholarly journals Neuronal profilins in health and disease: Relevance for spine plasticity and Fragile X syndrome

2016 ◽  
Vol 113 (12) ◽  
pp. 3365-3370 ◽  
Author(s):  
Kristin Michaelsen-Preusse ◽  
Sabine Zessin ◽  
Gayane Grigoryan ◽  
Franziska Scharkowski ◽  
Jonas Feuge ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Actin Polymerization ◽  
Fragile X ◽  
Autism Spectrum ◽  
Actin Dynamics ◽  
Functional Changes ◽  
Mature Neurons ◽  
Disease Relevance ◽  
Adult Spine ◽  
Spine Plasticity

Learning and memory, to a large extent, depend on functional changes at synapses. Actin dynamics orchestrate the formation of synapses, as well as their stabilization, and the ability to undergo plastic changes. Hence, profilins are of key interest as they bind to G-actin and enhance actin polymerization. However, profilins also compete with actin nucleators, thereby restricting filament formation. Here, we provide evidence that the two brain isoforms, profilin1 (PFN1) and PFN2a, regulate spine actin dynamics in an opposing fashion, and that whereas both profilins are needed during synaptogenesis, only PFN2a is crucial for adult spine plasticity. This finding suggests that PFN1 is the juvenile isoform important during development, whereas PFN2a is mandatory for spine stability and plasticity in mature neurons. In line with this finding, only PFN1 levels are altered in the mouse model of the developmental neurological disorder Fragile X syndrome. This finding is of high relevance because Fragile X syndrome is the most common monogenetic cause for autism spectrum disorder. Indeed, the expression of recombinant profilins rescued the impairment in spinogenesis, a hallmark in Fragile X syndrome, thereby linking the regulation of actin dynamics to synapse development and possible dysfunction.

FMRP Modulates Activity-Dependent Spine Plasticity by Binding Cofilin1 mRNA and Regulating Localization and Local Translation

2019 ◽  
Vol 29 (12) ◽  
pp. 5204-5216 ◽  
Author(s):  
Jonas Feuge ◽  
Franziska Scharkowski ◽  
Kristin Michaelsen-Preusse ◽  
Martin Korte
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Treatment Strategies ◽  
Actin Dynamics ◽  
Actin Remodeling ◽  
Dendritic Spine Morphology ◽  
Novel Treatment Strategies ◽  
Activity Dependent ◽  
Spine Plasticity

Abstract Multiple variants of intellectual disability, e.g., the Fragile X Syndrome are associated with alterations in dendritic spine morphology, thereby pointing to dysregulated actin dynamics during development and processes of synaptic plasticity. Surprisingly, although the necessity of spine actin remodeling was demonstrated repeatedly, the importance and precise role of actin regulators is often undervalued. Here, we provide evidence that structural and functional plasticity are severely impaired after NMDAR-dependent LTP in the hippocampus of Fmr1 KO mice. We can link these defects to an aberrant activity-dependent regulation of Cofilin 1 (cof1) as activity-dependent modulations of local cof1 mRNA availability, local cof1 translation as well as total cof1 expression are impaired in the absence of FMRP. Finally, we can rescue activity-dependent structural plasticity in KO neurons by mimicking the regulation of cof1 observed in WT cells, thereby illustrating the potential of actin modulators to provide novel treatment strategies for the Fragile X Syndrome.

scholarly journals Impaired perceptual learning in Fragile X syndrome is mediated by parvalbumin neuron dysfunction in V1 and is reversible

2017 ◽  
Author(s):  
Anubhuti Goel ◽  
Daniel A. Cantu ◽  
Janna Guilfoyle ◽  
Gunvant R. Chaudhari ◽  
Aditi Newadkar ◽  
...  
Keyword(s):  
Perceptual Learning ◽  
Fragile X Syndrome ◽  
Visual Discrimination ◽  
Fragile X ◽  
Human Subjects ◽  
Autistic Traits ◽  
Autism Spectrum ◽  
Orientation Tuning ◽  
Mechanistic Basis

Atypical sensory processing is a core characteristic in autism spectrum disorders1 that negatively impacts virtually all activities of daily living. Sensory symptoms are predictive of the subsequent appearance of impaired social behavior and other autistic traits2, 3. Thus, a better understanding of the changes in neural circuitry that disrupt perceptual learning in autism could shed light into the mechanistic basis and potential therapeutic avenues for a range of autistic symptoms2. Likewise, the lack of directly comparable behavioral paradigms in both humans and animal models currently limits the translational potential of discoveries in the latter. We adopted a symptom-to-circuit approach to uncover the circuit-level alterations in the Fmr1-/- mouse model of Fragile X syndrome (FXS) that underlie atypical visual discrimination in this disorder4, 5. Using a go/no-go task and in vivo 2-photon calcium imaging in primary visual cortex (V1), we find that impaired discrimination in Fmr1-/- mice correlates with marked deficits in orientation tuning of principal neurons, and a decrease in the activity of parvalbumin (PV) interneurons in V1. Restoring visually evoked activity in PV cells in Fmr1-/- mice with a chemogenetic (DREADD) strategy was sufficient to rescue their behavioral performance. Finally, we found that human subjects with FXS exhibit strikingly similar impairments in visual discrimination as Fmr1-/- mice. We conclude that manipulating orientation tuning in autism could improve visually guided behaviors that are critical for playing sports, driving or judging emotions.

Altered Behaviour Associated With Autism in a Mouse Model of Fragile X Syndrome Treated With Bacteroides Fragilis BF839

2020 ◽  
Author(s):  
Chu-Hui Lin ◽  
Ting Zeng ◽  
Jian-Hong Lin ◽  
Feng Xiao ◽  
Bing-Mei Li ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Escape Latency ◽  
Fragile X ◽  
Bacteroides Fragilis ◽  
Autism Spectrum ◽  
Cognitive Capacity ◽  
Surrounding Environment ◽  
Maze Test ◽  
Plus Maze ◽  
The Impact

Abstract Background: Fragile X syndrome (FXS), tightly related to the morbidity of Autism spectrum disorder (ASD), is a common hereditary syndrome often associated with retardation of intelligence. Some key symptoms of ASD such as anxiety, cognitive impairment and social anxiety disorder are also the predominant features in FXS. Children with ASD are often performed with gastrointestinal symptoms. According to the existing research, with the treatment with Bacteroides Fragilis BF839, mice with ASD will have better performance in communication and social behaviours with less anxiety and perceptual disorder. In this article, we have observed the impact of Bacteroides Fragilis BF839, a well-established Chinese bacteria strain with the human intestine origin, on mice with FXS and their behavioural disorders accordingly. Result: Based on the Open Field test, compared to the Fmr1KO group, mice treated with BF839 showed prolonged staying time in the center of the container. This finding suggests that BF839 can improve Fmr1KO mice's self-exploration behaviour and dented their anxiety. The Elevated Plus Maze test indicated BF839 treated mice presented more activities in entering open arms, prolonged time of staying and significantly less distance travelled at the plus-maze, along with less entering behaviours in the closed arms with less time of staying and more distance travelled. This result proved that with the treatment of BF839, Fmr1KO mice have improved ability in recognizing the surrounding environment and greater senses at detecting danger. Three-box Social Interaction test confirmed that BF839 strengthens the social novelty preference of the Fmr1KO mice, proven by their increasing duration and frequency in social interacting with the stranger mouse. The final experiment named the Pool Maze test presented the result that on the fourth day, BF839 treated mice have shown significantly shortened escape latency. Meanwhile, on Day 5, BF839 treated group performed increasing frequency in passing through the platform, which, along with the shortened escape latency, demonstrated BF839 has the function of improving Fmr1KO mice's cognitive capacity and their ability to extract information from the surrounding environment.Conclusion: Based on the outcome of each test performed, Bacteroides Fragilis BF839 can successfully improve Autism related abnormal behaviours in mice with FXS. Bacteroides Fragilis BF839 can be a potential intervention strategy in treating FXS and ASD safely and effectively.

scholarly journals Cascade Testing for Fragile X Syndrome in a Rural Setting in Cameroon (Sub-Saharan Africa)

Genes ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 136
Author(s):  
Karen Kengne Kamga ◽  
Séraphin Nguefack ◽  
Khuthala Minka ◽  
Edmond Wonkam Tingang ◽  
Alina Esterhuizen ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Sub Saharan Africa ◽  
Rural Setting ◽  
Premature Menopause ◽  
Molecular Testing ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Cgg Repeats

Fragile X Syndrome (FXS), an X-linked dominant monogenic condition, is the main genetic cause of intellectual disability (ID) and autism spectrum disorder (ASD). FXS is associated with an expansion of CGG repeat sequence in the Fragile X Mental Retardation gene 1 (FMR1) on chromosome X. Following a neuropediatric assessment of two male siblings who presented with signs of FXS that was confirmed with molecular testing, we provided cascade counselling and testing to the extended family. A total of 46 individuals were tested for FXS; among them, 58.70% (n = 27) were females. The mean age was 9.4 (±5) years for children and 45.9 (±15.9) years for adults. Pedigree analysis suggested that the founder of these families was likely a normal transmitting male. Four out of 19 males with clinical ID were confirmed to have a full mutation for FXS, while 14/27 females had a pathologic CGG expansion (>56 CGG repeats) on one of their X chromosomes. Two women with premature menopause were confirmed of being carriers of premutation (91 and 101 CGG repeats). We also identified maternal alleles (91 and 126 CGG repeats) which expanded to a full mutation in their offspring (>200 CGG repeats). This study is a rare report on FXS from Africa and illustrates the case scenario of implementing genetic medicine for a neurogenetic condition in a rural setting.

scholarly journals Towards Mechanism-Based Treatments for Fragile X Syndrome

2019 ◽  
Vol 9 (8) ◽  
pp. 202
Author(s):  
Daman Kumari ◽  
Inbal Gazy
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Spectrum Disorder

Fragile X syndrome (FXS) is the most common heritable form of intellectual disability, as well as the most common known monogenic cause of autism spectrum disorder (ASD), affecting 1 in 4000–8000 people worldwide [...]

scholarly journals Abnormal development of auditory responses in the inferior colliculus of a mouse model of Fragile X Syndrome

2020 ◽  
Vol 123 (6) ◽  
pp. 2101-2121 ◽  
Author(s):  
Anna O. Nguyen ◽  
Devin K. Binder ◽  
Iryna M. Ethell ◽  
Khaleel A. Razak
Keyword(s):  
Mouse Model ◽  
Inferior Colliculus ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Abnormal Development ◽  
Sensory Sensitivity ◽  
Auditory Responses ◽  
Underlying Mechanisms ◽  
Early Developmental

Autism spectrum disorders (ASD) are commonly associated with sensory sensitivity issues, but the underlying mechanisms are unclear. This study presents novel evidence for neural correlates of auditory hypersensitivity in the developing inferior colliculus (IC) in the Fmr1 knockout (KO) mouse, a mouse model of Fragile X Syndrome (FXS), a leading genetic cause of ASD. Responses begin to show genotype differences between postnatal days 14 and 21, suggesting an early developmental treatment window.

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