Neurodevelopmental disorders- Lucky Dip Flashcards
What is the relationship between the levels of brain-derived neurotrophic factor (BDNF) and ASD?
A systematic review and meta-analysis found that individuals with ASD tend to have lower levels of BDNF compared to neurotypical individuals
Rylaarsdam and Guemez-Gamboa 2019
What is the role of sex hormones in autism spectrum disorder (ASD) pathology?
Explain the potential role of sex hormones in the pathology of Autism Spectrum Disorder (ASD).
- Sex differences in ASD
- Testosterone influences dendritic spine density
- Estrogen recovers ASD phenotypes in animal models
- Testosterone and estrogen differently modulate immune system in ASD
Rylaarsdam and Guemez-Gamboa 2019
What are brain organoids, and how are they utilized in ASD research?
- Brain organoids are three-dimensional cell cultures that mimic the development of the human brain
- Created from iPSCs from ASD individuals-> can investigate specific genetic mutations
- Eg Wang et al 2022 used SNR-derived organoids to study SHANK3, organoids are functionally mature and capable of generating various electrical signals and oscillatory rhythms
How are SNR-derived organoids used to study ASD?
single neural rosettes= SNR
- SNRs are self-organized structures derived from stem cells; very similar organization and properties of anterior neural tube cells
- Used to study SHANK3 deletion (causes ASD)
- Generate many cell types: 1) neural progenitors, 2) excitatory/inhibitory interneurons 3) excitatory/inhibitory neurons
- In this study, telencephalic identity was confirmed with FOXG1 and absense of markers for other germ layers or brain regions
Wang et al., 2022
this study validates SNR-derived organoids as a model for studying brain development
This study identifies intrinsic, synaptic, and clustered protocadherin expression deficits in human telencephalic tissue with SHANK3 hemizygosity
Explain the significance of GSX2 expression in the context of brain organoid research and ASD
Wang et al 2021:
- The presence of GSX2-expressing NPs in these organoids may contribute to the successful generation of ISPNs, a cell type previously not observed in some telencephalic organoid models
- Transcription factor GSX2 appears to be crucial for the specification of inhibitory subpallial neurons, specifically inhibitory striatal projection neurons (ISPNs), in SNR-derived organoids.
- Relevant because imbalances in excitatory/inhibitory (E/I) signaling have been implicated in ASD.
- By manipulating GSX2 expression in organoid models, researchers can gain a deeper understanding of its impact on neuronal differentiation, circuit formation, and ultimately, the development of ASD phenotypes
Discuss the role of the SHANK3 gene in ASD and how its deficiency is modeled in brain organoids
- SHANK3 cruical protein regulating post synaptic density, and its deletion underlies ASD pathology
- SHANK3 deficiency (hemizygous +/-) is modeled in brain organoids (SNR) by using CRISPR/Cas9
- This allows researchers to study the effects of SHANK3 loss on neuronal development and function:
- Found 1) synaptic deficits, 2) neuronal hyperexcitability and 3) impaired clustered protocadherin expression
Wang et al 2022
synaptic gene deletions can disrupt the development and function of synapses, leading to alterations in neural circuitry and ultimately contributing to the behavioral and cognitive symptoms of ASD.
What are the electrophysiological differences observed between iCtrl and SHANK3-deficient neurons in brain organoids?
Wang et al 2021 found that SHANK3-deficient neurons exhibit increased excitability compared to control neurons. This is manifested in shorter action potential latency, smaller membrane capacitance, more hyperpolarized action potential threshold, reduced afterhyperpolarization potential amplitude, and increased firing rate in SHANK3-/- neurons.
Explain how targeted DNA methylation of the Mecp2 promoter is achieved and its implications for understanding ASD
Lu et al 2020 used dCas9-DNMTA3 to target DNA methylation of the Mecp2 promoter
- This system involves fusing the DNA methyltransferase DNMT3A to a catalytically inactive Cas9 (dCas9) guided by specific sgRNAs to the Mecp2 promoter region.
- This targeted methylation leads to gene silencing, allowing researchers to study the impact of Mecp2 downregulation on neuronal function and ASD-like phenotypes in animal models.
Discuss the rationale for targeting mGluR7 as a potential therapeutic target in Rett Syndrome.
Gogliotti et al 2017
Targeting mGluR7, a metabotropic glutamate receptor, is proposed as a potential therapeutic strategy in Rett Syndrome based on the finding that its function is impaired in Mecp2-deficient models.
Enhancing mGluR7 activity with positive allosteric modulators like VU0422288 has shown promise in rescuing synaptic plasticity defects and improving behavioral phenotypes associated with Rett Syndrome in preclinical studies
Explain the role of the MECP2 gene in Rett Syndrome
MECP2 causes Rett syndrome, located on X chromosome and necessary for brain development, regulates expression of a variety of developmental genes
Oluigbo 2023
What are the current therapeutic strategies for Timothy Syndrome?
Chen et al 2024 investigated antisense oligonucleotides (ASOs) which are synthetic molecules that specifically target and modify RNA- potentially correcting abnormal splicing of CACNA1C and restore normal Ca2+ channel function
Timothy Syndrome, a rare genetic disorder characterized by heart defects, autism, and distinctive facial features, is caused by mutations in the CACNA1C gene, which encodes L-type calcium channel.
