week 10 - disease and dendritic spines Flashcards
(14 cards)
Learning objectives
- Evidence for synaptic dysfunction in neurodevelopmental and psychiatric conditions
- linking genetics with synaptic dysfunction
- stem cell models of synaptic dysfunction
What are differences in dendritic spines and dendritic spine patholody in autism, rett syndrome and AD?
Name one caveat with these studys:
Read Kulkarni and Firestein (2012)
Read Fiala et al, 2012
-ASD shows more dendritic spines.
- SCZ shows to few dendritic spines
CAVEAT
- How do we distinguish between cause or consequence
- Especially because most of these studies are post-mortem
evidence that synapses play a critical role in these diseases
- studies in disease genetics indicate a critical role for synapses
- lots of gene variants associated with these conditions occur in genes that code for synaptic proteins or are implicated in synaptic function
- Forrest et al, 2018
What evidence links dendritic spine pathology to psychiatric disorders?
Post-mortem studies of human brains reveal significant alterations in dendritic spine number, morphology, and distribution in psychiatric conditions such as autism spectrum disorder, schizophrenia, and Alzheimer’s disease. For example, Glantz & Lewis (2000) reported reduced dendritic spine density in Layer 3 pyramidal neurons of the dorsolateral prefrontal cortex in patients with schizophrenia. These findings suggest disrupted excitatory synaptic input, potentially contributing to cognitive dysfunction.
How does genetics contribute to synaptic dysfunction in disease?
Genetic association studies, including genome-wide association studies (GWAS), have linked numerous risk variants to genes involved in synaptic function. Forrest et al. (2018) demonstrated that these variants often affect genes encoding postsynaptic density proteins, scaffolding molecules, and cell adhesion proteins. These genetic disruptions can impair synaptogenesis, plasticity, and connectivity, contributing to the pathophysiology of neurodevelopmental and psychiatric disorders.
What dendritic abnormalities are seen in schizophrenia?
Schizophrenia is associated with reduced dendritic branching, lower dendritic spine density, and decreased arbor complexity in pyramidal neurons, particularly in the cortex and hippocampus. Kulkarni & Firestein (2012) highlighted cytoskeletal disruptions as a cause of these structural deficits, which are believed to underlie impairments in working memory and executive function characteristic of the disorder.
How are synapses imaged in the human brain?
Synaptic density in vivo can be measured using positron emission tomography (PET) with tracers like [11C]UCB-J, which bind to the synaptic vesicle protein SV2A. This enables non-invasive assessment of synaptic integrity. Onwordi et al. (2020) found reduced SV2A binding in the frontal cortex, hippocampus, and anterior cingulate cortex in patients with schizophrenia, suggesting widespread synaptic loss and supporting the synaptopathy hypothesis.
What are the pros and cons of animal models for schizophrenia?
Animal models allow for precise genetic manipulation, targeted circuit interrogation, and reproducible behavioural assays. However, they often fail to capture the polygenic nature of human schizophrenia. Full gene knockouts may not reflect the subtler mutations found in patients, and species differences in brain organisation and behaviour limit translational validity. As such, results must be interpreted with caution when applying them to human disease.
What are iPSCs and how are they generated?
Induced pluripotent stem cells (iPSCs) are reprogrammed adult somatic cells (e.g., fibroblasts or blood cells) that regain the ability to differentiate into any cell type. This is achieved by introducing the Yamanaka factors (OCT4, SOX2, KLF4, and c-MYC). iPSCs can be differentiated into neurons, providing a human-relevant platform to model brain disorders in vitro, especially for diseases like schizophrenia where live brain tissue is inaccessible.
How do iPSC-neurons from schizophrenia patients differ from controls?
Neurons derived from schizophrenia patient iPSCs often show reduced dendritic arborisation, lower expression of synaptic proteins like PSD95, and impaired synaptic connectivity. Brennand et al. (2011) found these neurons form fewer synapses and exhibit altered electrophysiological properties, indicating disrupted neuronal development and function that may reflect underlying disease mechanisms.
What is the DISC1 mutation and its effect in iPSC models?
The DISC1 (Disrupted-in-Schizophrenia 1) 4-base pair deletion leads to ~80% reduction in DISC1 protein levels. Wan et al. (2014) showed that iPSC-derived neurons with this mutation exhibit significantly fewer synapses, decreased SV2A levels, and reduced frequency of miniature excitatory postsynaptic currents (mEPSCs), indicating compromised synaptic transmission. This supports DISC1’s role in synaptic development and schizophrenia pathology.
How does genome editing help study schizophrenia?
Genome editing tools like CRISPR/Cas9 allow researchers to correct or introduce specific mutations in iPSC-derived neurons. In Wan et al. (2014), correcting the DISC1 mutation in patient-derived neurons rescued synapse number and function. Conversely, introducing the mutation into control neurons reduced synaptic density. This demonstrates a direct, causal role of DISC1 disruption in synaptic pathology.
What kind of neurons do iPSCs generate?
Transcriptomic analysis shows that iPSC-derived neurons most closely resemble fetal human forebrain neurons. This makes them particularly suited to studying early developmental stages of psychiatric and neurodevelopmental disorders, where initial synaptic abnormalities and gene expression dysregulation may occur (Brennand et al., 2014).
