Modelling of Neuropsychiatric Diseases Flashcards
Disadvantages of mice
Lack of translational significance
No higher brain function, no polygenic variants
Disease-relevant cell types differ to humans, genetic differences
Human neocortex much more complex
Cell cycle times of neuronal progenitors are much larger
Other used models
Post mortem tissue
Imaging for structural & functional studies
GWAS (Associate traits to genes)
Primate models
iPSC
phNPCs
Primary human neuroal precursor cells
From fetal postmortem cortex
Aggregated in neurospheres, differentiated into neurons & glia = In vivo fetal cortical development up to mid gestation
iPSC
From primary human cell –> iPSC –> NPC –> Differentiated neuronal cells
Low genetic stability (CNV or SNV), epigenetic markers rest during reprogramming
Study causal links between disease variants & cellular phenotypes
iNeurons
Induced neurons
Directly from primary human cell by combination of induction factors
Retain many epigenetic markers but do no allow featl brain development study
Patterned 2D culture
Small-molecule patterning & TF induction on cellular level
Increased enriched uniform populations of targeted cell types, scalable & reproducible
Do not fully capture in vivo development
Patterned 3D culture
Small-molecule patterning on brain structure level
Capture architecture & cellular environment, interaction of different cell types
But: Much longer differentiation time & less scalable
Unguided organoid differentiation
Potential to develop into multiple neural structures
Used to observe patterning, cell-cell interactions through region, synapse formation
Composition inconsistent across experiments
Vary in size & cell type composition different regional identities
Guided differentiation
Small molecules to promote neural induction
Manipulation of relevant signaling pathways –> Different structures
Cortical organoids
Day 0: SMAD inhibition
Day6: FGF2, EGF
Day 25: BDNF, NT3
Strengths of organoids
Indistinguishable compendium of cell types, following similar developmental trajectories with a degree of organoid-to-organoid variability comparable to human brains
Consistent reproducibility if derived from different stem cell lines
Genome-wide transition mapping (TMAP)
Assess extent of overlap between in vivo cortical development & in vitro differentiation
Assembloids
Organoids generated by spatially organizing multiple cell types = Tissue function
Region-specific organoid differentiation –> 3D assembly of spheroids –> Multiregion
Long distance projections possible & interneuron migration
Use to assemble a multi-synaptic circuit in vitro
