Methods to Study NDDs Flashcards

1
Q

Give examples of NDDs

A
  • intellectual disability
  • communication disorders
  • autism spectrum disorder
  • ADHD
  • neurodevelopmental motor disorders
  • specific learning disorders
  • schizophrenia
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2
Q

What are the DSM-5?

A

a group of conditions with onset in the developmental period, inducing deficits that produce impairments of functioning

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3
Q

What causes neurodevelopmental disorders?

A

disruption of formation of neuronal networks

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4
Q

What causes neurodegenerative disorders?

A

disruption of established neuronal networks

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5
Q

What is the time of onset of degenerative disorders?

A

after neuronal circuits have been formed

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6
Q

Give examples of degenerative disorders

A
  • AD
  • PD
  • HD
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7
Q

Give examples of developmental disorders

A
  • autism
  • ADHD
  • anxiety disorders
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8
Q

What does the time of onset of developmental disorders correlate to?

A

development of the brain

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9
Q

Which developmental stages are affected by neurodevelopmental diseases?

A
  • neurogenesis
  • neuronal migration
  • neuronal differentiation
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10
Q

Which biological processes are affected by neurodevelopmental diseases?

A
  • regulation of protein synthesis
  • regulation of transcription
  • epigenetic regulation
  • synaptic signalling
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11
Q

Give examples of common themes between human NDDs

A

changes in neuronal networks and synaptic function

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12
Q

What are synaptopathies?

A

brain disorders with underlying synaptic dysfunction that result from alterations in intrinsic synaptic molecular mechanisms

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13
Q

What are causes of synaptopathies?

A
  • mutations of synaptic genes
  • mutations of genes involved in neuronal and synapse development
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14
Q

What are the 8 steps of synaptic transmission?

A
  1. synaptic vesicle loading
  2. docking
  3. priming
  4. vesicle fusion
  5. clathrin-mediated endocytosis
  6. uncoating
  7. endosome fusion
  8. synaptic vesicle reformation
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15
Q

What does the postsynaptic density do?

A

mediate clustering of receptors and cell-adhesion molecules and orchestrate the coupling of diverse signalling components

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16
Q

Give examples of implicated presynaptic genes

A
  • synapsins
  • synaptophysin
  • piccolo
  • SNAP25
  • cadherin
17
Q

Give examples of implicated postsynaptic genes

A
  • neuroligin 3 and 4
  • neurexin 1
  • ApoE e4 allele
  • calcineurin
18
Q

What are dendritic spines?

A

tiny protrusions from dendrites, which form functional contacts with neighbouring axons of other neurons and receive input from one excitatory synapse

19
Q

What do dendritic spines do?

A
  • implement input-specific synaptic plasticity
  • enhance synaptic connectivity
  • modify synaptic potentials
20
Q

What do dendritic spines represent?

A

excitatory postsynaptic compartments

21
Q

What is synaptic pruning?

A

he process in which the brain removes neurons and synapses that it does not need (normally happens between age 2-10)

22
Q

What changes in neuropsychiatric disorders?

A

spine density

23
Q

What do changes in spine density affect?

A

neuronal networks

24
Q

What do guidance cues do?

A

wire neurons into networks

25
Q

What is the first step in studying synaptopathies?

A

identifying the genes involved

26
Q

How can specific genes be identified?

A
  • forward genetics (mutagenesis, positional cloning)
  • reverse genetics (ectopic expression, gene silencing, gene targeting)
  • GWAS
  • whole genome sequencing
27
Q

Give examples of models used to study synaptic disorders

A
  • 2D cell cultures
  • C. elegans
  • drosophila
  • zebrafish
  • mouse
  • human organoids
28
Q

Give examples of methods used to study synaptopathies

A
  • synaptosomes/synaptoneurosome isolation
  • neuropil microdissection
  • axon-TRAP
  • fluorescent activation cell sorting for synaptosomes
  • puromycin proximity ligation assay
  • expansion sequencing
29
Q

Give examples of microscopic strategies for studying synapses

A
  • enumeration of spine density and morphologies
  • investigation of synaptic marker distribution
  • investigating nanoscale synaptic organisation
  • whole cell / single synapse imaging of synaptic transmission
  • electrophysiology
30
Q

How can axons and dendrite development be viewed?

A

Sholl analysis

31
Q

What happens during Sholl analysis?

A

concentric ircles are superimposed on the dendritic processes and at each point of intersection, the number of crosses is counted to produce a plot

32
Q

What do brain organoids do?

A

capture the key features of human brain development and organisation

33
Q

What can brain organoids be used for?

A

precision medicine

34
Q

What are the limitations of organoid technologies?

A
  • cellular components
  • standardisation
  • costly
  • scalability issues
  • heterogeneity
  • lack of output compared to whole organisms