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Current - BFoMH [Private] > From the dynamic synapse to synaptopathies > Flashcards

From the dynamic synapse to synaptopathies Flashcards

1
Q

What are synapses?

A
  • Sites of synaptic communication
    • can occur from sensory organs and neurons, between neurons, from neurons to target organs
    • unidirectional flow of info: pre-synaptic neuron to post-synaptic neuron
    • disruption of synapse structure and/or function -> brain dysfunction
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2
Q

What are the types of synapses?

A
  • Axodendritic
  • axon to dendrite
  • excitatory, inhibitory, or neuromodulatory
  • Axosomatic
  • axon to cell body
  • inhibitory or neuromodulatory
  • Axoaxonic
  • axon to axon
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3
Q

What are the parts of a dendritic spine?

A
  • Spine neck
  • Spine head
  • Post-synaptic Density (PSD) (tip of spine head)
    • contains various proteins, including NTs
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4
Q

Why have dendritic spines?

A
  1. Increase surface area and synaptic connections a post-synaptic neuron can make
  2. Able to compartmentalise electrical and biochemical signals from the cell -> influence the output of the neuron
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5
Q

How are dendritic spines able to compartmentalise electrical and biochemical signals from a cell?

A
  1. Spines have specialised shapes and vast numbers of proteins
    - receptors
    - adhesion proteins (physically connect pre- and post- synapses)
    - scaffold protein (e.g. PSD-95)
  2. F-actin allows dendritic spines to change shape
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6
Q

What are the organelles found in dendritic spines?

A
  • Receptors: NMDA and AMPA
  • Scaffold protein (e.g. PSD-95)
  • Adhesion proteins
  • Mitochondria (energy)
  • Polyribosomes: production of new proteins
  • F-Actin: allows dendritic spine to change shape
  • G-protein coupled receptors (GPCRs)
  • Spine apparatus
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7
Q

What is the physiological role of dendritic spines?

A
  1. Synapse formation
    - early development: dendritic spines emerge and search for pre-synaptic partner -> synaptic connection
    - > formation of neural circuits/networks
  2. Structural encoding of information
    - LTP increases the size of existing dendritic spines
    - Spine has the potential to form a synapse
  3. Neural circuit remodelling
    - dendritic spines change in number and shape
    - essential to normal brain function

=> changes in synaptic connectivity can occur in a bi-directional manner

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8
Q

Which processes are explained in the filopodial model?

A
  • Spinogenesis
  • Synaptogenesis
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9
Q

What is the process of spinogenesis in the filopodial model?
What is ‘target selection’?

A
  • Dendrite creates a dendritic protrusion: filopodia
  • it’s dynamic: moves around the neuropil, appears/disappears very quickly
  • do not have a head structure
  • do not contain the necessary proteins for synaptic connections (no post-synaptic density)
  • filopodia searches for a pre-synaptic partner = ‘target selection’
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10
Q

What are the phases of synaptogenesis explained by the filopodial model?

A
  1. Synapse assembly
  2. Synapse stabilisation
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11
Q

What happens during synapse assembling (filopodial model)?

A
  • NMDA receptors, scaffold protein PSD-95, and adhesion proteins are recruited to the nascent dendritic protrusion (filopodia)
  • Recruitment of these synaptic proteins signals the change of the filopodia into a dendritic spine
  • Nascent dendritic spine has a head with PSD and contains key elements for synaptic communication
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12
Q

What happens during synapse stabilisation (filopodial model)?

A

Synaptic activity induces recruitment of more adhesion molecules, NMDAR and other synaptic proteins (after synapse assembly) to further stabilise the dendritic spines

-> establish pre- and post-synaptic structures as fully functional synaptic connection

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13
Q

What is the association between dendritic spine structure and synaptic function?

A
  • The shape and size of a dendritic spine can provide information on its function
    • larger dendritic spines -> larger synaptic connections
    • thinner spines -> smaller connections
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14
Q

What is the evidence behind the link between dendritic spine structure and synaptic function?

A
  • AMPA receptors are enriched in dendritic spines
    • large spines -> lot of GluA1-containing AMPAR
      • more likely to have bigger reactions to Glu or synaptic activities
    • thin spines -> much less GluA1-containg AMPAR
      • smaller responses to Glu
  • Functional AMPAR content is correlated with spin geometry
    • larger dendritic spines typically contain more AMPA receptors and generate larger excitatory post-synaptic currents, than smaller spines
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15
Q

How do dendritic spines have structural plasticity?
What is it essential for?

A

Dendritic spines can change shape in response to different stimuli

  • LTP -> dendritic spines increase in size
  • LTD -> dendritic spines decrease in size

=> Structural plasticity, essential role in encoding information

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16
Q

Are structural and functional plasticity linked in dendritic spines?

A

Kopec et al. (2006): Induction of chemical LTP (cLTP)

  • Spine size increased, and the amount of GluA1 as well
  • As spine size increased, amount of AMPAR also increased

=> Structural and functional plasticity are linked

17
Q

What is the process from structural plasticity of dendritic spines to the refinement of neural circuitry?

A
  1. Physiological stimulus can change
    - number and size of dendritic spines
  2. Causes an increase in the amount of AMPA receptors within spines
    - > change of synaptic strength

=> Structural and functional plasticity are linked and can be changed
=> Refined neural circuitry

18
Q

What is the association between dendritic spine structure and mental ill-health?

A
  • Aberrant dendritic architecture or abnormal dendritic spine density
    • altered neuronal activity -> lost synaptic connections, altered Glu/GABAergic connections
    • Cognitive deficits seen in brain disorders (e.g. ASD, schizophrenia, Rett syndrome, Fragile X syndrome, Down syndrome, Alzheimer’s disease)
19
Q

How is dendritic spine pathology linked to the emergence of disease?

A

Occurrence of specific disease symptoms coincides with critical periods of synapse formation:

  • symptoms of ASD emerge during early childhood, when there is increased spine and synapse formation
  • symptoms of schizophrenia emerge during adolescence and early adulthood, period of synaptic connection refinement (synapse pruning)

Theory: increase of synapse elimination during adolescence / early childhood might contribute to emergence of schizophrenia symptoms

20
Q

What do disease genetics indicate?

A

Critical role of synapses:

  • large studies identified increasing number of genetic variants that can cause a change in the sequence of specific proteins associated with disease risk
  • e.g. many de novo protein coding mutations associated with neurodevelopmental and psychiatric disorders occur in proteins found in synapses
21
Q

What are the molecular underpinnings of synaptic deficits in neuropsychiatric disorders?

A
  • Genes implicated with disease encode for proteins localised at dendritic spines
  • And have critical roles in dendritic spine formation, maintenance and remodelling
  • AMPA/NMDA receptors
  • voltage-gated Ca2+ channels
  • cell adhesion molecules
  • Glu receptors
  • Scaffold proteins
  • Ca2+ signalling molecules
  • GTPase signalling molecules
  • Alteration in the function of these proteins could result in dysfunction of dendritic spines -> impacting synaptic communication and connectivity
22
Q

What are the current treatments for schizophrenia?

A
  • Antipsychotic drugs (haloperidol, olanzapine, clozapine)
  • Behavioural treatment (CBT, adherence therapy)
23
Q

What characterises the effects of antipsychotic drugs?

A
  • Good at addressing positive symptoms
  • 1/4 of patients are non-responsive
  • Little impact on negative symptoms and thought disorders or cognitive deficits
  • Side effects include sedation, weight gain, and motor deficits
24
Q

What is the implication of the little impact of antipsychotic drugs on negative symptoms, thought disorders or cognitive deficits?

A

Major implications in functional recovery:
- the severity of negative and cognitive symptoms of schizophrenia most associated with the functional recovery of patients

25
Q

What characterises behavioural treatments of schizophrenia?

A
  • Used as an adjunct to anti-psychotic drug treatment
  • effective in reducing relapse and resistant symptoms
  • Little impact on the negative and cognitive symptoms, therefore little impact on functional recovery
26
Q

What is the structural and functional pathology of schizophrenia?

A

> Reduced grey matter (neuronal cell bodies) in patients vs. controls
> Differences in overall brain volume

> EEG and MEG studies: dysfunction in neuronal network function in schizophrenic patients

> Reduced number of dendritic spines in patients with schizophrenia

27
Q

What are the environmental factors for the onset of schizophrenia?

A

> Infections
> Hypoxia
> Drug abuse
> Stress

28
Q

What is the genetic susceptibility in the onset of schizophrenia?

A

> Rare mutations: low occurence, high penetrance
- e.g. DISC1, NRXN1, 22q11,2 deletion

> Common variants: high occurence, low penetrance
- e.g. TCF4, ZNF804A

29
Q

What increases the chance of onset schizophrenia?

A

Combination of genetic susceptibility (rare and common genetic variants) and environmental factors

30
Q

What is the chain of consequence from the combination of environmental factors x genetic susceptivity, to schizophrenic symptoms?

A

Altered gene expression -> Altered brain wiring -> Impaired information processing -> Schizophrenic symptoms

31
Q

What makes the genetic landscape of schizophrenia highly complex?

A
  • Some mutations are very rare but with strong effect
  • Many variants have a weak effect, only slightly increasing chances of developing schizophrenia
32
Q

Why use animal models for modelling synaptic defects in schizophrenia?

A
  • Ability to look at overall morphology of the cell
  • Examine how altering specific gene expressions can impact animal behaviour
33
Q

Why use primary neuronal cell culture for modelling synaptic defects in schizophrenia?

A
  • An easy way to manipulate gene expression of target gene, image neurons
  • Allows us to examine dendritic spines in detail (dendritic spine analysis)
34
Q

What is DISC1?

A

‘Disrupted in schizophrenia one’ gene:

  • related to schizophrenia, schizoaffective disorder, bipolar disorder, ASD, recurrent major depression
35
Q

What is often seen resulting from mutation of DISC1?

A
  • Reduction in the expression of the protein
    or
  • Dominant negative effect
36
Q

What is a dominant negative effect?

A

Mutation that dominantly affects the phenotype
- by means of a defective protein or RNA molecule that interferes with the function of the normal gene product in the same cell

37
Q

What is the effect of reduced levels of DISC1 on dendritic spines?
What does that show?

A

Fewer dendritic spines, consistent with previous studies

=> DISC1 plays a significant role in maintenance of dendritic spines
=> Alterations in the expression level of the protein could impact synaptic connectivity in the brain

Current - BFoMH [Private] (15 decks)

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