From the dynamic synapse to synaptopathies Flashcards
What are synapses?
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
What are the types of synapses?
> Axodendritic
- axon to dendrite
- excitatory, inhibitory, or neuromodulatory
> Axosomatic
- axon to cell body
- inhibitory or neuromodulatory
> Axoaxonic
- axon to axon
What are the parts of a dendritic spine?
> Spine neck
Spine head
Post-synaptic Density (PSD) (tip of spine head)
- contains various proteins, including NTs
Why have dendritic spines?
- Increase surface area and synaptic connections a post-synaptic neuron can make
- Able to compartmentalise electrical and biochemical signals from the cell
- > influence the output of the neuron
How are dendritic spines able to compartmentalise electrical and biochemical signals from a cell?
> Spines have specialised shapes and vast numbers of proteins
- receptors
- adhesion proteins (physically connect pre- and post- synapses)
- scaffold protein (e.g. PSD-95)
> F-actin allows dendritic spines to change shape
What are the organelles found in dendritic spines?
> 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
What is the physiological role of dendritic spines?
- Synapse formation
- early development: dendritic spines emerge and search for pre-synaptic partner -> synaptic connection
- > formation of neural circuits/networks - Structural encoding of information
- LTP increases the size of existing dendritic spines
- Spine has the potential to form a synapse - 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
Which processes are explained in the filopodial model?
> Spinogenesis
> Synaptogenesis
What is the process of spinogenesis in the filopodial model?
What is ‘target selection’?
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’
What are the phases of synaptogenesis explained by the filopodial model?
- Synapse assembly
2. Synapse stabilisation
What happens during synapse assembling (filopodial model)?
> 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
What happens during synapse stabilisation (filopodial model)?
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
What is the association between dendritic spine structure and synaptic function?
The shape and size of a dendritic spine can provide information on its function
- larger dendritic spines -> larger synaptic connections
- thinner spines -> smaller connections
What is the evidence behind the link between dendritic spine structure and synaptic function?
> 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
How do dendritic spines have structural plasticity?
What is it essential for?
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
Are structural and functional plasticity linked in dendritic spines?
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
What is the process from structural plasticity of dendritic spines to the refinement of neural circuitry?
- Physiological stimulus can change
- number and size of dendritic spines - 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
What is the association between dendritic spine structure and mental ill-health?
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)
How is dendritic spine pathology linked to the emergence of disease?
Occurence 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
What do disease genetics indicate?
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
What are the molecular underpinnings of synaptic deficits in neuropsychiatric disorders?
> 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
What are the current treatments for schizophrenia?
> Antipsychotic drugs (haloperidol, olanzapine, clozapine)
> Behavioural treatment (CBT, adherence therapy)
What characterises the effects of antipsychotic drugs?
> 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
What is the implication of the little impact of antipsychotic drugs on negative symptoms, thought disorders or cognitive deficits?
Major implications in functional recovery:
- the severity of negative and cognitive symptoms of schizophrenia most associated with the functional recovery of patients
What characterises behavioural treatments of schizophrenia?
> 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
What is the structural and functional pathology of schizophrenia?
> 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
What are the environmental factors for the onset of schizophrenia?
> Infections
Hypoxia
Drug abuse
Stress
What is the genetic susceptibility in the onset of schizophrenia?
> Rare mutations: low occurence, high penetrance
- e.g. DISC1, NRXN1, 22q11,2 deletion
> Common variants: high occurence, low penetrance
- e.g. TCF4, ZNF804A
What increases the chance of onset schizophrenia?
Combination of genetic susceptibility (rare and common genetic variants) and environmental factors
What is the chain of consequence from the combination of environmental factors x genetic susceptivity, to schizophrenic symptoms?
Altered gene expression -> Altered brain wiring
-> Impaired information processing -> Schizophrenic symptoms
What makes the genetic landscape of schizophrenia highly complex?
> Some mutations are very rare but with strong effet
> Many variants have a weak effect, only slightly increasing chances of developing schizophrenia
Why use animal models for modelling synaptic defects in schizophrenia?
> Ability to look at overall morphology of the cell
> Examine how altering specific gene expressions can impact animal behaviour
Why use primary neuronal cell culture for modelling synaptic defects in schizophrenia?
> An easy way to manipulate gene expression of target gene, image neurons
Allows us to examine dendritic spines in detail
- dendritic spine analysis
What is DISC1?
‘Disrupted in schizophrenia one’ gene:
- related to schizophrenia, schizoaffective disorder, bipolar disorder, ASD, recurrent major depression
What is often seen resulting from mutation of DISC1?
> Reduction in the expression of the protein
or
Dominant negative effect
What is a dominant negative effect?
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
What is the effect of reduced levels of DISC1 on dendritic spines?
What does that show?
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
