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synaptogenesis, synapse function and refinement - Coggle Diagram

- - - - GABA = main inhibitory neurotransmitter
      - glutamate receiving are peripheral, inhibitory are close to soma
      - glutamate = excitatory neurotransmitter
      - proximal part of axon (AIS - where axon potentials are initiated) - lots of inhibitory synapses so that over excitation doesn't occur
      - most excitatory synapses are on spines
- - - - newly formed synapses have few, if any, vesicles in the presynaptic terminal
      - there is a close apposition of pre and post synaptic membranes (a tight junction)
      - postsynaptic membrane does not yet display a postsynaptic density
  - - - accumulation of Golgi apparatus
      - appearance of coated vesicles
    - - receptors must arrive in postsynaptic membrane through vesicles - made of glycoproteins
- - - - axodendritic
        
        most common
      - axosomatic
    - - axo-axonic
        
        axon initial segment (AIS) contact are GABA releasing to inhibit over excitation
      - dendro-dendritic
        
        most rare
  - - - creates the question - where are contacts first formed?
        
        filopodia
        
        small protrusions from soma and dendrite
        
        exploratory, very dynamic
        
        first contact
        
        at the end of filopodia psd95 expression shows contact has been made (GFP imaging)
        
        myopodia
        
        filopodia on muscle fibres
        
        first contact between motor neuron and five
        
        eventually reaches full synaptic junction
  - - - synapse formation is required for the development of neuronal structure in the functioning brain
      - some contacts are stabilised, innappropriate contacts will be removed
        
        removing the synapse automatically removes the filopodium
        
        stabilised filopodium generates new filopodia looking for possible partners
        
        if stabilised new filopodia generate from there
  - - - imaging contact events in vivo is considerably challenging, particularly in the CNS
      - neuromuscular junction is more accessible to labelling and imaging
        
        found that motor neurons, although they innervate clusters, pretty much always post synaptic differentiation appears first pre innervation
        
        always exceptions - cases where we see post synaptic structures in the absence of presynaptic neurons
        
        most of the time we know post synaptic differentiates first
        
        observations suggest the postsynaptic differentiation occurs in the absence of a presynaptic partner
  - - - works in concert with Neuregulin, known to activate transcription of synaptic receptos
      - we know that Agrin is secreted by the presynaptic neuron, binding to MuSK receptors and dimerising them with LRP4 - activating rapsyn
        
        rapsyn links multiple acetylecoholine receptors together
        
        you need agrin secreted by the motor neuron or mature and organise the post synaptic receptor
    - - neural agrin induces ACh receptors to cluster
        
        synaptic basal lamina forms
        
        the motor neuron specific form of agrin (cognate ligand for musk, proteoglycan) binds to two molecules of MuSK (receptor Tyrosine kinase), dimerising them along with molecule soft coreceptor LRP4
        
        assembly of a MuSK/LRP4 complex autophosphorylates internal portion of MuSK which activates raspyn
        
        raspin directly binds and anchors the cytoplasmic portion of several AChRs together and to the synaptic site
- - - - nt is packaged inside small vesicles in the presynaptic nerve terminal
      - when an action potential invades the nerve terminal, voltage gated calcium channels open and calcium flows into the cell
      - the influx of calcium triggers the fusion of the neurotransmitter-filled synaptic vesicles with the cell membrane, thereby releasing their contents into the synaptic cleft
    - - glutamate -> NMDA, AMPA receptors
      - GABA -> GABA receptors
      - Ach -> AChRs
  - - - stimulating motor neuron - immediately after contact see a small amplitude of PSC (post synaptic current), few minutes later muck bigger
        
        spontaneous AND evoked PSC
        
        both growth cone and postsynaptic cell generate many necessary components for communication pre innervation
    - - muscle cell contact enhances spontaneous and evoked transmission
      - both the growth cone and postsynaptic cell generate many of the components needed for neurotransmission well before innervation occurs
- - - - each target cell is innervated by the 'right' number of axons
      - each axon innervates the 'right' number of target cells
    - - much on what we know about synaptic refinement came from simpler and more accessible parts of the nervous system eg. neuromuscular junction and peripheral nervous system
    - - removal of immature contacts from all but one or few axons on each target and the focus on fewer target cells by a progressively increasing amount of synaptic machinery for each axon that remains
      - 1:1 relationship for motor neurons and muscle fibres - innervation might occur at mutiple targets but by maturation only one remains
  - - - multiple climbing fibres innervate form the inferior olivary nucleus synapse on purkinje cell somas
        
        by P11 in mice many somatic climbing fibre synapses are eliminates
        
        in second stage p12-p17 any remaining somatic climbing fiber synapses are pruned away (requires hebbian type plasticity)
        
        strengthening of single climbing fibre input occurs, while other inputs weaken and are eliminated
        
        additional influences of microglia promote the weakening of a subset of climbing fibre synapses
        
        climbing fibre input most synchronous to the purkinje neuron burst output becomes the 'winner'
        
        increased GABAergic innervation onto the purkinje cell soma from cerebellar basket cells drives the relative weakening of the losing climbing fibre inputs during the first stage of pruning
        
        during the later stage of pruning, signalling downstream of metabotropic glutamatergic receptors (mGluR1) in purkinje cell dendrites drives the pruning of any remaining somatic climbing finer synapses
        
        mGluR1 singaling simulates expression of membrane tethered semaphore Sema7a and the release of Brain-derived neurotropic factor from purkinje neurons onto remaining somatic climbing fibre synapses to facilitate their removal
        
        molecules eliminate losing climbing fibres and stabilise winning ones
        
        Sema3A is seceted from purkinje neurons to promote stabilisation and maturation of winning climbing fibres throughout pruning stages
        
        progranulin (derived from purkinje cells) binds to climbing fibres via Sort1 to strengthen and stabilise them
        
        influence of glia particularly specialised cerebellar astrocytes called Bergman glia is crucial in strengthening the winning synapses and preventing excessive climbing finer innervation along purkinje cell dendrites during later pruning stages
        
        a winning climbing fibre translocates and synapses on the purkinje cell dendrites
        
        differential neuronal activity drives a competitive pruning process (demonstrated by retinogenicular and cerebellar climbing fibre circuits)
        
        process of cerebellar climbing fibre pruning provides further insight into the activity dependent molecules that drive this competitive process
      - lots of cells pre pruning but ends up with only one
      - ALL POST NATAL
    - - when we are born have a similar number of neurons to adulthood
      - during early childhood lots of synaptic contacts are made in the brain
      - period of synaptic pruning occurs between 4-6 years - infantile amnesia?
      - synaptic pruning is very important - specific forces drive it
        
        trophic support and electrical activity sculpt connections
        
        axons compete for a limited amount of trophic factors, such as neurotrophina, provided by the target cell
        
        only contacts receiving sufficient amount of trophic support will survive and mature, rest is eliminated
        
        fine tuning of synaptic connections is determined by the pattern of electrical activity in the presynaptic neurons. a post synaptic cell may initially be innervated by many different presynaptic cells
        
        only presynaptic inputs whose activity is correlated in time with postsynaptic activity are maintiaed
        
        three presynaptic neurons make contact
        
        amount of neuronal activity differs
        
        two have similar amounts of activity
        
        one is asynchronous/diffeent amount of activity
        
        lack of synchrony causes axonal input to eventually be eliminated
        
        lots of other factors but key driver is electrical activity
        
        immune signalling
        
        MHC class I molecules and MHC receptor PirB
        
        neuronal pentraxins - cyclic multimeric proteins involved in calcium dependent ligand binding
        
        could be working together via microglia - resident macrophages of the CNS
        
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