lec 14-16. axon-target interactions Flashcards
trophic factors
“food” molecules that allow neurons to develop
neurotrophic factor hypothesis
1) neurons are produced in excess and then eliminated
2) targets release neurotrophic to promote survival, according to tissue size
effectively size control -> keeps tissue size and innervation proportional
how are excess axons eliminated
through cell death
cell death proteins and c. elegans homologues
Bcl-2: non-apoptotic (ced9)
Ced-3/4: pro-apoptotic (caspase1/ced4)
Bax
caspase 1/9
two types of caspases
caspase 9 - initiator
caspase 1 - executioner
nerve growth factor (NGF)
a type of neurotrophin dimer with active subunit B-NGF. affects cell survival, neurite survival, and even guides growth cones. binds to recetoprs and is internalised and transported to soma (DRG cell bodies also take up TrkA receptor)
TrkA receptor
high affinity receptor for NGF
tyrosine kinase receptor that forms signalling endosome and is transported throughout the cell
works by activating MAP kinase pathway (affecting proliferation) and Akt pathway (inhibits apoptosis)
p75-NTR
low affinity receptor for NGF, and also pro-NGF
can promote either cell survival or cell death based on the context (balance between ligand and receptor)
has intracellular death domain which initiates caspase mediated cell death in the absence of a ligand, and is thus a “dependence receptor”
neurotrophin family
- brain-derived neurotrophic factors (BDNFs)
- NT3
- NT4/5
all are also dimers
examples of how different neurons are dependent on different neurotrophins
nodose - BDNF, NT3 DRGs - BDNF, NTF, NGF sympathetics - NT3, NGF ruffini afferents - BDNF Merkel - NT3, NGF, p75
how dependency of neurotrophins change with time
they initially have no dependency, then during development need NT3 and BDNF to reach target, then once at target need NGF and MSP
other families that neurotrophic factors belong to
- glial-derived neutrotrophic factors
- cytokines (CNTF, HGF, MSP)
pruning
prune back excess axons, common in development and shares features such as cell fragmentation and phagocytosis with cell death
two examples of pruning
1) cortio-spinal and cortico-collicular initially start the same
2) can separate cell body and axon so axon is NGF-deprived so it starts shedding caspase 6 which binds to death receptor 6 and causes axon degradation
death receptor 6
a tumour necrosis factor with an intracellular death domain and causes cell death (or axon degradation) upon binding of ligand. therefore a “death receptor”
morphological changes that occur when growth cone turns into pre-synapse
1) filopodia retraction
2) membrane proteins + extracellular glycoproteins added
3) presynaptic vesicles, dense ECM, PSD, and receptors accumulate in the cleft
contacts by which neuron areas can initiate synapses?
growth cones mainly
but also axon branches, and dendritic filopodia
when does synaptogenesis occur in spinal cord vs. cortex?
spinal cord and brainstem occurs pre-birth
cortex synapse form after birth
Neurexins and Neuroligins
highly specific synapse CAMs that function in synapse specification (selecting appropriate contact), induction (clustering), and axon guidance
intracellular domains of neurexins and neuroligins can..
assemble parts into active zone and post synaptic density
spatial segregation of excitatory and inhibitory inputs
neurexins and neuroligins allow pre-synaptic cells to make contacts with multiple different post-synaptic partners
post-synaptic cells localise neuroligins which allows excitatory and inhibitory innervation by pre-synaptic cells to be separated
single neurons get multiple inputs and synapses are plastic and can be rearranged
3 models for synapse/spine formation
1) dendritic spines develop independently of pre-synaptic inputs and dictate where these will be
2) pre-synaptic inputs induce spine formation
3) dendritic filopodia induce synapses in axons that are growing past
how are contacts between dendrites and axons mediated?
they are directly mediated by CAMs (eg. neurexins/neuroligins) or through soluble factors released by either pre/post-synaptic cell
CASK and PSD-95
contact triggers calcium influx which recruits cask (pre-synaptic) and PSD-95 (post-synaptic) which are scaffolding proteins that provide the framework for protein complexes in the active zone and pre-synaptic density
