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
stages of receptor clustering in neuromuscular junction
1) AChRs mRNA is expressed at low levels and channels are distributed
2) Agrin binds to MuSK which recruits Rapsyn which directly recruits AChRs
3) Neuregulin induces AChR expression in synaptic nuclei
4) Ach is released and can activate AChR anywhere, BUT if there is no agrin, its inhibits and destabalizes extra-synaptic AChRs
TTX
a neurotoxin that block activity in neurons and leads to synapse loss
survival of neurons depends on
coordinated electrical activity between pre and post synaptic cells
proBDNF and p75-NTR
proBDNF binds to p75-NTR and triggers depression and retraction of axons
BDNF and TrkB
BDNF binds to TrkB and triggers potentiation
MMP
when there is coordinated electrical activity between two cells, it increases MMP activity which processes proBDNF to BDNF to strengthen the synapse through TrkB maturation
ocular dominance columns
inputs from the LGN are segregated into eye-specific columns in layer 4 of the visual cortex. these columns reflect which eye/input is dominant. labelling only becomes apparent after eye opening
long term potentiation
high frequency stimulation of a hippocampal synapse results in increased post-synaptic EPSP
long term depression
low frequency stimulation of a hippocampal synapse results in decreased post-synaptic EPSP
why NMDAr is a coincidence receptor
because first AMPAr need to be activated by glutamate to release Na+ and cause depolarisation which removes block from NMDA so it can allow Ca+ influx
so it is activated by pre-synaptic glutamate release and a post-synaptic action potential
3 mechanisms operating in potentiation
1) changes in density and responsiveness to AMPAr -> increasing LTP and LTD
2) increase in synaptic size
3) changes in neurotransmitter release due to retrograde signals (NO, BDNF)
development of neurotransmitter phenotypes
in early patterning phenotypes, a set of transcription factors are turned on which dictate the types of neurons progenitors give rise to and these same TFs stay on to dictate the set of neurotransmitters expressed
motor neurons in triceps and pectoralis muscles have ___ inputs by ____
motor neurons in triceps and pectoralis muscles have monosynaptic inputs by proprioceptive Ia sensory neurons
motor neurons in cutaneous max and latissimus dorsi have ___ inputs by ___ due to ____
motor neurons in cutaneous max and latissimus dorsi have polysynaptic inputs by interneurons due to muscles releasing GDNF which turns on Pea3 in motor neurons
Er81
muscles expressing NT3 induce proprioceptive Ia sensory neurons to express Er81 which is required to develop central projection
examples of dependent and independent targets
dependent: muscle spindles need sensory input to differentiate
independent: merkel discs are present before sensory innervation
examples of how neurons can change as targets mature
- early action potentials are produced by Ca+
- responses can also change from excitatory to inhibitory (GABAr switches from outward Cl- to inward Cl-)
