HTHSCI 1DT3 Study Guide - Quiz Guide: Basal Ganglia, Tropomyosin Receptor Kinase C, Rac1
23 Jun 2018
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“Neurons do the talking and astrocytes just clear up afterwards” Discuss the extent to which
this is true and consider ways in which it is not the case.
Introduction
Neurons and astrocytes form a major part of the central nervous system and its vastly
complex, intricate circuitry.
Both neurons and astrocytes associated with CNS – develop from the neural tube of the
embryo.
Neurons are classically known for their crucial role in signal transmission – receiving
inhibitory and excitatory signals through dendrites, which are then processed and
modulated to determine whether a resultant signal is propagated through the axon.
Astrocytes form part of the macroglia subset of cells (along with oligodendrocytes) in the
nervous system – which are traditionally known for their supportive function in
maintaining an environment for the neurones to function correctly in.
Typically stellate shape, and form intimate attachments with neurons. Also form large
syncytial networks
Astrocyte function to support neurones and ‘clear up’:
Gateway: Astrocytes act as a gateway at the BBB between general circulation and
neurons of the brain, in association with endothelial cells – they wrap their endfeet around
endothelia. Allows transfer of nutrients to neurones, and removal of waste material into
the blood.
Removal of K+: K+ important for neurotransmission, and extracellular levels can increase
following periods of neuronal activity. Important to keep extracellular concentrations low
– redistribution by astrocytic network (gap junctions), and acts as K+ reservoir.
Removal of neuronal debris (phagocytic role): from CNS, transports away to the
bloodstream
Regulate concentration of neurotramsitter: Clears used neurotransmitters (involved in
recycling) e.g. EAAT2 glutamate reuptake.
Failure of these associated with diseases such as ALS (leading to excitotoxicity of
postsynaptic neurons).
Astrocytes arguably have additional functions:
Energy Store: Store glycogen and provide energy to neurons (in the form of lactate).
Water Reservoir: Large cytoplasmic water content with relatively few organelles – act as a
water reservoir in CNS.
Structural Support: Astrocytes have a strong stellate shape that provides support in the
CNS to neuronal structure. High presence of IF GFAP – allows for reinforced tensile
strength important for maintaining support of the CNS structure.
Neurodevelopment (radial glia) – neuronal migration: Early in development, radial glia
(precursors of astrocytes) are important to allow migration of neuronal precursors. Radial
glia span ventricular surface to pial surface, and permit migration of neuronal precursors
along them to form cortical regions (inside-out).
Once development/migration is complete – gliogenic phase develops radial glia into
astrocytes.
Stem Cells – Progenitor cells from neuronal development thought to still exist as stem
cells in subventricular regions (held in quiescence by GABA spillover?), and in
hippocampal (subgranular zone) in mice?
Astrocytes also provide guidance cues for migration of growth cones during axonal
outgrowth, through production of soluble chemoattractants and soluble survival factors.
Similar importance in synaptogenesis - Retinal ganglion cells in eye forms more synapses
in vitro if on a layer of astrocytes (due to increased cholesterol – Mauch 2001)
Trophic support:
Astrocytes provide short range positive cues to guide growth:
Laminin – guides axons during development by providing stimulatory signals for growth.
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Laminin – guides axons during development by providing stimulatory signals for growth.
E.g. Retinal ganglion cells navigating from retina to the optic tectum via laminin path laid
down by astrocytic end feet.
Protective Role – maintain BBB/repair BBB during damage to the CNS (proliferation of
astrocytes as part of reactive phenotype).
Upregulation of GFAP and chondroitin sulphate proteoglycan
Can become very fibrous
Form astrocytic scars (seals BBB) to form a continuous layer
BUT Astrocytes can stop axon regeneration by forming a molecular layer
which axons cannot pass to reconnect.
Conclusion
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Mechanisms of axonal growth and guidance (Short range soluble cues etc.)
Discuss the role of growth factors in CNS development
Introduction
The nervous system is an important but complex system of the body, and its development
requires precise control to ensure different regions of the body are appropriately innervated
by the correct neurones.
In order for this to occur, once initial nervous system development through key mitotic
divisions, the ability of neurones to extent axons towards their target tissue is largely
dependent on several molecular ‘cues’ to guide them to the correct location.
Molecular cues can be long or short acting, repulsive or attractive, and may have survival-
promoting properties.
Growth cone receptors on the terminal ‘growing’ end of the axon express specific receptors
(depending on the type of neuronal population, their location and role), and a degree of
receptor-specificity towards particular cues ensure that only the correct neurones with the
appropriate receptor will grow towards the ‘correct’ area.
Limiting target-derived trophic factor ensures that only the neurons that are ‘supposed’ to be
in a particular target tissue (expressing the correct receptors) are stimulated to survive.
Once axons have reached their target:
Key molecular cues help differentiate the growth cone into a synapse that can appropriately
attach with its target tissue.
Wnt – important secreted molecule stimulates pre-synaptic differentiation by
modulating microtubule dynamics in the growth cone.
Neurexin/Neuroligin – expression of neuroligin on the postsynaptic target cell binds
to neurexin receptors on the presynapse (growth cone), and stimulates presynaptic
differentiation into a fully formed synapse.
Idea that target and growth cone begins differentiating for their targets even before
reaching it.
Idea that synapses can form completely without any neuronal activity (i.e. purely
based on growth factors and axonal guidance cues).
However, after synapses have formed – need to have activity during critical period or
synapses are remodelled/lost (use it or lose it).
Synaptic plasticity – remodelling of synapses important for learning and memory.
Long Range Positive Cues
Netrin
Netrin 2 – Long Range, Gradual Gradient (highest in ventral region)
Netrin 1 – Short Range, Steep Gradient (higest in ventral region)
Netrin classically have been shown to act as long range positive cues in commissural
neurones that are found in the dorsal half of the spinal cord.
Respondent neurones express DCC Receptors (Deleted in Colorectal Cancer), which
binds Netrin and attracts them towards the ventral surface via changes in
concentration gradients.
Can act as long range chemorepulsive (negative) cues (e.g. trochlear neurones which
express Unc5 and DCC neurones) – example of how growth cues can be specific to
particular neuronal populations.
Neurotrophins – only receptors expressing the relevant neurotrophin receptor will bind and
be ‘rescued’, further evidencing how only the neurones that should be in a particular region
will grow e.g. NGF will only bind to growth cones expressing TrkA.
TrkA binds NGF (e.g. nociceptive neurons express TrkA) – Dimeric ligand causes
transautophosphorylation which stimulates intracellular cascades.
TrkB binds NT4/5, BDNF
TrkC binds NT3 (e.g. proprioceptive neurons express TrkC)
NGF discovered to have neurite promoting and survival effects.
NGF/TrkA – also implicated in Alzheimer’s disease:
NGF important to provide trophic support to enable cell survival
TrkA receptors transported by fast anterograde transport (cell membrane
associated component) – requires APP for fast anterograde transport.
Reduced functioning APP in AD (incorrect cleavage by beta/gamma
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Document Summary
Neurons do the talking and astrocytes just clear up afterwards discuss the extent to which this is true and consider ways in which it is not the case. Neurons and astrocytes form a major part of the central nervous system and its vastly complex, intricate circuitry. Both neurons and astrocytes associated with cns develop from the neural tube of the embryo. Neurons are classically known for their crucial role in signal transmission receiving inhibitory and excitatory signals through dendrites, which are then processed and modulated to determine whether a resultant signal is propagated through the axon. Astrocytes form part of the macroglia subset of cells (along with oligodendrocytes) in the nervous system which are traditionally known for their supportive function in maintaining an environment for the neurones to function correctly in. Typically stellate shape, and form intimate attachments with neurons. Astrocyte function to support neurones and clear up": o o o o.
