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Extensive Summary BBS2002 Case 1 till 12
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Very extensive summary of all cases BBS2002: From cradle to grave in the second year of Bachelor Biomedical Sciences Maastricht University FHML
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Case 1: Neural developmentPre-discussion:
- Embryonic neural development
- Proliferation, migration and differentiation of brain cells
- Neuronal stem cells
- Notch signaling
- Anatomy neural cells
- The 3 layers, mesoderm, endoderm, ectoderm
- Neurotransmitters
Learning goals:
- Recap the anatomy of neural cells? (really short)
Two cell types in nervous system are neuroglial cells and neurons. There are sensory
neurons, motor neurons and interneurons. Sensory neurons receive info from body parts
and sends these signals to the CNS. Motor neurons get info from other neurons and set
these through to the destination to get wanted results such as movements but also organ
functioning. Interneurons receive info from neurons and give them to other neurons.
Neuroglial cells can be present in both the CNS and PNS. In the CNS you have
• Astrocytes à guides CNS homeostasis
• Microglia à surveillance cells, immune cells from CNS, APC, phagocytic cells and
remove and restructure neurons
• Oligodendrocytes à insulation and axon à myelination
• Ependymal cells à around brain ventricles and central canal of spinal cord
In the PNS:
• Satellite cells à support cell body
• Schwann cells à myelin sheath
- How does the brain develop? ( Neurulation )
3 weeks after fertilization gastrulation starts. The 3 germ layers are formed from epiblast; the
ectoderm, endoderm, mesoderm. The ectoderm forms the nervous system. Neurulation is a
process that happens during embryo folding. The mesoderm forms the notochord, on that
place the neural tube is formed. The notochord induced the development of the neural
groove and neural plate what forms the whole nervous system. Ectoderm expresses BMP,
which blocks differentiation into neural plate is formed there. When the neural place thickens
the neural groove is formed and this groove closes and forms the neural tube
The neural tube is divided into the forebrain, midbrain and hindbrain and spinal cord. The
brain is divided in 3 divisions by 3 brain vesicles.
During the 5th week after fertilization the midbrain grows and the fore and hind brain both
split in 2 portions forming 5 secondary brain vesicles out of 3 primary brain vesicles
Prosencephalon: telencephalon, diencephalon
Mesencephalon: mesencephalon
1
,Rhombencephalon: metencephalon, myelencephalon
The peripheral nervous system forms from neural crest cells which is neural ectoderm layer
of the neural tube.
- How does the cell formation work? (Neurogenesis, proliferation, migration,
differentiation and Notch signaling)
These neuronal structures develop via proliferation, migration and differentiation. These
processes take place in the walls of the secondary vesicles. This wall consists of the
ventricular and marginal zone. Ventricular is in the inside of each vesicle and marginal faces
the overlying pia. Within these layer, a cellular ballet is performed to give rise to neurons and
glia.
Proliferation: is the division of neural stem cells.
Cell division:
1. Cell extends upwards to the pial surface
2. Cell nucleus migrates upwards from ventricular to marginal zone to pial surface
where DNA is copied
3. The nucleus which now contains 2 copies settles back to ventricular surface
4. Cells retracts its arm from pial surface, the nucleus moves back to ventricular zone
again
5. Cell divides in 2. This can happen in 2 ways
Neural progenitor vs neurons
Neural progenitors are a mitotic cell population and they can divide to form new cells.
Neurons are post mitotic, once formed not able to divide or produce new cells. These
progenitor (stem cells) cells are radial glial cells.
In the whole process, first neurons and cortex are formed, then the glial cells.
Symmetrical division: both daughter cells remain in ventricular zone to divide one more time
Asymmetrical division: the daughter cell furthest away from ventricular zone will not go on
with further division and migrates away to take up a position in the cortex. Early
2
,asymmetrical division promotes an increase of the neuron population and late asymmetrical
division promotes glia production.
The neural progenitors that give rise to all neurons and astrocytes are the radial glial cells.
Early in embryonic development these radial glial cells are with hundreds and give rise to
billions of neurons in the brain. Every daughter cell after proliferation has the same fate so
this can be regulated by gene expression. In symmetrical division Notch-1 and Numb and
divided evenly. In asymmetrical cleavage the uneven differentiation of enzymes and
transcription factors causes differentiation.
Migration: The daughter cells migrate along fibers emitted by radial glial cells than span the
distance between the pia and ventricular zone. The immature neurons (neural precursors)
follow this radial path from the ventricular zone toward the surface of the brain. Not all
migrating cells follow this path, some migrate horizontally towards the cortex.
Somal translocation: early in the neocortical development the distances a neuron must travel
are small so they can use somal translocation as migration mode.
1. Somal translocation: neuron extends long basal process, extension of cell body just
beyond the VZ edge into outer region of brain compartment.
2. Basal processes attach to the pial surface which is the outer surface of the
developing brain
3. Nucleus of cell moves through cytoplasm of basal process
4. Nucleus move sup, shorter and thicker but attached to pial surface
5. At the end of process, nucleus of cell moves out VZ into embryonic cortex.
Radial glial guides:
Development proceeds and brain grows. Migration changes. Neurons must migrate larger
distances with radial glial guides cells to support migration
3
,Cortex development: (inside-out). First cells that migrate to cortical plate are those that form
the subplate. These differentiate into neurons that become layer 4 and collect in cortical
plate. This process repeats again and again until all layers of the cortex have differentiated.
The subplate neurons then disappear and the cortical plate will be used completely.
Myelination:
Information transmission efficiency is greatly enhanced by myelin. This is a fatty substance
hence white matter.
4
,Differentiation:
This is the process which a cell take son the appearance and characteristics of a neuron. It
is the consequence of a specific spatiotemporal pattern of gene expression. Neural
precursor cell differentiation begins as soon as the precursor cells divide with asymmetric
distribution of cells constituents. Further neuronal differentiation occurs when the neural
plate precursor cells arrive in the cortical plate. Layer 5 and 6 have differentiated in
recognizable pyramidal cells before layer 2 cells have migrated to the cortical plate.
Neuronal differentiation occurs first , astrocyte differentiation peak at the time of birth and
oligodendrocytes are the last ones to differentiate.
Differentiation of the neural precursor cells into a neuron begins with neurites that are
sprouting out of the cell body. Firstly these neurites appear about the same but eventually
one becomes an axon and the other a dendrite. This depends on intracellular signals such
as Notch.
The notch-1 and numb proteins are differentially distributed in the precursor cells of the
developing neocortex. Symmetrical cleavage partitions these proteins equally in daughters,
but asymmetrical cleavage does not. Differences in distribution of proteins in the daughter
cells causes then to have different fates.
Notch signaling is a molecular mechanism that regulates the balance between neural stem
cell maintenance and differentiation. In an developing NS, protein products from proneural
genes such as basic helix-loop-helix transcriptional activators Mash1 and Neurogenins
induce neuronal differentiation. These gene products also activate expression of notch
receptor ligands such as delta-like 1 and Jagged1. These activate Notch. This causes the
notch intracellular domain to release from the transmembrane portion and transferred to the
nucleus where it forms a complex with DNA binding proteins. This complex is a
transcriptional activator and induces expression of bHLH transcriptional repressors such as
Hes1 and Hes5. These then repress expression of proneural genes and delta like 1 thereby
inhibiting neuronal differentiation and maintenance of neural stem cells. Via this lateral
inhibition, the differentiating neuron prevents neural stem cells from differentiating and
thereby promote asymmetric division into one neural stem cell and one differentiating
daughter neuron.
https://link.springer.com/article/10.1007/s12035-011-8186-0
5
,Cell differentiation order:
1. Neuronal differentiation: pre-natal
2. Astrocyte differentiation: peaks around birth
3. Oligodendrocytes
Astrocytes have diverse roles such as clearance of debris, synaptic transmission,
inflammation. Oligodendrocytes form the myelin sheath in the CNS, Schwann cells do this in
the PNS. These cells are the main nervous system cells with the neurons.
- How do synapses form + plasticity? (PNS vs CNS) Neuromuscular junctions
Growth cone migration à during neuronal migration the nerve is guided to its target by a
specialized structure on the tip of the axon = growth cone. This contains service receptors
that allow it to respond to specific cues in the environment by altering cytoskeletons,
changing membrane growth and coordinating cell adhesion.
6
,The peripheral growth cone contains lamellipodia, which are broad membrane sheets
supported by short branch actin networks. Lamellipodia are responsible for the neurite
movement. Finger like projectecs called filopedia extend into the environment by longer
polymers of actin. The filopedia act as sensory network receiving cues from the environment.
The centre of the growth cone contains microtubules, polymers of tubulin which are
responsible for sending the axon shaft. Regulation of actin polymerization directs the growth
cone movement. GTPases carry out cytoskeletal changes by regulating actin microfilament
growth in response to cues from the environment.
Attractant cues cause polymerization of actin and tubulin towards those cues. In contrast
repulsive cues cause actin and tubulin dimers to depolymerize which destabilizes the growth
cone on the side of the repulsive stimuli. Instead actin and tubulin are transported to the
opposite side of the cell to extend the growth cone away from the repulsive cues.
In order for net movement to occur, integrins on the surface of the cone form temporary focal
adhesions with extracellular matrix to pull the neutron along.
Synapse formation à when an axon approaches the target, it forms a junction: synapse.
Growth cone approaches muscle fibre for example, then agrin is released to cause
acetylcholine receptors in the muscle to cluster benath axons.
Neurotransmitter vesicles enter axon and at this point the extracellular matric containing
neuron specific laminin is produced to connect the axon terminal to the muscle cell.
Other axons begin to converge the same synaptic site on the muscle but the most active
neuron ultimately outcompetes the others. A survival factor called neurotrophin is key to
determining which axons remains at synapse. Surviving axon continues to branch and is
sheathed by Schwann cells à stable neuromuscular junction!
Summary
1. Axons find target
2. Dendritic filopodium contacts axon
3. Contact .leads to recruitment of synaptic vesicles and active zone proteins to
presynaptic membrane
4. Neurotransmitter receptors accumulate post synaptically
7
,DETAILED VERSION DIFFERENT SOURCE
The assembly of neuromuscular synapses is a multistep process. It requires coordinated
interactions between motor neurons and muscle fibers which will lead to a postsynaptic
membrane and a nerve terminal. Acetylcholine receptors become highly concentrated in the
postsynaptic membrane and arranged in perfect register with active zones in the presynaptic
nerve terminal, ensuring fast, robust and reliable transmission. A large number of proteins
contribute to the process of synapse formation, several of which play a fundamental role:
- Agrin: Motor neuron derived ligand, Stabilize nascent synapses
- Lrp4:Receptor for agrin
- Musk: Receptor tyrosine kinase that transduces the agrin signal
- Dok-7: adaptor protein recruited to activate musk
- Rapsyn: AchR associated protein that anchors AchRs at synapses
The synapse is formed through the following steps:
1. The growing motor neuron secretes the protein Agrin into the basal lamina
2. Agrin interacts with Musk in the muscle cell membrane
3. The clustering of AchR in the postsynaptic membrane via the actions of
Rapsyn
Neuron-neuron synapses à found in CNS. Main excitatory neurotransmitter is glutamate.
Inhibitory neurotransmitter is GABA.
PNS synapse = neuromuscular junctions à connecting between axon from CNS to modal
end plate of muscle cell. Main excitatory neurotransmitter is acetylcholine
Similarities CNS and PNS synapses
- Structurally similar
- Bi-directional signaling (retrograde)
8
, - Clustering neurotransmitter receptors
- Synaptic vesicles have similar components
- Synapse elimination during development (pruning)
Differences CNS and PNS synapses
- CNS synapses have no basal lamina
- CNS synapse have no junctional fold but dendritic spines
- Neurotransmitter
o CNS
▪ Exc. Glutamate
▪ Inh. GABA and glycine
o PNS
▪ Ext AcH, acetylcholine
Synaptic plasticity
Ability synapse to strengthen or weaken over time in response to increase or decrease in
activity. Plastic change results in alteration of number of neurotransmitter receptors on a
synapse
• LTP
Long term potentiation. Is persist strengthening of synapses based on recent patterns of
activity. These are patterns of synaptic activity that produce a long-lasting increase in
signal transmission between 2 neurons.
LTP is a phenomenon underlying neural plasticity. Memories are encoded by synaptic
strength, LTP is widely considered one of the major cellular mechanisms that underlies
learning and memory
• Synaptic transmission
• Induction LTP
1. More neurotransmitter release
2. Binds to receptors
3. Post synaptic membrane depolarized
4. Magnesium block is released (positive charge)
5. Calcium enters cell
6. Starts signaling cascade
7. More AMPA receptors made
9
, • Expression LTP à main effects of LTP on synaptic transmission
1. Activation protein kinases enhances current through AMPA
2. Retrograde messengers activate protein kinases in the presynaptic
terminal to enhance subsequent transmitter release.
• LTD
Long term depression à activity dependent reduction in neuronal synapse efficacy lasting
hours or longer following a long patterned stimulus. Process serves to selectively
weaken specific synapses in order to make constructive use of synaptic strengthening
caused by LTP.
Necessary because if all synapses keep increasing strength it reaches a max level which
inhibits encoding of new info.
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