Central Nervous System Development

DAAN VAN KRUINING

28 October, 2021
BBS2002
X4 90%
FORMING CONNECTIONS
CHANGES THOUGH EXPERIENCE
How does the pre-natal brain develop?
Embryogenesis

The embryo begins as a flat disk with 3 layers of cells:

Endoderm
Mesoderm
Ectoderm Nervous System

Neurulation

neural plate neural tube

hollow tube
brain + spinal cord

After neural tube formation, the forerunners of the major brain regions become apparent

Principles of Neural Science, Kandel et al . Ch.52

Successive stages in the development of the
neural tube

Three-vesicle stage. At early stages of development only

three brain vesicles are present.

Five-vesicle stage. At later stages two additional vesicles

form, one in the area of the forebrain (1a and 1b) and
the other in the hindbrain (3a and 3b).
Micrograph showing a dorsal view of the neural tube at
an early stage of development.

Principles of Neural Science, Kandel et al . Ch.52

How do brain cells develop?
Neurogenesis
Neuronal structure develops in three major stages:

(1) cell proliferation

(2) cell migration
(3) cell differentiation

The brain develops from the walls of the five fluid-filled vesicles, in the
early stages consisting of two layers: the ventricular zone and the
marginal zone.
Cell proliferation is associated with 5 “positions”
The choreography of cell proliferation

(a) Each cell performs a characteristic “dance” as

it divides.

1. cell extends a process

2. cell’s DNA is copied

3. two complete copies of DNA

4. cell retracts arm from pia surface

5. cell divides in two

Neuroscience: Exploring the Brain, Bear et al. Ch.23

Cell proliferation is associated with 5 “positions”
The choreography of cell proliferation

(b, c) The fate of the daughter cells depends on the

plane of cleavage during division.

Symmetrical cell division  both daughters remain

in the ventricular zone to divide again.

Asymmetrical cell division  the daughter farthest

away from the ventricle ceases further division and
migrates away.

Neuroscience: Exploring the Brain, Bear et al. Ch.23

Radial glial cells
Radial glial cells: progenitor (stem-like) cells that generate both neurons and glial cells

• Symmetrical division: produces 2 progenitor cells (to expand the population of proliferative
progenitor cells)
• Early asymmetrical cell division: promotes increase neuron population
• Later asymmetrical cell division: promotes glia production
Principles of Neural Science, Kandel et al. Ch. 53
Cell Migration
Daughter cells migrate along the thin
fibers emitted by radial glial cells that
span the distance between the
ventricular zone and the pia.

The immature neurons, called neural

precursor cells, follow this radial path
from the ventricular zone toward the
surface of the brain

Neuroscience: Exploring the Brain, Bear et al. Ch.23

Inside-out development of the cortex

• The first cells to migrate to the cortical

plate are those that form the subplate.

• As these differentiate into neurons, the

neural precursor cells destined to become
layer VI cells migrate past and collect in
the cortical plate.

• This process repeats again and again until

all layers of the cortex have differentiated.

• The subplate neurons then disappear.

Neuroscience: Exploring the Brain, Bear et al. Ch.23

 Cell differentiation

1st Neuronal differentiation

(primarily pre-natal)

2nd Astrocyte differentiation

(peaks around time of birth)

3rd Oligodendrocytes differentiation

Notch signaling regulates the fate of cells in the developing

cerebral cortex
 Cell differentiation
Notch: A cell-surface receptor that interacts with a
ligand (e.g. Delta)

Notch has various functions in different stages of neurodevelopment:

During pre-natal development: Notch signaling regulates self-renewal of

developing and adult neural stem cells.

During (mostly) post-natal development: Notch promotes gliogenesis

Principles of Neural Science, Kandel et al. Ch. 53
 Neuronal cell differentiation
The growth cone identifies the
appropriate path for neurite elongation

Principles of Neural Science, Kandel et al. Ch. 54

Why do some neurons survive while others do not?
 The neurotrophic factor hypothesis
Neurons extend their axons to target
cells, which secrete low levels of
neurotrophic factors.

The neurotrophic factor binds to specific

receptors and is internalized and
transported to the cell body, where it
promotes neuronal survival.

Principles of Neural Science, Kandel et al. Ch. 53

 The neurotrophic factor hypothesis
Neurons that fail to receive adequate
amounts of neurotrophic factor die
through a program of cell death
 apoptosis.

Nerve growth factor is a trophic factor

promoting neuronal survival.
Part of family called neurotrophins.

Principles of Neural Science, Kandel et al. Ch. 53

 The neurotrophic factor hypothesis

Neurotrophins act on cell surface

receptors, mostly tyrosine kinase (Trk)
receptors.
 regulate synaptic strength and
plasticity in the mammalian
nervous system

Neurons communicate with each other using

electrochemical signals

Not connect directly but junction in between,

called synapse Principles of Neural Science, Kandel et al. Ch. 53
Central and peripheral nervous system
synapses
 When the growth cone comes in contact with its
target, a synapse is formed

1. A dendritic filopodium contacts an axon

2. Contact leads to the recruitment of

synaptic vesicles and active zone
proteins to the presynaptic membrane

3. Neurotransmitter receptors accumulate

post-synaptically

Neuroscience: Exploring the Brain, Bear et al. Ch.23

The central nervous system synapse
Neuron-neuron and neuron-muscle synapses
develop by similar mechanisms
 Formation of peripheral synapse =
neuromuscular synapse

The neuromuscular junction. The postsynaptic membrane, known as the motor end-
plate, contains junctional folds with numerous neurotransmitter receptors
Neuroscience: Exploring the Brain, Bear et al. Ch. 5
The neuromuscular junction
Analogies of central synapses and neuromuscular junctions

• Structurally similar

• Bi-directional signaling

• Clustering of neurotransmitter receptors

• Synaptic vesicles have similar components

• Synapse elimination during development

Differences

• Central synapses have no basal lamina (a structured form of

extracellular matrix)
• Central synapses have no junctional folds but dendritic spines
• Difference in neurotransmitters
In central synapses, excitatory synapses use glutamate
In peripheral synapses, excitatory synapses use ACh

• Different neurotransmitter receptors

Synapses strengthen or weaken over time

synaptic plasticity
 Synaptic plasticity
The ability of synapses to strengthen or weaken over time
Normal synaptic transmission

Principles of Neural Science, Kandel et al. Ch 67

 Induction of long term potentiation
high-frequency tetanus  large depolarization

Principles of Neural Science, Kandel et al. Ch 67

Expression of long term potentiation
Two main effects on synaptic
transmission:

• activation of protein kinases

enhances current through
the AMPA receptors

• retrograde messengers that

activate protein kinases in
the presynaptic terminal
enhance subsequent
transmitter release

Principles of Neural Science, Kandel et al. Ch 67

 Neurons that fire together wire together

Neurons that fire out of sync lose their link

Functional brain development
Human Brain Development: Neurogenesis in the
Hippocampus through Experience-dependent
Synapse Formation

Leisman, et al., Psicología Educativa, 2015

Can neuronal stem cells still generate cells
in the adult brain?
Neural stem cells: progenitor cells that generate neurons and glial cells but
themselves remain in the cell cycle.

Proliferating neural cells use themselves up during development so sources of

new neurons in an adult animal are extremely limited.

 Damage to CNS more serious than other organs, such as

skin or liver (where stem cells that persist into adulthood can replace injured tissue)

In adult mammals, neural stem cells persist in the hippocampus.

Regeneration of the nervous system
Axotomy affects the injured neuron and its synaptic partners

Principles of Neural Science, Kandel et al. Ch. 57

 Axons in the periphery regenerate better than
those in the central nervous system

Peripheral and central

nerves differ in their
ability to support
axonal regeneration.

In the peripheral
nervous system,
severed axons regrow
past the site of injury.

In the central nervous

system, severed axons
typically fail to regrow
past the site of injury

Principles of Neural Science, Kandel et al Ch. 57

 Differences CNS and PNS regeneration
 Environmental factors: Peripheral cells provide growth-promoting
factors to the injured areas; factors normally absent from the brain.

 Components of Myelin Inhibit Neurite Outgrowth: Fragments of

central myelin are potent inhibitors of neurite outgrowth

 Injury-Induced Scarring Hinders Axonal Regeneration: astrocytes

become activated and proliferate following injury, acquiring
features of reactive astrocytes that generate scar tissue at sites of
injury.
 Differences CNS and PNS regeneration

 An Intrinsic Growth Program Promotes Regeneration.

Environmental differences cannot completely account for the poor
regeneration of central axons. Even though they can regenerate in
peripheral nerves, central axons grow much less well than
peripheral axons when navigating the same path. Thus, adult
central axons may be less capable than peripheral axons of
regeneration.
In conclusion…
13 weeks

van Kruining, 2021