Developmental Disorders

Question 1

What is the process of cellular nervous system development?

Answer 1

Position cells –> mitosis –> specify cell fates –> migration –> axonal growth –> synapse

Question 2

What causes development of the neural tube?

Answer 2

1. Differential rates of cell division causes bulges (“telencephalon, diencephalon, etc…)
2. The position of cells within the tube determines what kind of cell they become
3. Cell fate is a result of transcription factors and diffusible factors

Question 3

What is sonic hedgehog?

Answer 3

Diffusible factor in the spinal cord that determines cell fate in dorsal-ventral axis (high Shh = motor, low Shh= sensory)

Question 4

What is Spina bifida?

Answer 4

Failure of closure of neural tube caused by lack of folic acid during pregnancy

Question 5

What is cell migration controlled by?

Answer 5

Migration is controlled by many cell-surface, transmembrane molecules (=CAMs) & components of the extracellular matrix

Question 6

What are some examples of cells in the CNS that migrate long distances?

Answer 6

1. Granule cells in the cerebrum migrate from the midbrain area
2. GABA-ergic interneurons in the cerebral cortex migrate from the striatal area to the cortex
3. GnRH cells migrate from the olfactory epithelium to the hypothalamus

Question 7

How many layers are formed in the cerebral cortex? Which layer is formed first?

Answer 7

Migration of cells from the ventricular wall form the 6 layers of the cerebral cortex. Layer 6 cells are born first.

Question 8

What is Reelin? What can it cause?

Answer 8

Reelin is a cell adhesion molecule that is expressed in high levels during the development of the brain. Reelin mutations cause less white matter, enlarged ventricles and disrupted sulci and gyri.

Question 9

How does an axon grow?

Answer 9

Diffusibile factors with specific receptors can at as chemoattractants or chemorepulsants (=tropic factors).

Question 10

How does axonal guidance in the spinal cord work?

Answer 10

Axons are attracted to the midline, but then the attracters are silenced so the axon can go away from the midline

Question 11

What are neurexins? Neuroligins?

Answer 11

Neurexins are presynaptic and localize synaptic vesicles and docking proteins. Neuroligins are postsynaptic and affect clustering of AMPA and NMDA receptors.

Question 12

What is the neurotrophic hypothesis in the PNS?

Answer 12

Neurons compete for a limited supply of survival factors such as neurotrophins. This explains why we make many more synapses than we ever need.

Question 13

How does synapse refinement at NMJ work?

Answer 13

In early development there are multiple axons of motor neurons synapse with each muscle cell, but eventually these connections are refined so only 1 motor neuron synapses on each muscle cell

Question 14

What is Hebb’s postulate?

Answer 14

Neurons that fire together, wire together

Question 15

How does gray matter develop in humans?

Answer 15

In human brains gray matter increases at first, then decreases during late childhood and early adolescence. Myelination = late process

Question 16

What do Down Syndrome, Fragile X, Rett’s Disease, and Autism all have in common?

Answer 16

1. All affect synapse development “synaptopathies”
2. All present with intellectual impairment
3. All have “gene dosage” effect

Question 17

Where are most excitatory synapses found?

Answer 17

Most excitatory synapses in the cortex are on dendritic spines.

Question 18

What causes DS?

Answer 18

Due to an extra chromosome 21, a problem with gene dosage not with mutated proteins

Question 19

What are symptoms of DS?

Answer 19

Dysmorphic facial features, intellectual disability, stunted growth, congenital heart defect, seizures, obesity, early onset AD, lower life expectancy

Question 20

What is the enhanced GABAergic activity theory in DS?

Answer 20

• Excessive GABAergic inhibition leads to increased LTD and decreased LTP.
• GIRK2 = G-protein coupled K+ channel activated by GABA receptors
• Olig 1 & Olig 2 = transcription factors that drive overgrowth of GABAergic interneurons

Question 21

What do you see in DS transgenic mice?

Answer 21

See decreased synapse density and decreased spine numbers but abnormally large spines and wrong placement of GABAergic synapses on the dendritic shaft instead of at the base of the spine head.

Question 22

What does the wrong placement of GABAergic synapses on the dendrite cause?

Answer 22

Synapse on the shaft have a bigger effect

Question 23

What is the neurodegeneration theory in DS?

Answer 23

• extra copy of APP gene so more amyloid plaques

- extra copy of SOD1 gene so reduced protein clearance via ubiquitin proteasome

Question 24

What are treatments for DS? What are the risks?

Answer 24

1. Blocking GABA-R
2. GABA-A receptor antagonist
3. blocking GIRK2
   * risky because blocking GABA can lead to seizures

Question 25

What causes Fragile X syndrome?

Answer 25

CGG expansion on X-chromosome (not on coding region- promoter region 5' UTR) causes silencing of FMR1 gene

Question 26

What are the symptoms of Fragile X?

Answer 26

Delayed language, biting, hand-flapping, autistic, dysmorphic facial features, enlarged ears, long faces

Question 27

What are the changes in spine morphology in FXS?

Answer 27

Increased numbers of long, thin dendritic spines

Question 28

How does enhanced mGluR5 signaling affect FXS?

Answer 28

Some mGluR5 regulated mRNAs are suppressed by fragile X mental retardation protein (FMRP) causing mGluR5 signaling to be exaggerated, leading to excessive LTD and abnormal spines

Question 29

What are the symptoms of Rett Syndrome?

Answer 29

- Normal development initially, with regression at 6-18 months - Speech lost - Intellectual disability with transient autism - Replace purposeful hand movements with stereotypies

Question 30

What causes Rett Syndrome?

Answer 30

> 95% Rett syndrome is caused by de novo loss of function mutations in MeCP2 gene. MeCP2 can activate or inhibit gene expression.

Question 31

How does MeCP2 work?

Answer 31

Normal MeCP2 recruits histone deactelysas that prevent transcription. MeCP2 normally allows activity of dependent transcription and release of BDNF, but in Rett syndrome lack of functional MeCP2 impairs release of BDNF

Question 32

What dendritic spine changes do you see in Rett Syndrome?

Answer 32

Decrease in number and size

Question 33

What is the role of microglia in Rett?

Answer 33

Bone marrow stem cells give rise to macrophages and microglia, harvest cells and select for the 50% MeCP2 wild types to re-implant into patients

Question 34

What is impaired in autism, physical or intentional causality?

Answer 34

Intentional Causality

Question 35

What are the changes in synapses associated with Autism?

Answer 35

Increased synapses

Question 36

What is hypo-connectivity in Autism?

Answer 36

Despite more synapses and increased spine density, there is less network activity. This suggests less connectivity in ASD, long pathways are activated less