Developmental Disorders Flashcards
What is the process of cellular nervous system development?
Position cells –> mitosis –> specify cell fates –> migration –> axonal growth –> synapse
What causes development of the neural tube?
- Differential rates of cell division causes bulges (“telencephalon, diencephalon, etc…)
- The position of cells within the tube determines what kind of cell they become
- Cell fate is a result of transcription factors and diffusible factors
What is sonic hedgehog?
Diffusible factor in the spinal cord that determines cell fate in dorsal-ventral axis (high Shh = motor, low Shh= sensory)
What is Spina bifida?
Failure of closure of neural tube caused by lack of folic acid during pregnancy
What is cell migration controlled by?
Migration is controlled by many cell-surface, transmembrane molecules (=CAMs) & components of the extracellular matrix
What are some examples of cells in the CNS that migrate long distances?
- Granule cells in the cerebrum migrate from the midbrain area
- GABA-ergic interneurons in the cerebral cortex migrate from the striatal area to the cortex
- GnRH cells migrate from the olfactory epithelium to the hypothalamus
How many layers are formed in the cerebral cortex? Which layer is formed first?
Migration of cells from the ventricular wall form the 6 layers of the cerebral cortex. Layer 6 cells are born first.
What is Reelin? What can it cause?
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.
How does an axon grow?
Diffusibile factors with specific receptors can at as chemoattractants or chemorepulsants (=tropic factors).
How does axonal guidance in the spinal cord work?
Axons are attracted to the midline, but then the attracters are silenced so the axon can go away from the midline
What are neurexins? Neuroligins?
Neurexins are presynaptic and localize synaptic vesicles and docking proteins. Neuroligins are postsynaptic and affect clustering of AMPA and NMDA receptors.
What is the neurotrophic hypothesis in the PNS?
Neurons compete for a limited supply of survival factors such as neurotrophins. This explains why we make many more synapses than we ever need.
How does synapse refinement at NMJ work?
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
What is Hebb’s postulate?
Neurons that fire together, wire together
How does gray matter develop in humans?
In human brains gray matter increases at first, then decreases during late childhood and early adolescence. Myelination = late process
What do Down Syndrome, Fragile X, Rett’s Disease, and Autism all have in common?
- All affect synapse development “synaptopathies”
- All present with intellectual impairment
- All have “gene dosage” effect
Where are most excitatory synapses found?
Most excitatory synapses in the cortex are on dendritic spines.
What causes DS?
Due to an extra chromosome 21, a problem with gene dosage not with mutated proteins
What are symptoms of DS?
Dysmorphic facial features, intellectual disability, stunted growth, congenital heart defect, seizures, obesity, early onset AD, lower life expectancy
What is the enhanced GABAergic activity theory in DS?
- 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
What do you see in DS transgenic mice?
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.
What does the wrong placement of GABAergic synapses on the dendrite cause?
Synapse on the shaft have a bigger effect
What is the neurodegeneration theory in DS?
- extra copy of APP gene so more amyloid plaques
- extra copy of SOD1 gene so reduced protein clearance via ubiquitin proteasome
What are treatments for DS? What are the risks?
- Blocking GABA-R
- GABA-A receptor antagonist
- blocking GIRK2
* risky because blocking GABA can lead to seizures
