L02 - Development and Anomalies of Development in the CNS

Brain development
1. Understanding pathology with age comes from understanding the development
2. Key points in development
  1. Development continues throughout life - not complete at birth
  2. First neurones are created at 3 weeks - early start to development
    1. Damage easily caused by toxic substances
  3. By 3 months there is an early brain plan
  4. 6-9 months white matter develops
  5. After being born for 12 months - no neuronal proliferation, but slight ability to regenerate
  6. Myelination is 50% complete by 18 months (not complete until teens)
  7. By 20, the brain is mature in structure and it looks like this for the rest of your life
  8. Dynamic processes of the brain (formation & destruction of synapses) continues throughout life
Issues
1. How do some cells end up as neurones?
  1. In the embryo, Gastrulation occurs
    1. Ball of cells polarised
      1. Head and tail discernible
        Layers
        Endoderm
        Viscera
        Ectoderm
        Musculoskeletal system
        Ectoderm
        Nervous system (+skin)
        Neurulation
        Occurs 3 weeks after conception
        Therefore can be dysrupted by toxic agents
        Formation of the neural plate
        Due to interactions between cell surface proteins of the ectoderm, notochord and mesoderm
        Cells near the notochord form the neural plate
        Neural plate formation due to conc. gradient of secreted molecules by the notochord
        Neural folds form, with a neural groove in between
        Involves; (i) changes in cell shape, (ii) movement of cells, (iii) interactions with surrounding tissues
        Neural folds fuse, forming:
        Neural Tube
        Spinal Cord
        Brain Cells
        Clinical relevance
        Defective closure of neural tube
        Anteriorly
        Anencephaly
        Posteriorly
        Spina Bifida
        Massive cell division
        Dependent on folic acid
        Gene Defects
        Defects in protein expression
        Affect Cell-Cell interactions
        Often results in embryo death
        Neural crest
        Neurones with cells body in Peripheral NS
        e.g. Dorsal Root Ganglia, Sympathetic chain, Schwann cells
2. How do they become organised in the developing brain?
  1. Anterior-Posterior patterning
    1. Anterior end
      1. 3 Vesicles
        All brain derived from walls
    2. Signals for polarity; secreted and cell-surface
      1. Dickkopf ('fat brain' in German)
        Anteriorising, over-expression = large forehead
      2. Noggin
      3. Vit. A
        Used in organisation pathway
        Excess intake can interrupt anterior brain formation in the embryo
  2. Dorsal-Ventral (Top-Bottom) patterning
    1. Sonic Hedgehog (Shh)
      1. (Mutation causes spikey effect)
      2. Causes ventral formation
        Motor neurones of cranial nerves
        Dopaminergic neurones
        Impact in Parkinsons Disease
        Serotonergic neurones
        Impact in psychiatric issues (depression) - therapy?
  3. Organisation into regions/nuclei
    1. Cortical Layering
      1. Migration of neuroblasts (created weeks 5-20) from the Ventricular Zone into the Cortical Plate
        Along Radial Glia
        Migration Abnormalities
        Cortical Dysgenesis
        Many syndromes with differing degrees of migration issues and differing degrees of impact
        Lissencephaly
        Significant cortical dysgenesis
        Smooth cortex
        Large functional issues
        Other disorders
        Autism
        Schizophrenia
        Epilepsy
        Dyslexia
        Cerebral palsy
        Specific disorders due to cortical dysgenesis in particular areas
        Differentiation
        Cell maturation and differentiation
        Inputs - Dendritic Processes form
        Outputs - Axons form
        No further division (after processes formed)
        This is why damage is such a problem
        Differential gene activation
        Transmitters/Receptors
3. How do they make appropriate connections with each other?
  1. Axons Need to...
    1. Extend
      1. Lamellipodia
        Receptors on the axon which attach to the extracellular environment (proteins such as laminin) and promote growth
      2. Grow in groups
        Form white matter tracts (bundles)
        Fasciculation into fascicles
        Cell adhesive molecules allow this - surface receptors
    2. Grow towards correct targets
      1. Chemoattractants
        Attract axon
        e.g. netrin
      2. Chemorepellants
        Repel axon
        e.g. ephrin
      3. This occurs due to axon receptor expression - creating a specific chemical environment
  2. Synaptogenesis
    1. Two-way signalling
      1. Presynaptic sends an invitation
      2. Postsynaptic must accept/reject signal
      3. Signalling via trophic factors such as NGF
    2. Synaptic loss important in degeneration of brain function
  3. Refinement
    1. Organised apoptosis of neuronal cells
      1. Removing sub-standard/incorrect signalling cells
        Controlled by gene expression
      2. Also occurs pathologically
        Alzheimer's Dementia
        Parkinsons Disease
  4. Neurodevelopmental disorders
    1. Autism
    2. Schizophrenia
    3. Cerebral palsy
    4. Epilepsy
    5. Dyslexia
    6. Gene expression vital in development
Therapeutic Revevance
1. Hijack processes
2. Stem cells
  1. Activating stem cells in adults
    1. CNS repair?
  2. Spinal cord damage
  3. Stem cell transplant in neurodegenerative disorders?
    1. SC must develop in neurone in developing brain - problem

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L02 - Development and Anomalies of Development in the CNS

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	Created by chris.brees almost 11 years ago