Normal and Abnormal Brain Development

Normal and Abnormal Brain Development

1. Cell Proliferation

   • Non-Embryonic Cell Cycle
     • G1: mitogens signal the start, G1 checkpoint, restriction point
       • S phase: unwinds into 2, ATCG = DNA per daughter cell
         • G2: new cell organelles, checkpoint, high p53 = apoptosis
           • Mitosis: organelles, split, QA checkpoint = daughter cells
             • Either G0 or G1
               • In mature organism neurones are permanently/semi G0
     • Mitogens (>50: broad or specific)

2. Cell Differentiation

   • Gene Expression
     • Transcription: RNA polymerase makes a RNA copy of DNA - cytoplasm as mRNA
       • Transcription factors block or induce RNA polymerase
         • Translation: GM of mRNA into a protein by ribosomes in RER

3. When proteins go wrong...

   • Alzheimer's: Faulty APP & Tau
     • Autism: Cereblon (thalidomide exposure and foetal development) - 20-24 days
       • Rett Syndrome - MECP2 gene (Guy et al., 2007: mice, 4 weeks- loss of neurological symptoms

4. Axon Growth

   • Growth cones extend extensions called filipodia (Stirling & Dunlop, 1995)
     • Molecular signals attract or repel - guide the axons direction/length

5. How do growth cones know where to go?

   • Chemoaffinity Hypothesis: releases a specific chemical, axon attracted to the target
     • Blueprint Hypothesis: chemical trails that axons follow
       • By cell adhesion molecules (CAMS)- Van Vactor 1998
       • Fasiculation: subsequent axons follow pioneer growth cones
       • Not explain in vitro
       • Transplanted reach their target (Lance-Jones & Landmesser, 1980)
       • Topographic gradient hypothesis: one sheet to another by relative positions on original sheet, 2 intersecting gradients
         • Anterior-posterior, medial-lateral
         • Molecular gradients (retina/tectum) Holt & Harris, 1998
         • Preserved across sheets in neurodevelopment (Reh & Constantine-Paton, 1984)
         • Following lesions = spread out to targets
     • Sperry (1943): optic nerve in frogs
     • In vitro: rat VC & LGN (Yamamoto et al., 1989)
     • Stoeckli & Landmesser (1989) chemical have been identified
     • Transplanted- incorrect cells (Whitelaw & Hollyday, 1983)
     • Axon growth indirect (Batiani et al., 1985)
     • Insufficient number of genes to code individually

6. Postnatal Development

   • Most neurones developed by 7th mo
   • Brain volume 4x birth to adulthood (Johnson, 1997)
   • Due to synaptogenesis, myelination, dendritic arborisation

7. Synaptogenesis (new synapses)

   • Dependent on glial cells
   • Increase after both, uneven in cortical (Huttenlocher, 1994)
   • PFC max at 24mo
   • PV & AC large increase at 4, max at 7mo
   • Synapse loss in V1 density at 5yo
   • Mirrors functional development (auditory, wenicke, broca)
   • How do synapses in the brain know where to grow?
     • Mediated by glutamate and NMDA receptor
       • Activation of NDMA receptor initiates synaptogenesis by downstream products (Ghiani et al., 2007)
         • Heightened NMDA receptor activity = influx of calcium = LTP of synapse
           • Cell differentiation via gene expression

8. Fragile X Syndrome

   • Non expression of the FMRP protein controlled by FRM1 gene (Verheij et al., 1993)
   • Thin long post synaptic spines like in neo-cortical development (Comery et al., 1997)
   • Bred knock out mice - FMR1 gene disrupted = dendrites longer, dendritic spine density is increased