Genetics and NeuroDevDisorders

Genetics and NeuroDevDisorders

1. Brain Development

   • Neurodevelopment begins ~18 days post fertilisation and carries on long after birth. • The brain begins as a layer of cells called the neural plate The neural plate folds over something called the neural groove, eventually forming the neural tube. • This is called neurulation.
   • The Neural tube
     • The neural tube becomes the brain and spinal cord. It develops by differentiating in three different dimensions: Longitudinally – along the length of the tube. Circumferentially – around the tube. Radially – From the inside of the tube outwards (or vice versa).
     • Neurulation
       • The steps that go with it
       • Neurogenisis
         • 1) Near the central surface of the neural tube are proliferative areas, where neurones and glial cells are ‘born’. Most neurogenesis is completed prenatally. There is some postnatal neurogenesis – but only in small areas (will see this later) As cells are “born”, they must migrate to the correct location To do this – they follow chemical cues
         • Concentration gradient
           • The common mechanism to control migration, patterning (throughout brain and body) Concentration gradients – Support growth and differentiation of neurones – Attract or repulse moving neurones to coax them into the correct place in the cortex – Support “patterning”, layer formation, etc. • Any disruption of genes coding for these patterning proteins = serious problem
           • Example: Double gradient BMP released by roof plate and diffuses ventrally SHH released by floorplate and diffuses dorsally Relative concentrations of both the sets up a pattern of regions specific to particular neurone types If you know the concentration of each, you know what kind of neurone is there. These neurone types then set up specific regions in the central nervous system. This is the way the central nervous system is patterned in the dorsal to ventral direction.
         • 2) First neural stem cells multiply until there are enough “progenitor cells” These progenitor cells migrate to their correct location in the nervous system • There they divide to produce daughter cells – Symmetric division produces more progenitor cells – Asymmetric division produces neurones (they will never divide again) Most neurones are not replaced if they die. Adult neurogenesis in 3 places: – Dentate Gyrus in the hippocampus – Subventricular zone (lines the ventricles) – Olfactory bulbs
         • Stem and progenitor cell niches
         • Neural Migration
           • How do neurones find their destination? Neurones migrate along radial glial cells. Chemical exchanges between neurones and glia tell neurones when to ‘get off’. Use concentration gradients (grow towards attractive cues, grow away from repulsive cues) Ectopic (out of place) neurons linked with a variety of neurodevelopmental conditions.
             • Differentiation
               • 25 different neuron types (80% Pyramidal) A. Pyramidal cell (hippocampus) B. Purkinje cell (cerebellum) C. Motor neuron (spinal cord)
               • Axonal Growth
                 • To communicate with one another, neurons need to grow axons. • These axons need to make the right connections • Tip of a new axon is called a growth cone. • Growth cones also allow the axon to move.
                   • Growth cones are sensitive to chemicals excreted by nearby cells, which either attract or repel them. These chemical attractors and repellents can be used to create a variety of neural architecture – Retinotopy is controlled by gradients of different chemical signals. – Chemical signals between the hemispheres attract commisural axons but repel others.
                 • Dendritic Change
                   • A lot of change, including some forms of learning and memory, rely on the formation of new synapses Dendrites (increase in number, length) Spines (increase in number, density or maturity)
                   • Synaptogenesis and pruning
                     • Synaptic connections First – many, many more synapses are formed than are needed – then they are removed – Age 2-4 150% of adult connections
                     • ‘Regressive growth’ in development
                       • ~50% of neurons die prenatally • Neurons that make successful connections will survive, others that don’t make active cell-cell contacts, won’t. Synapses that are “effective” are kept – others are pruned • This “regressive growth” continues throughout development
                       • ‘Regressive growth’
                         • Lots of extra synapses are formed • Developing brains more interconnected than adult brains. • Unneeded or less “effective” connections are pruned as development proceeds. • Mutant mice who do not prune transient connection have severe CNS abnormalities. • Exuberant synaptogenesis, followed by pruning is a common pattern across the brain (not specific to one region or age) • Timecourses across the cortex vary
                         • Hebb’s postulate
                           • Neurons that fire together wire together • Use it or lose it
                           • Plasticity: Experience dependent change
                             • Some synapses are “experience independent” – (genetically pre-determined path). • Others are “experience expecting” experience prunes them or strengthens and consolidate them (patterning of visual cortex) • Later synapses develop in response to specific experiences (learning to read, practicing the piano) – they are “experience-dependent” • All involve selective synapse formation and selective synaptic loss. • Experience changes neural networks by both adding and pruning synapses.
                             • Cortical changes over age – volume
                               • why does the brain get bigger?
                                 • Due to changes in a bunch of different things: – neuron size (soma size) – dendritic branching – spine density – increasing numbers of synapses (with experience) – glial numbers – more support, better function – blood vessel enrichment
                                 • Glial Cells
                                   • Astrocytes - clean up brain, transport nutrients, hold neurons in place • Microglia - digest dead neurons • Oligodendroglia – Creates myelin in central nervous system • Satellite cells - support peripheral nervous system • Schwann cells – Creates myelin to neurons in peripheral nervous system 10-50 more times glia than neurons
                                   • Myelination
                                     • Myelin is a fatty coating which forms a ‘sheath’ around some axons. • Insulates the axon, increasing velocity of electrical signals. • Myelination (in CNS) carried out by oligodendrocytes. • Mainly post-natal.
                                     • Developmental Timecourse
                                       • Character of developmental stages may depend on relative level of development in different regions and structure – Whether more or less is better (neurons, synapses, myelination) depends on when you ask that question – That’s the nature of developmental questions!
                                       • Know the main developmental mechanisms – Neurogenesis, neural migration, synapse formation – “Regressive growth”, synaptic pruning – Types of plasticity – Chemical gradients • Concept of development as complicated “ballet” – what is “normal” depends on when you’re asking