8. Myelination.pdf

Myelination Alyson Fournier [email protected] The need for speed Brain Spinal cord Nerves DRG neuron Myelination Myelination is the process by which glial cells produce and insulation sheath (myelin) that ensheaths axons of neurons Myelin speeds of the transmission of neural impulses Myelin...

Myelination Alyson Fournier [email protected] The need for speed Brain Spinal cord Nerves DRG neuron Myelination Myelination is the process by which glial cells produce and insulation sheath (myelin) that ensheaths axons of neurons Myelin speeds of the transmission of neural impulses Myelin progresses along the rostral caudal axis from spinal cord, to hindbrain to midbrain to forebrain beginning in the third trimester and continuing to adulthood Myelination is the main cause of increase in the child’s brain size and contributes to an increase in brain size to 80% of its adult weight in the 1st four years of life. Can be heavily impacted by malnutrition or alcohol exposure pre or postnatally. Myelination – better judgment and impulse control, decision making, social interactions Neuropsychopharmacology volume 35, pages147–168(2010) Myelinating Glia Saltatory conduction The Myelin-Forming Cells of the Nervous System Oligodendrocyte – Central Nervous System Schwann Cell – Peripheral Nervous System Nucleus Nucleus A A A = Axon N = Nucleus of Oligodendrocyte or Schwann Cell Unmyelinated and Myelinated Neurons https://www.wisegeek.com/what-are-nerve-fibers.htm# The Cells of Schwann (Theodor Schwann 1810-1882) Schwann Cell Myelin Internodes Schwann Cell Axon Schwann Cells specification and myelination The fate of Schwann cells is determined by the axons that they associate with Myelination occurs in Schwann cells that envelop large diameter axons Schwann cells that ensheath small diameter axons (less than 1 µm) progress to become mature non-myelinating cells. A Schwann cell wraps around a single axon Nature Reviews Neuroscience volume 6, pages671–682(2005) J Peripher Nerv Syst. 2008 Jun;13(2):122-35 Intrinsic and extrinsic signals control Schwann cell myelination SOX-10 NRG1 Notch FGF2 Adenosine ATP Autocrine survival factors b1-integrin C-Jun Claw paw Ets transcription factors IGF Laminin NRG1 NT3 SOX2 P38 p75NTR TGFb Myelinating Schwann Cells ATP C-Jun Notch NT3 PAX3 SOX2 TGFb Axon Neural crest cell BDNF BRN2 cAMP GDNF IGF KROX20/NAB1/2 Laminin NF-kB NRG1 OCT6 Progesterone PI3K-Akt SKI Schwann Cell precurser Immature Schwann Cells Endothelin BMP2/4 AP2a Nature Reviews Neuroscience 2005DOI:10.1038/nrn1746 Oligodendrocyte Specification and Maturation During spinal cord development, ventral neural progenitor cells that express the transcription factors Olig1 and Olig2, called pMN progenitors, produce motor neurons and then oligodendrocytes. The restricted area of the progenitor pool is surprising considering that Oligodendrocytes are found abundantly in the white and grey matter in the adult Shh regulates the expression of Olig1 and Olig2, key transcription factors for Oligodendrocyte development Extensions from a single oligodendrocyte can extend its processes to 50 axons and can form segments of myelin for several adjacent axons. Brain Sciences 3(3):1282-324 Nature. 2010 Nov 11;468(7321):214-22. doi: 10.1038/nature09611 Intrinsic and extrinsic signals control Oligodendrocyte myelination Trends in Cell Biology 26(2) · October 2015 Myelinating Glia Saltatory conduction One OL can make multiple wrappings on multiple axons whereas a SC can only wrap a single axon and needs many SCs to wrap along the axonal length. How glial cells wrap axons with myelin - Compact myelin around axon – thickness controlled by axonal diameter. - Below a 1µm threshold axons are unmyelinated IMA = inner mesaxon OMA = outer mesaxon Nat Rev Neurosci. 2003 Dec;4(12):968-80. The local differentiation of myelinated axons at nodes of Ranvier. Poliak S, Peles E. What a Schwann cell might look like “unrolled - Very thin, a few channels of cytoplasm - Tight association between membranes regulated by P0 - Pulls membranes tightly together, only water and small ions can pass between Molecular Composition of Compact Myelin The major dense line is formed by apposition of the cytoplasmic faces The two external surfaces of membrane form the myelin intraperiod line. Physiological Reviews. Vol 81, No. 2, April 2001 Myelin basic protein (MBP) Myelin Basic Protein is located on the cytoplasmic face of the membranes and acts to stabilize the major dense line in myelin sheath. PNS CNS PLP MBP PLP PLP PLP PO PO PO PO PMP 22 PLP MBP MBP MBP P2 Proteolipid protein (PLP) >Its expression is largely restricted to oligodendrocytes. >It is a transmembrane protein. >It plays a major role in stabilizing the intraperiod line of CNS myelination. PNS CNS PLP MBP PLP PLP PLP PO PO PO PO PMP 22 PLP MBP MBP MBP P2 Protein zero (Po) > It represents a member of the immunoglobulin superfamily of cell adhesion molecules. > Its expression is restricted to myelin forming Schwann cells only. > The extracellular domain of Po which functions as a homophilic cell adhesion molecule promotes the formation of the intraperiod line whereas the cytoplasmic domain is considered to be involved in making of the major dense line of PNS myelin. PNS CNS PLP MBP PLP PLP PLP PO PO PO PO PMP 22 PLP MBP MBP MBP P2 Mutant mice such as shiverer (deletion in large portion of the MBP gene), or jimpy (frameshipt mutation in the PLP gene) display neurological symptoms including tremor, convulsions and finally death. The shiverer mouse shows either complete loss of myelin or deformed structure (i.e., lack of dense lines) in the CNS while the PNS myelin is very little affected. Shiverer movie https://www.youtube.com/watch?v=4tr7fPxFqlI Myelin Lipids Myelin contains 70-85% lipid and 15-30% protein (i.e., high lipid to protein ratio). Myelin lipids: There is no lipid specific to myelin. Additionally, myelin of the central and peripheral nervous systems, apart from quantitative differences, contain more or less the same lipids. The lipids which are present in myelin are: a) 25-28% cholesterol b) 27-30% galactosphingolipids (i.e., cerebrosides, sulphatides) c) 40-45% phospholipids (i.e., phosphatidyl ethanolamineand choline) How does myelin regulate axonal conduction- Nodes of Ranvier Na+ Channels Area of polarity reversal (node of Ranvier) Nodes Internode Myelin sheath Nav1.6 Distal Axon PNJ NOR Rosenbluth, Int J Dev Neurosci 1998 NOR Lorincz et al., Science 2010 - Nodes of Ranvier are gaps between sections of myelin - Act as booster stations to maintain strong depolarization and maintain action potential propogation - High concentration of votage-gated ion channels at nodes of Ranvier (Na+ and K+) - Boost conduction speed 100 X - Located at about 1 mm intervals - Current spreads between nodes, depolarizing membrane in that region producing a new action potential - Action potentials leap from node to node in a process called saltatory conduction http://www.physiol.arizona.edu/PSIO201/fall02/notes/lec31.pdf Schematic of a longitudinal cut of a myelination fibre around the node of Ranvier Basal lamina Microvilli PNS Septate like junction Node, paranode, juxtaparanode (JXP) and internode The node is contacted by Schwann cell microvilli in the PNS or processes from perinodal astrocytes in the CNS Internode CNS JXP. Paranode. Node Myelinated fibres in the PNS are covered by a basal lamina Paranodal loop Perinodal astrocyte Nat Rev Neurosci. 2003 Dec;4(12):968-80. The local differentiation of myelinated axons at nodes of Ranvier. Poliak S, Peles E. Distinct axoglial adhesion complexes control the functional organization of myelinated axons WT KO NaCh/Caspr/NFH WT Kv.2/Caspr NaCh/Kv1.2 KO Clustering WT Membrane barrier KO Kv1.2 KO Scaffold Polarization Jonah Chan, UCSF Demyelinating diseases and axonal conduction Nat Rev Neurol. 2013 Sep;9(9):535-40. Demyelinating Diseases Degenerative disease Traumatic injury and axon regeneration Experience dependent myelination