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BIO271 2014 Lecture 2.pdf

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University of Toronto St. George
Christopher Garside

  Lecture  2:  Neurobiology  Section     The  Synapse   -­‐ Once  the  wave  of  depolarization  reaches  the  axon  terminal,  this   electrical  signal  must  be  transferred  to  the  postsynaptic   cell   -­‐ Not  all  neurons  release  chemical  neurotransmitters,  some  neurons  have  gap  junctions  that  directly  connect  them  to   their  target  cells   -­‐ Synapses  in  which  presynaptic  and  postsynaptic  cells  are  con nected  via  gap  junctions:   electrical  synapses   -­‐ Most  neurons  do  not  form  gap  junctions,  instead  they  form   chemical  synapses  –  presynaptic  neuron  converts  its   electrical  signal  to  a  chemical  signal  in  the  form  of  a  neurotransmitter  (which  diffuses  across  the   synapse  to  the   postsynaptic  cell  and  binds  to  receptors  on  the  postsynaptic  membrane)   -­‐ Chemical  signal  (neurotransmitter)  that  crosses  the  synaptic  clef,  gets  converted  back  to  an  electrical  signal   -­‐ signal  transmission  from  neuron  to  another  cell  (one  direction)   • presynaptic  cell  (boutons)  à  synaptic  cleft  à  postsynaptic  cell   • not  a  lot  of  evidence  for  retrograde  transmission  (only  NO  and  other  gases)   -­‐ synapse  synaptic  cleft   • space  between  the  presynaptic  and  postsynaptic  cell   -­‐ postsynaptic  cell   • may  be  a  neuron,  muscle  cell,  or  endocrine  cell   -­‐ neuromuscular  junction   • synapse  between  a  motor  neuron  (a  neuron  at  the  spinal  cord  that  innervates  and  forms  a  synapse  on  a  muscle)   and  a  skeletal  muscle  cell     Electrical  Synapse   -­‐ transmission  is  instantaneous  –  not  associated  with  any  synaptic  delay   -­‐ can  easily  convey  information  in  either  direction  because  electrical  currents/ions  can  move  freely  in  either   direction  through  the  gap  junctions  connecting  the  cells   -­‐ the  signal  in  postsynaptic  cell  is  always  similar  to  the  signal  s ent  by  the  presynaptic  cell   à  this  direct  electrical  coupling  across  an  electrical  synapse  limits  the  diversity  of  the  signal  in  the  postsynaptic   cell   -­‐ present  in  neural  pathways  involved  in  escape  behaviours  (increases  speed  of  escape  response)     Chemical  Synapse   -­‐ primary  flow  of  information  if  from  the  presynaptic  cell  to  the  postsynaptic  cell  (not  in  reverse  direction)   -­‐ transmission  is  relatively  slow  compared  to  the  speed  of  propagation  in  action  potentials  because  of  the  need  for   docking  and  fusion  of  syna ptic  vesicles,  diffusion  across  synapse,  and  signal  transduction  in  the  postsynaptic  cell   -­‐ advantage:  signal  in  postsynaptic  cell  is  not  necessarily  the  same  as  in  the  presynaptic  cell   -­‐ provide  an  additional  level  of  regulation  for  the  nervous  system                       Signal  Transmission  at  a  Chemical  Synapse     -­‐ the  axon  of  a  motor  neuron  splits  into     several  terminal  branches  –  each   branch  terminates  in  a  swelling  called   the  axon  terminal  (or  terminal  bouton)   1) action  potentials  arrive  at  axon   terminal   à  action  potential  reaches   terminal/bouton       à  now  we  have  to  convert  electrical  signal  (action  potential)  to  the  release  of  chemical  neurotransmitter  (happens   due  to  a  calcium  dependent  process)   2) voltage  gated  Ca2+  channels  open   3) Ca2+  enters  the  cell   à  normally,  calcium  is  kept  at  an  almost  nonexistent  level  in  the  cell  (calcium  wants  to  go  in  the  cell)   à  so  when  calcium  comes  in,  we  can  detect  it  very  readily   à  many  proteins  inside  are  calcium  sensitive   4) Ca2+  signals  to  vesicles   à  when  calcium  comes  in,  it  starts  binding  to  calcium  sensitive  proteins  (to  release  vesicles  of  neurotransmitters)     5) Vesicles  move  to  the  membrane   6) Docked  vesicles  release  neurotransmitter  by  exocytosis   à  vesicles  are  released  to  the   active  zone   7) Neurotransmitter  diffuses  across  the  synaptic  cleft  and  binds  to  receptors   à  if  lucky,  neurotransmitter  will  bind  to  a  receptor  on  postsynaptic  membrane   8) Binding  of  neurotransmitter  to  receptor  activates  signal  transduction  pathway  (elicits  a  response)     Amount  of  Neurotransmitter  Released   -­‐ [Ca2+] = i  acellular  calcium   -­‐ [Ca2+]  i   presynaptic  terminal  is  affected  by  the  action  potential  frequency   • big  action  potential  frequency  =  more  open  voltage -­‐gated  Ca2+  channels  =  increase  in  [Ca2+] =  more  transIitter   released   • depends  on  how  many  voltage  gated  calcium  channels  are  opening,   and  how  well  that  terminal  can  regulate   intracellular  concentration  (terminal  is  full  of  buffers  that  buffer  calcium  when  it  comes  in)   -­‐ calcium  level  is  maintained;  have  one  action  potential  come  i n  =  calcium  comes  in  =  quickly,  presynaptic  terminal  is   trying  to  clear  calcium  out  à  so  when  next  action  potential  comes  in,  we  can  detect  that  influx  of  calcium   -­‐ factors  that  lower  intracellular  [Ca2+]   i • binding  with  intracellular  buffers  =  decrease  in  [Ca 2+]   i • Ca2+  ATPase  decreases  [Ca2+]  =  puts  calcium  right  back   I -­‐ high  action  potential  frequency   à  Ca2+  influx  is  greater  than  removal   à  increase  in  [Ca2+]  à  mani  synaptic  vesicles   release  their  contents  à  high  [neurotransmitter]  in  synapse     Neurotransmission   -­‐ why  does  Ca2+  flow  into  the  presynaptic  terminal  when  voltage -­‐gated  Ca2+  channels  are  opened?   à  calcium  is  like  sodium,  positively  charged   –  and  graded  à  concentration  gradient  is  inward   -­‐ What  is  the  equilibrium  potential  for  Ca2+   à  two  forces  driving  it  in  (concentration  and  electrical  gradient)   –  equilibrium  potential  =  above  100mV  (much  higher   than  sodium  potential)   à  tells  us  that  calcium  has  a  very  strong  force  to  get  inside     Synaptic  Vesicles   -­‐ synaptic  vesicles  are  covered  in  synaptic  proteins   -­‐ these  proteins  help  direct  vesicles  to  where  it  goes   a) Docking  and  priming   • Vesicles  located  near  regions  near   active  zone   • Recycling  pool  of  vesicles   • Calcium  comes  in  and  acts  on  some  of   those  proteins  that  are  in  the   membrane  of  synaptic  vesicles   • Cause  them  to  undergo  docking  and   priming   • Primed  for  release   • Vesicle  is  ready  to  release  their   neurotransmitter   b) Exocytosis   • Membrane  fuses  –  vesicles  and   presynaptic  membrane       • Spill  contents  of  vesicles  (neurotransmitter)  into  the  membrane   c) Release  site  clearance   • Need  to  make  more  membranes   • Clear  all  transmitter  from  the  region   d) Endocytosis   • Cut  out  that  part  of  membrane,  form  vesicles   e) Vesicles  recycling  and  reclustering   • Vesicle  gets  reloaded  and  recycled  for  use   -­‐ From  recycling  pool,  docking  and  prime,  exocytosis  are  all  calcium  dependent     Acetylcholine  (ACh)   -­‐ when  used  at  a  synapse,  it  is  often   called  Cholinergic  transmission   -­‐ ACh  is  released  from  motor  neuron   onto  muscles   -­‐ Also  used  in  many  parts  of  the  brain   -­‐ ACh  is  synthesized  in  the  presynaptic   terminal  in  a  reaction  catalyzed  by  the   enzyme  choline  acetyl  transferase:   -­‐ Neurotransmitter  function  is   DEPENDENT  on  receptor   -­‐ Can  excite  or  inhibit  postsynaptic   region   -­‐ ACh  is  packaged  into  vesicles  and   stored  until  an  action  potential  arrives   1) Acetyl  CoA  is  synthesized  in  the   mitochondria   2) Choline  acetyl  transferase  catalyzes   the  conversion  of  choline  and  acetyl   CoA  to  acetylcholine  (ACh)     3) The  ACh  is  packaged  into  synaptic  vesicles   4) ACh  is  released  into  the  synapse   5) ACh  binds  to  its  receptor  on  the  postsynaptic  cell   1. Acetylcholineterase  (AChE)   breaks  down  ACh  into  choline  and  acetate,  terminating  the  signal  in  the  postsynaptic  cell   (doesn’t  want  transmitter  to  hang  around  too  long,  if  next  action  potential  arrives,  there  will  be  a  build  up  of   transmitters)  à  can  diffuse  it  or  reuptake  it  (recycl e  and  put  it  back  into  vesicles)  –  diffusion,  reuptake,  enzymatic   degradation   2. The  presynaptic  cell  takes  up  and  recycle  the  choline,  and  the  acetate  diffuses  out  of  the  synapse   Postsynaptic  Cells   -­‐ postsynaptic  cells  have  specific  receptors  for  neurotransmit ters     -­‐ receptors  determine  neurotransmitter  function   o ex.  Nicotinic  ACh  receptors  –  can  be  activated  by  ACh  or  nicotine   o similar  to  specific  hormone  receptors  on  target  cells   o binding  of  neurotransmitter  (opens  gate)  to  receptor  alters  ion  permeability  of  post synaptic  cell   à  change  in  membrane  potential  of  postsynaptic  cell   à  change  in  membrane  potential  =  graded  potential   -­‐ graded  potentials  in  dendrites   à  graded  potentials  makes  action  potential   à  action  potential  travels  down  axon   for  release  of  transmitter à  transmitter  cross  the  synaptic  cleft à   binds  to  receptorà    causes  change  in   membrane  potential     Transmission  of  Signal  Strength  at  Synapse   -­‐ response  of  postsynaptic  cell  influenced  by  amount  of   neurotransmitter  in  synapse  and  number  of  receptors   (the  more  receptors  =  larger  the  response  signal)   • amount  of  neurotransmitter   § rate  of  release  –  rate  of  removal   § released  determined  by  frequency  of  action   potentials   § removal  determined  by:       -­‐ passive  diffusion  out  of  synapse   -­‐ degradation  by  synaptic  enzymes   -­‐ uptake  by  surrounding  cells  (synapse  is  actually  surrounded  by  glial  cells  that  will  uptake  transmitters)   • number  of  receptors   § density  of  receptors  on  postsynaptic  cell     Synaptic  Transmission   -­‐ transfer  of  electrical  signal  from  presynaptic  cell  to  postsynaptic  cell   • Electrical  synapse  –  gap  junctions   § tail  flip  reflex:  mediated  by  gap  junctions   –  some  sensory  input  activates  motor  neuron  by  gap  junction  to   flip  the  tail   § electrical  synapses  are  fast,  but  restricted  (static   –  not  a  lot  of  changing)   • Chemical  synapse  –  chemical  messenger  crosses  synaptic  cleft     § Variety  of  responses  in  postsynaptic  cell   à  can  change  the  type  of  receptor  the  postsynaptic  cell  expresses   § A  lot  more  options     Electrical  Synapse   Chemical  Synapse   Rare  in  complex  animals     Common  in  complex  animals   (humans  only  have  little  –  cortex,   hippocampus,  between  inhibitory  neurons   (makes  tightly  controlled  inhibition))   Common  in  simple  animals  (invertebrates)   Rare  in  simple  animals     Fast   Slow   Bi-­‐directional  (charge  can  go  from  pre  to  post,   Unidirectional   post  to  pre)   Postsynaptic  signal  is  similar  to  presynaptic   Postsynaptic  signal  can  be  different   -­‐  hard  to  modify     -­‐ synaptic  plasticity   -­‐ when  we  want  to  learn  something,  this   process  happens  because  we  are   modifying  the  strength  of  s ynapses   (increasing/decreasing  the  strength)  à   essential  for  higher  order  function,   cognition,  and  memory   Excitatory  (positive  charge  flowing  through)   Excitatory  or  Inhibitory   Structural  Diversity  of  Chemical  Synapses   -­‐ synapses  can  be  formed  in  different  locations   -­‐ axodendritic  synapse:  when  the  axon  from  the   presynaptic  cell  forms  a  synapse  with  the   dendrite  of  the  postsynaptic  cell   -­‐ axosomatic  synapse:  axon    synapses  onto  the   cell  body  (powerful  à  when  these  synapses   occur,  the  postsynaptic  response  is  a   graded   potential  à  graded  potential  then  has  to   travel  down  the  axon  hillock  à  as  it  travels,   the  graded  potential  decreases  as  it  moves,  so   since  there  is  a  shorter  distance  to  travel  from   the  soma  to  the  axon  hillock,  the  amount  the   potential  decreases  is  less   -­‐ axoaxonic  synapse:  axon  makes  a  synapse  to   the  axon  itself  à  rare,  but  when  they  do   occur,  they  have  a  major  effect     à  if  this  is  an  inhibitory  synapse,  whatever   fires  will  be  prevented   -­‐ dendrodendritic  synapse:  very  rare     Neurotransmitter   -­‐ characteristics  of  neurotransmitters   • synthesized  in  neurons       • released  at  presynaptic  cell  following  depolarization  (action  potential  that  causes  depolarization  initiates  the   release)   • bind  to  a  postsynaptic  receptor  and  cause  an  effect   -­‐ more  than  50  known  substances   -­‐ categories:  amino  acids,  neuropeptides,  biogenic  amines,  acetylcholine,  others  (gases,  purines,  etc.)   -­‐ a  single  neuron  can  produce  and  release  more  than  one  neurotransmitter     Neurotransmitter   Receptor   Receptor  Type   Receptor  Location   Effect   Acetylcholine   Nicotinic   Ionotropic   Skeletal  muscles,   Excitatory   autonomic  neurons,   CNS     Muscarinic   Metabotropic   Smooth  and  cardiac   Excitatory  or   muscle,  endocrine  and   inhibitory   exocrine  glands,  CNS   Amino  Acids           Glycine   Gycine   Ionotropic   CNS   Inhibitory   Aspartate   Aspartate   Ionotropic   CNS   Excitatory   Glutamate   AMPA   Ionotropic   CNS   Excitatory     NMDA   Ionotropic   CNS   Excitatory     mGlu1-­‐8   Metabotropic   CNS   Excitatory  or   inhibitory   GABA   GABA-­‐A   Ionotropic   CNS   Inhibitory     GABA-­‐B   Metabotropic   CNS   Generally  Inhibitory   Biogenic  Amines           Dopamine   Dopamine   Metabotropic   CNS   Excitatory  or   inhibitory   Norepinephrine    Α  and  β  adrenergic   Metabotropic   CNS  and  PNS,  cardiac   Excitatory  or   muscle,  smooth   inhibitory   muscle   Epinephrine      Α  and  β  adrenergic   Metabotropic   Cardiac  muscle,   Excitatory  or   smooth  muscle,  CNS   inhibitory   -­‐ for  many  amino  acids,  there  are  multiple  receptors,  each  receptor  type  has  dozens  of  subtypes   -­‐ each  subtype  receptor  produces  a  different  effect   -­‐ effect  of  neurotransmitter  depends  on  the  receptor  it  binds  to   -­‐ variety  of  actions  from  a  neurotransmitter  is  based  on  the  variety  of  subtypes  these  receptors  have   -­‐ inhibitory  transmitters  and  excitatory  transmitters  are  still  based  on  the  receptors     Neurotransmitter  Action  (depends  on  receptors)   -­‐ is  it  preventing  or  helping  generate  an  action  potential?   -­‐ If  cell  is  excitable,  its  got  an  action  potential   -­‐ Inhibitory  Neurotransmitters   •
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