This document summarizes synaptic transmission between nerve cells. It discusses the key discoveries in the field, including that synaptic transmission can be either chemical or electrical. Chemical transmission involves the release of neurotransmitters from the presynaptic cell that bind to and activate receptors on the postsynaptic cell. The process requires calcium influx into the presynaptic terminal to trigger neurotransmitter release from synaptic vesicles.

1. SINAPSE

4. NERVNO-MIŠIĆNA SINAPSA Sinapsa je mesto funkcionalnog kontakta i komunikacije između bilo koje dve nadražljive ćelije Nervno-mišićna sinapsa ili motorna sinapsa - sinapsa između vlakna motorne nervne ćelije i mišićne ćelije hemijske sinapse -poruke se prenose posredstvom hemijskih agenasa - neurotransmitera

6. Električne sinapse -AP se prenosi direktno sa jedne ćelije na drugu Nervni-mišićna sinapsa je sinapsa koja se formira između završnog dugmića motorne nervne ćelije i mišićne ćelije Motorna nervna ćelija je presinaptička ćelija , a mišićna ćelija je postsinaptička ćelija

7. Membrane presinaptičke i postsinaptičke ćelije nisu u direktnom kontaktu-razdvojene su sinaptičkom pukotinom ( vanćelijskim prostorom od nekoliko desetina nm) U završnim dugmićima MNĆ nalazi se veliki broj sinaptičkih vezikula od kojih svaka sadrži nekoliko hiljada molekula neurotransmitera-actilholina (Ach) -hemijskog glasnika, prenosioca poruke

8. Postsinaptička membrana sadrži specifične proteine receptore za Ach - jonski kanali prohodni pretežno za jone Na koji ulaze u ćeliju Kada AP stigne do završnih dugmića motorne nervne ćelije promena potencijala presinaptičke membrane uslovljava prolazno povećanje unutarćelijske koncentracije jona Ca 2+

9. Povećanje koncentracije Ca 2+ u citoplazmi završnog dugmića izaziva pomeranje sinaptičkih vezikula prema presinaptičkoj membrani , njihovo spajanje sa njom i oslobađanje Ach iz vezikula u sinaptičku pukotinu procesom egzocitoze Ach putuje kroz sinaptičku pukotinu i vezuje se za receptore na postsinaptičkoj membrani što dovodi do ulaska jona Na i depolarizaciju membrane mišićne ćelije - potencijal motorne ploče

10. Potencijal motorne ploče izaziva otvarnje voltažno-zavisnih kanala za Na i nastaje AP

11. CENTRALANA SINAPSA

12. Centralne sinapse - sinapse koje se uspostavljaju između NĆ u CNS-u Većina NĆ gradi sinapse sa ogromnim brojem, najčešće nekoliko stotina, drugih NĆ Prenos signala sa jedne NĆ na drugu u CNS-u je posredovan različitim transmiterima od kojih svaki prepoznaje svoj specifični receptor Efekat delovanja neurotransmitera u centralnoj sinapsi zavisi od same prirode neurotransmitera , kao i od receptora za koji se vezuje

13. Sinaptičke veze između NĆ su hemijske sinapse i najčešće se uspostavljaju između nervnog vlakna presinaptičke NĆ i dendrita postsinaptičke NĆ- AKSODENDRITSKE SINAPSE Presinaptička membrana – membrana terminalnih dugmića i postsinaptička membrana - dendritska membrana su razdvojene sinaptičkom pukotinom Na postsinaptičkoj membrani su receptori za neurotransmiter

16. Različite NĆ sadrže različite neurotransmitere Neurotransmiteri se prema hemijskoj strukturi mogu svstati u četiri kategorije: amino-kiseline , amini , peptidi i purinski nukleotidi Vezivanje neurotransmitera za receptor uslovljava promenu oblika receptorskog proteina i on postaje funkcionalan

17. Efekat neurotransmitera je ekscitatoran kada nakon vezivanja neurotransmitera dođe do promene oblika receptorskog proteina , što dovodi do otvaranja jonskih kanala koji su pod kontrolom ovog receptora i propuštanja jona Na pri čemu dolazi do depolarizacije postsinaptičke membrane- ekscitatorni postsianptički potencijal (EPSP)

18. Efekat neurotransmitera je inhibitoran kada bezivanje neurotransmitera za receptor na postsinaptičkoj memebrani uslovljava otvaranje jona za K ili Cl , jer tada dolazi do hiperpolarizacije postsinaptičke membrane - inhibitorni postsinaptički potencijal (IPSP)

19. Pojedinačni EPSP nema dovoljnu amplitudu da izazove AP, ali kako NĆ uspostavljaju sinapse sa velikim brojem drugih NĆ istovremena aktivnost većeg broja presinaptičkih NĆ može dovesti do sabiranja sinaptičkih potencijala i nastanka AP Ovaj tip sabirajućeg uticaja većeg broja presinaptičkih neurona naziva se PROSTORNO SABIRANJE Ukoliko se višestruka sinaptička transmisija dešava sa jedne na drugu NĆ na drugu NĆ takođe dolazi do sabiranja – VREMENSKOG SABIRANJA

20. SYNAPTIC TRANSMISSION I Tim Murphy NRSC 500, 2009 The definition of synaptic transmission is simply the communication between two nerve cells. Communication believed to involve specialized structures termed "synapses". We will focus on: 1) The discovery of synaptic transmission 2) The form of transmission, i.e. chemical or electrical 3) Criteria for a chemical transmitter 4) Ionic requirement for release 5) Quantal aspects of release: vesicle theory

22. Shepherd 1997 TINS Cajal’s drawings Sherrington’s insights 1890s. of golgi stain.

23. Modern golgi staining, YFP mouse cortical fluorescence, can be bred to other KO’s, transgenics.

24. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm

27. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm

28. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm Chemical Electrical

29. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm

31. Electrical synaptic transmission . Fundamental Neuro.

33. Saint-Amant and Drapeau Neuron 2001 Chemical transmission inhibitors do not block transmission in developing Zebrafish.

34. Saint-Amant and Drapeau Neuron 2001 Gap junction inhibitors block transmission in developing Zebrafish.

37. A hall mark of chemical transmission is a delay between presynaptic Ca2+ elevation and secretion. The delay can be as short as 0.1 ms, but is usually longer due to a variety of factors. Fundamental Neuro. 2002

39. Synaptic delays can be less than 0.2 ms from calcium entry (Fund. Neurosci. Chap 8) to the beginning of secretion, but are typically longer when all steps are considered. From Sudhof 2004

41. See http://synapses.mcg.edu/atlas Josef Spacek Type I Excitatory Type II Inhibitory

42. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm

43. Synapse structure like real estate location, location, location!! From Squire et al. Fund. Neurosci 2 nd ed. Multiple release sites NMJ

47. Slope on a log-log plot indicates power relation, a small change in calcium produces a large change in release. Slope=5.0 Slope=1.6 Release~[Ca]^3-5 from Delaney Enc. of Sci.

48. G. Augustine Curr. Op. in Neurobiol. Neurotransmitter release is triggered by a locally-activated low affinity sensor since bulk cytosolic [Ca] rarely exceeds 10 -6 M, yet transmitter release requires much higher [Ca].

52. Reviewed in EF Stanley TINS 1997 Calcium channels are clustered on the release face of the chick caylx synapse. Outside of synapse Release face of synapse Patch config.

56. Kd or Km, concentration at ½ max binding or activity. Kd=Km=kdissoc/kassoc affinity=1/km, low affinity means a big km which usually means a large kdissoc Note koff=kdissoc and kon=kassoc

58. For a simple reaction. [ES] [E]+[S] k on *[S] k off The time constant will be :   k off + k on *[S]) 20  s=1/( 5x10 4 s -1 + 5x10 8 M –1 s –1 *1x10 -7 M) For reference

59. Local domains of Ca 2+ near channel mouths control transmitter release. EF Stanley TINS 1997 It is unclear whether release is always triggered by a single channel or whether multiple ones cooperate.

60. Transmitter release microdomains. 1.8 mM Activation of Ca channels Resting state just after channel closure, bulk Ca is up only 10%.

61. Atwood & Shanker Karunanithi DIVERSIFICATION OF SYNAPTIC STRENGTH: PRESYNAPTIC ELEMENTS Nature Reviews Neuroscience 3, 497 -516 (2002). To make full use of microdomains the vesicle must be bound to the calcium channels.

62. Atwood & Shanker Karunanithi DIVERSIFICATION OF SYNAPTIC STRENGTH: PRESYNAPTIC ELEMENTS Nature Reviews Neuroscience 3, 497 -516 (2002). B BAPTA, a faster buffer than EGTA more readily blocks synaptic transmission. Given 100  M Ca 2+ , BAPTA equilibrates in <20  s while EGTA takes ~1000  s.

66. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm

67. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm

68. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm

69. 1X 4X 2X Stimulation 1 mV 1X 2X 3X 4X mini Mini histogram. Evoked amplitudes. Squire Fund. Neurosci. 2002

72. From Kristin Harris Lectures. http://synapses.mcg.edu/lab/harris/lectures.htm Define the number of readily releasable vesicles a synapse has available. A consequence of having of limited number is depletion at high stimulus frequency.

73. Many vesicles In the RRP. Few vesicles in the RRP, undergoes depression. Fundamental Neuro. 2002 Remember depression over short timescales can be caused by other mechanisms including desensitization and autoreceptors.

74. Residual Ca can facilitate transmission if not all quanta are released on the first stimulus. If transmission is robust on the first stimulus most readily releasable vesicles will be gone and depression results. Squire Fundamental Neurosci. 2002 Short term plasticity, history dependent changes in responsiveness. Stim.

75. Time Voltage Response types at single CNS synapses with different #s of release sites. failure 1 vesicle 2 ves. 1 ves. fail

76. Response of CNS synapse can reflect sum behavior of individual synapses that may act in an all or none manner. electrode

77. When multiple synapses (or release sites) are involved facilitation can reflect an increase in release probability (all or none secretion) at single synapses. Trial 1 Trial 2, 25 ms later electrode