1. SYNAPTIC TRANSMISSION

2. Introduction SYNAPTIC TRANSMISSION
The process by which neurons transfer information at a synapse
Charles Sherrington (1897) : named ‘Synapse’
Chemical synapse vs. Electrical synapse
Otto Loewi (1921) : Chemical synapses
Edwin Furshpan and David Potter (1959) : Electrical synapses
John Eccles (1951) : Glass microelectrode

3. Types of Synapses Electrical Synapses
Direct transfer of ionic current from one cell to the next
Gap junction
The membranes of two cells are held together by clusters of connexins
Connexon
A channel formed by six connexins
Two connexons combine to from a gap junction channel
Allows ions to pass from one cell to the other
1-2 nm wide : large enough for all the major cellular ions and many small organic molecules to pass

4. Types of Synapses Electrical Synapses
Cells connected by gap junctions are said to be “electrically coupled”
Flow of ions from cytoplasm to cytoplasm bidirectionally
Very fast, fail-safe transmission
Almost simultaneous action potential generations
Common in mammalian CNS as well as in invertebrates

5. Electrical synapses Postsynaptic potential (PSP)
Caused by a small amount of ionic current that flow into through the gap junction channels
Bidirectional coupling
PSP generated by a single electrical synapse is small (~1 mV)
Several PSPs occuring simultaneously may excite a neuron to trigger an action potential

6. Electrical synapses High temporal precision
Paired recording reveals synchronous voltage responses upon depolarizing or hyperpolarizing current injections
Often found where normal function requires that the neighboring neurons be highly synchronized
Oscillations, brain rhythm, state dependent…

7. Types of Synapses Chemical Synapses
Synaptic cleft : nm wide (gap junctions : 3.5 nm)
Adhere to each other by the help of a matrix of fibrous extracellular proteins in the synaptic cleft
Presynaptic element (= axon terminal) contains
Synaptic vesicles
Secretory granules (~100nm) (=dense-core vesicles)
Membrane differentiations
Active zone
Postsynaptic density

8. Chemical Synapses vs Electrical synapses

9. Types of Synapses CNS Synapses Axoaxonic: Axon to axon
Axodendritic: Axon to dendrite
Axosomatic: Axon to cell body
Axoaxonic: Axon to axon
Dendrodendritic: Dendrite to dendrite

11. Types of Synapses CNS Synapses Gray’s Type I: Asymmetrical, excitatory
Gray’s Type II: Symmetrical, inhibitory

12. Types of Synapses The Neuromuscular Junction (NMJ)
Synapses between the axons of motor neurons of the spinal cord and skeletal muscle
Studies of NMJ established principles of synaptic transmission
Fast and reliable synaptic transmission(AP of motor neuron always generates AP in the muscle cell it innervates) thanks to the specialized structural features
The largest synapse in the body
Precise alignment of synaptic terminals with junctional folds

13. Principles of Chemical Synaptic Transmission
Basic Steps
Neurotransmitter synthesis
Load neurotransmitter into synaptic vesicles
Vesicles fuse to presynaptic terminal
Neurotransmitter spills into synaptic cleft
Binds to postsynaptic receptors
Biochemical/Electrical response elicited in postsynaptic cell
Removal of neurotransmitter from synaptic cleft
Must happen RAPIDLY!

14. Principles of Chemical Synaptic Transmission
Neurotransmitters
Amino acids
Amines
Peptides

15. Principles of Chemical Synaptic Transmission
Neurotransmitters
Amino acids and amines are stored in synaptic vesicles
Peptides are stored in and released from secretory granules
Often coexist in the same axon terminals
Fast synaptic transmission and slower synaptic transmission

16. Principles of Chemical Synaptic Transmission
Neurotransmitter Synthesis and Storage
Natural building blocks vs specialized neurotransmitters

17. Principles of Chemical Synaptic Transmission
Neurotransmitter Release
Voltage-gated calcium channels open - rapid increase from mM to greater than 0.1 mM
Exocytosis can occur very rapidly (within 0.2 msec) because Ca2+ enters directly into active zone
‘Docked’ vesicles are rapidly fused with plasma membrane
Protein-protein interactions regulate the process (e.g. SNAREs) of ‘docking’ as well as Ca2+- induced membrane fusion
Vesicle membrane recovered by endocytosis

19. Principles of Chemical Synaptic Transmission
Neurotransmitter Release
Reserve pool and Readily releasable pool (RRP)

20. Fig. 1. Scattered distribution of RRP vesicles
S. O. Rizzoli et al., Science 303, (2004)
Published by AAAS

21. Principles of Chemical Synaptic Transmission
Neurotransmitter Release
Secretory granules
Released from membranes that are away from the active zones
Requires high-frequency trains of action potentials to be released
Ca2+ needs to be build up throughout the axon terminal
Leisurely process (50 msec)

22. Principles of Chemical Synaptic Transmission
Neurotransmitter receptors:
Ionotropic: Transmitter-gated ion channels
Ligand-binding causes a slight conformational change that leads to the opening of channels
Not as selective to ions as voltage-gated channels
Depending on the ions that can pass through, channels are either excitatory or inhibitory
Reversal potential

23. Principles of Chemical Synaptic Transmission
Excitatory and Inhibitory Postsynaptic Potentials:
EPSP:Transient postsynaptic membrane depolarization by presynaptic release of neurotransmitter
Ach- and glutamate-gated channels cause EPSPs

24. Principles of Chemical Synaptic Transmission
Excitatory and Inhibitory Postsynaptic Potentials:
IPSP: Transient hyperpolarization of postsynaptic membrane potential caused by presynaptic release of neurotransmitter
Glycine- and GABA-gated channels cause IPSPs

25. Principles of Chemical Synaptic Transmission
Metabotropic: G-protein-coupled receptors
Trigger slower, longer-lasting and more diverse postsynaptic actions
Same neurotransmitter could exert different actions depending on what receptors it bind to
Autoreceptors: present on the presynaptic terminal
Typically, G-protein coupled receptors
Commonly, inhibit the release or synthesis of neurotransmitter
Negative feedback
Effector proteins

26. Principles of Chemical Synaptic Transmission
Neurotransmitter Recovery and Degradation
Clearing of neurotransmitter is necessary for the next round of synaptic transmission
Simple Diffusion
Reuptake aids the diffusion
Neurotransmitter re-enters presynaptic axon terminal or enters glial cells through transporter proteins
The transporters are to be distinguished from the vesicular forms
Enzymatic destruction
In the synaptic cleft
Acetylcholinesterase (AchE)
Desensitization:
Channels close despite the continued presence of ligand
Can last several seconds after the neurotransmitter is cleared
Nerve gases (e.g. sarin) inhibit AchE - increased Ach - AchR desensitization - muscle paralysis

27. Principles of Chemical Synaptic Transmission
Neuropharmacology
The study of effect of drugs on nervous system tissue
Receptor antagonists: Inhibitors of neurotransmitter receptors
e.g. Curare binds tightly to Ach receptors of skeletal muscle
Receptor agonists: Mimic actions of naturally occurring neurotransmitters
E.g. Nicotine binds and activates the Ach receptors of skeletal muscle (nicotinic Ach receptors)
Toxins and venoms
Defective neurotransmission: Root cause of neurological and psychiatric disorders

28. Principles of Synaptic Integration
Process by which multiple synaptic potentials combine within one postsynaptic neuron
Basic principle of neural computation
The Integration of EPSPs + - - + + -

29. Principles of Synaptic Integration
The integration of EPSPs
Quantal Analysis of EPSPs
Synaptic vesicles: Elementary units of synaptic transmission
Contains the same number of transmitter molecules (several thousands)
Postsynaptic EPSPs at a given synapse is quantized = The amplitude of EPSP is an integer multiple of the quantum
Quantum: An indivisible unit determined by
the number of transmitter molecules in a synaptic vesicle
the number of postsynaptic receptors available at the synapse
Miniature postsynaptic potential (“mini”) is generated by spontaneous, un-stimulated exocytosis of synaptic vesicles
Quantal analysis: Used to determine number of vesicles that release during neurotransmission
Neuromuscular junction: About 200 synaptic vesicles, EPSP of 40mV or more
CNS synapse: Single vesicle, EPSP of few tenths of a millivolt

30. Principles of Synaptic Integration
EPSP Summation
Allows for neurons to perform sophisticated computations
Integration: EPSPs added together to produce significant postsynaptic depolarization
Spatial summation : adding together of EPSPs generated simultaneously at different synapses
Temporal summation : adding together of EPSPs generated at the same synapse in rapid succession (within msec of one another)

31. Principles of Synaptic Integration
The Contribution of Dendritic Properties to Synaptic Integration
Dendrite as a straight cable : EPSPs have to travel down to spike-initiation zone to generate action potential
Membrane depolarization falls off exponentially with increasing distance
Vx = Vo/ex/ 
Vo : depolarization at the origin
 : Dendritic length constant
Distance where the depolarization is 37% of origin (V= 0.37 Vo)
In reality, dendrites have branches, changing diameter..

32. Principles of Synaptic Integration
The Contribution of Dendritic Properties to Synaptic Integration
Length constant ()
An index of how far depolarization can spread down a dendrite or an axon
Depends on two factors
internal resistance (ri) : the resistance to current flowing longitudinally down the dendrite
membrane resistance (rm) : the resistance to current flowing across the membrane
While ri is relatively constant (largely determined by the diameter of dendrite and electrical property of cytoplasm) in a mature neuron, rm changes from moment to moment (depends on the number of opne channels)
Excitable Dendrites
Dendrites of neurons having voltage-gated sodium, calcium, and potassium channels
Can act as amplifiers (vs. passive) : EPSPs that are large enough to open voltage-gated channels can reach the soma by the boost offered by added currents through VGSCs
Dendritic sodium channels: May carry electrical signals in opposite direction, from soma outward along dendrites : back-propagating action potential might inform the dendrites that an action potential has been generated
I added this slide, it may be helpful to include the figure hear for the instructor

33. Principles of Synaptic Integration
Inhibition
Action of synapses to take membrane potential away from action potential threshold
IPSPs and Shunting Inhibition
Excitatory vs. inhibitory synapses: Bind different neurotransmitters, allow different ions to pass through channels
GABA or glycine :: Cl-
Ecl : -65 mV, at resting membrane potential no IPSP is visible

34. Principles of Synaptic Integration
Shunting Inhibition
Inhibiting current flow from soma to axon hillock
The Geometry of Excitatory and Inhibitory Synapses
Inhibitory synapses
Gray’s type II morphology
Clustered on soma and near axon hillock
Powerful position to influence the activity of the postsynaptic neuron

35. Principles of Synaptic Integration
Modulation
Synaptic transmission that does not directly evoke EPSPs and IPSPs but instead modifies the effectiveness of EPSPs generated by other synapses with transmitter-gated ion channels
Mediated by G-protein-coupled neurotransmitter receptors
Example: Activating NE β receptor
Suggest inserting figure 5.21 of NE example