1. Neural Zones
Figure 5.2

2. How Neurons connect

3. The Synapse A functional connection between surfaces
Signal transmission zone
Synapse – synaptic cleft, presynaptic cell, and postsynaptic cell
Synaptic cleft – space in between the presynaptic and postsynaptic cell
Postsynaptic cell – neurons, muscles, and endocrine glands
Neuromuscular junction – synapse between a motor neuron and a muscle

4. * * * * The Synapse Axon terminal: found in motor neurons
Axon varicosities: ie swellings. Arranged like beads on a string and contain neurotransmitter containing vesicles
En passant synapse: CNS. Consists of a swelling along the axon
Spine synapse: presynaptic cell connects with a dendritic spine on the dendrite of the postsynaptic cell * * * *

5. The Synapse
Axodentritic: between axon terminal of one neuron and the dendrite of another
Axosomatic: between the axon terminal of one neuron and the cell body of another
Dendrodendritic: between dendrites of neurons (often are electricla synapses)
Axoaxonic: between an axon terminal of a presynatpic neuron and the axon of a postsynaptic neuron. * * * *

6. Diversity of Signal Conduction
So far:
Electrotonic
Action potentials
Saltatory conduction
Chemical and electrical synapses

7. Diversity of Synaptic Transmission
Figure 5.26

8. Electrical and Chemical Synapses
Electrical synapse
Chemical synapse
Rare in complex animals
Common in complex animals
Common in simple animals
Rare in simple animals
Fast
Sloooooow
Bi-directional ↔
Unidirectional →
Postsynaptic signal is similar to presynaptic
Postsynaptic signal can be different
Excitatory
Excitatory or inhibitory

9. Electrical synapses cells connect via gap junctions
membranes are separated by 2 nm
gap junctions link the cytosol of two cells
provide a passageway for movement of very
small molecules and ions between the cells
gap junction channels have a large conductance
NO synaptic delay (current spread from cell to cell is instantaneous) - important in some reflexes
chemical synapses do have a significant delay ie slow
commonly found in other cell types as well i.e. glia
can be modulated by intracellular Ca2+ , pH, membrane voltage, calmodulin
clusters of proteins that span the gap such that ions and small molecules can pass directly from one cell to another  

10. More about electrical synapses
cells connect via gap junctions
- made up of 6 protein subunits arranged around a central pore, made up of the connexin protein
- the two sides come together to make a complete unit of 12 proteins around the central pore

11. Chemical Synapse Diversity
Vary in structure and location
Figure 5.27

12. Chemical Synapse most common type of synapse
electrical signal in the presynaptic cell is communicated to the postsynaptic cell by a chemical (the neurotransmitter)
separation between presynaptic and postsynaptic membranes is about 20 to 30 nm
a chemical transmitter is released and diffuses to bind to receptors on postsynaptic side
bind leads (directly or indirectly) to changes in the postsynaptic membrane potential (usually by opening or closing transmitter sensitive ion channels)
the response of the neurotransmitter receptor can depolarizes (excitatory postsynaptic potential; epsp) or hyperpolarizes (inhibitory postsynaptic potential; ipsp) the post-synaptic cell and changes its activity
significant delay in signal (1 msec) but far more flexible than electrical synapse  

13. More about chemical Synapses
Some types of chemical synapse include
Excitatory - excite (depolarize the postsynaptic cell
Inhibitory - inhibit (hyperpolarize the postsynaptic cell)
Modulatory - modulates the postsynaptic cells response to other synapses

14. General sequence of events* * * * * * *

15. General sequence of events
1. Nerve impulse arrives at presynaptic terminal
2. Depolarization causes voltage-gated Ca 2+ channels to open - increases Ca 2+ influx, get a transient elevation of internal Ca 2+ ~100 mM
3. Vesicle exocytosis - increase in Ca 2+ induces fusion of synaptic vesicles to membrane - vesicles contain neurotransmitters
4. Vesicle fusion to membrane releases stored neurotransmitter
5. Transmitter diffuses across cleft to postsynaptic side
6. Neurotransmitters bind to receptor either: i) ligand-gated ion channel or ii) receptors linked to 2nd messenger systems
7. Binding results in a conductance change - channels open or close or - binding results in modulation of postsynaptic side
Cont…….

16. General sequence of events
8. Postsynaptic response - change in membrane potential (e.g. muscle contraction in the case of a motorneuron at a neuromuscular junction)
9. Neurotransmitter is removed from the cleft by two mechanisms i) transmitter is destroyed by an enzyme such as acetylcholine esterase ii) transmitter is taken back up into the presynaptic cell and recycled e.g. - acetylcholine esterase, breaks down acetylcholine in cleft, choline is recycled back into the presynaptic terminal

17. Neurotransmitters Characteristics Synthesized in neurons
Released at the presynaptic cell following depolarization
Bind to a postsynaptic receptor and causes an effect

18. Neurotransmitters, Cont.
More than 50 known substances
Categories
Amino acids
Neuropeptides
Biogenic amines
Acetylcholine
Miscellaneous …..
Neurons can synthesize many kinds of neurotransmitters

19. Neurotransmitters

20. Neurotransmitters cont.

21. Influenced by neurotransmitter amount and receptor activity
Signal Strength
Influenced by neurotransmitter amount and receptor activity
Neurotransmitter amount: Rate of release vs. rate of removal
Release: due to frequency of APs
Removal
Passive diffusion out of synapse
Degradation by synaptic enzymes
Uptake by surrounding cells
Receptor activity: density of receptors on postsynaptic cell

22. Graded Potentials via Neurotransmitters
Vary in magnitude depending on the strength of the stimulus
e.g., more neurotransmitter  more ion channels will open
Can depolarize (Na+ and Ca2+ channels) or hyperpolarize (K+ and Cl- channels) the cell

23. Graded Potentials
Figure 5.4

24. Graded Potentials Travel Short Distances
Figure 5.6

25. Neurotransmitter Receptor Function
Ionotropic
Ligand-gated ion channels
Fast
e.g., nicotinic ACh
Metabotropic
Channel changes shape
Signal transmitted via secondary messenger
Ultimately sends signal to an ion channel
Slow
Long-term changes
Figure 5.28

26. Second Messenger again
When activated by a ligand the catalytic domain starts a phosphorylation cascade
Named based on the reaction catalyzed

27. Second Messengers to know

28. Neurotransmitter receptors
Different types of neurotransmitter receptors
Functional Type Ligand Ion Channel
Excitatory Receptors Acetylcholine Na+/K+ 
Glutamate Na+/K+; Ca2+ 
Glutamate Na+/K+ 
Serotonin Na+/K+
Inhibitory Receptors Aminobutyric acid, GABA Cl- 
Glycine Cl-

29. Amount of Neurotransmitter
Influenced by AP frequency which influences Ca2+ concentration
Control of [Ca2+]
Open voltage-gated Ca2+ channels  [Ca2+]
Binding with intracellular buffers  [Ca2+]
Ca2+ ATPases  [Ca2+]
High AP frequency  influx is greater than removal  high [Ca2+]  many synaptic vesicles release their contents  high [neurotransmitter]

30. Removal of Neurotransmitter
broken down by enzyme
- acetylcholine esterase breaks down acetylcholine in the synaptic cleft
- many nerve gases and insecticides work by blocking acetylcholine esterase – Yikes!
- prolongs synaptic communication
b) recycled by uptake
- most neurotransmitters are removed by Na+/neurotransmitter symporters
- due to a specific neurotransmitter transporter
- recycled by uptake into presynaptic terminal or other cells   (glial cells will take up neurotransmitters)
c) diffusion: simple diffusion away from site  

31. Neurotransmitters - stages
Synthesis
- all small chemical neurotransmitters are made in the nerve terminal
- responsible for fast synaptic signalling
- synthetic enzymes + precursors transported into nerve terminal
- subject to feedback inhibition (from recycled neurotransmitters
- can be stimulated to increase activity (via Ca2+ stimulated phosphorylation)
2. Packaging into vesicles
- neurotransmitters packaged into vesicles
- packaged in small "classical" vesicles
- involves a pump powered by a pH gradient between outside and inside of vesicle
- pump blocked by drugs and these block neurotransmitter release

32. Presynaptic vesicles
Two groups  i) low molecular weight, non-peptide  e.g. acetylcholine, glycine, glutamate
 ii) neuropeptide (over 40 identified so far and counting…..)  

33. Presynaptic vesicles There are 2 types of secretory vesicles
We will only talk about small chemical synaptic vesicles
Neuropeptides are made and packaged in the cell body and transported to synapse)
Small chemical neurotransmitter vesicles
responsible for fast synaptic signaling
store non-peptide neurotransmitters,   e.g. acetylcholine, glycine, glutamate
enough vesicles in the typical nerve terminal to transmit a few thousand impulses
exocytosis only occurs after an increase of internal Ca 2+ (due to depolarization) and at active zones (regions in the presynaptic membrane adjacent to the cleft)  

34. Presynaptic vesicles * * * * * * * *

35. Vesicle Exocytosis
A group of 6 to 7 proteins work together to respond to Ca 2+ influx and regulate vesicle fusion
after exocytosis the synaptic vesicle membranes are reinternalized by endocytosis and reused (reloaded with neurotransmitter by a transmitter transporter system)
vesicles are also transported from the cell body to the nerve terminal - transmitter is synthesized in the terminal and loaded into the vesicles - enzymes and substrates necessary are present in the terminal - i.e. acetylcholine, acetyl-CoA + choline used by choline acetyltransferase 

36. Vesicle Exocytosis non-peptide transmitters
exocytosis only occurs after an increase of internal Ca 2+ (due to depolarization)
at active zones (regions in the presynaptic membrane adjacent to the synaptic cleft)
peptide-transmitters (same as for non-peptide transmitters except:)
exocytosis is NOT restricted to active zones
exocytosis is triggered by trains of action potentials  

37. SNARE hypothesis
The SNARE Hypothesis for Transport Vesicle Targeting and Fusion
SNARE is an acronym for SNAP receptor (SNAP stands for soluble N-ethylmaleimide-sensitive factor attachment proteins).
SNARES are involved in the mediation of protein transport between
various plant organelles by small membrane vesicles.
Two families:
i) V-SNARE - vesicle membrane proteins ii) T-SNARE - target membrane proteins

38. SNARE hypothesis
Vesicle docking occurs between the V-SNARE and T-SNARE proteins
The combined proteins act as a receptor for an ATPase that utilizes ATP to generate the "docked" form
One of the proteins is a Ca2+ sensor such that when Ca2+ enters the synapse the vesicle fuses with the plasma membrane and releases its contents
The membrane and proteins are then recycled through endocytosis (clatharin coat and dynamin etc.) and reused.

39. Acetylcholine
Primary neurotransmitter at the vertebrate neuromuscular junction
Figure 5.17

40. Synaptic Plasticity
Change in synaptic function in response to patterns of use
Synaptic facilitation –  APs   neurotransmitter release
Synaptic depression –  APs   neurotransmitter release
Post-tetanic potentiation (PTP) – after a train of high frequency APs   neurotransmitter release
Figure 5.32

41. Long-term potentiation

42. Postsynaptic Cells
Have specific receptors for specific neurotransmitters
e.g., Nicotinic ACh receptors

43. Diversity of Signal Conduction
So far:
Electrotonic
Action potentials
Saltatory conduction
Chemical and electrical synapses
Also:
Shape and speed of action potential
Due to diversity of Na+ and K+ channels

44. Ion Channel Isoforms Multiple isoforms Encoded by many genes
Variants of the same protein
Voltage-gated K+ channels are highly diverse (18 genes encode for 50 isoforms in mammals)
Na+ channels are less diverse (11 isoforms in mammals)
Table 5.2

45. Higher density of voltage-gated Na+ channels
Channel Density
Higher density of voltage-gated Na+ channels
Lower threshold
Shorter relative refractory period

46. Voltage-Gated Ca2+ Channels
Open at the same time or instead of voltage-gated Na+ channels
Ca2+ enters the cell causing a depolarization
Ca2+ influx is slower and more sustained
Slower rate of APs due to a longer refractory period
Critical to the functioning of cardiac muscle