Synthesis and Storage of Neurotransmitters

A synapse is a gap that is present between two neurones. Action potentials are propagated across the synapse by synaptic transmission, also known as neurotransmission. The neurone that sends the signal is the presynaptic neurone, whilst the postsynaptic neurone receives the signal.Neurotransmission starts with the release of a readily available neurotransmitter from the presynaptic neurone, followed by its diffusion and binding to the postsynaptic receptors. Then the postsynaptic cell responds according to the neurotransmitter. Following this, the neurotransmitter is removed or deactivated, allowing the entire cycle to occur again.Synthesis and Storage of Neurotransmitters
This is the first step of synaptic transmission. Some neurotransmitters (eg acetylcholine, ACh) are synthesised in the axon, while others (eg neuropeptides) are made in the cell body.Acetylcholine – This is synthesised within the synaptic terminal of the axon. Its precursors (choline, acetate) are taken into the cell by membrane channels or created as byproducts of other processes. Enzymes (such as choline acetyltransferase) convert precursors into the neurotransmitter.
Endogenous opioids (eg. enkephalins) – These are an example of neuropeptides. These large neurotransmitters are produced within the cell body via transcription in the nucleus and translation in the endoplasmic reticulum. Synthesised precursors are then packaged into secretory granules and sent to the axonal terminal. Importantly, proteases present in the granules cleave the precursors into their mature neuropeptide form during this journey.Once synthesised, neurotransmitters are stored in vesicles within the synaptic terminal until an action potential arrives, causing their release. Neurotransmitters such as acetylcholine are stored within the small synaptic vesicles, whereas neuropeptides reside within large dense-core vesicles.Once the post-synaptic membrane has responded to the neurotransmitter in the synaptic cleft; it is either inactivated or removed. This can be done in several ways:

Re-uptake – serotonin is taken back into the pre-synaptic neurone by the transporter proteins in the neuronal membrane. These neurotransmitters are subsequently either recycled by re-packaging into vesicles or broken down by enzymes.
Breakdown – acetylcholine is broken down by acetylcholinesterase present in the synaptic cleft, inactivating the neurotransmitter.
Diffusion – into surrounding areasAction potentials depolarising the synaptic terminal lead to the opening of voltage-gated calcium channels. This allows an influx of calcium in the terminal and fusion of the synaptic vesicles with the cell membrane (exocytosis). Consequently, the neurotransmitter is released into the synaptic cleft.The neurotransmitter in the synaptic cleft diffuses across the gap to the post-synaptic membrane. Here, they can bind to two types of post-synaptic receptors.Acetylcholinesterase inhibitors are a class of drug that inhibits the activity of

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Neuroscience: Exploring the Brain, 3e
Chapter 5: Synaptic Transmission

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Introduction
•Synaptic Transmission
–Information transfer at a synapse
–Plays role in all the operations of the nervous system
–1897: Charles Sherrington-“synapse”
•Cajal vs Golgi (1906)
–Chemical and electrical synapses
•1921-Otto Loewi
•1959-Furshpan and Potter

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Types of Synapses
•Direction of Information Flow
–In one direction: Neuron to target cell
–First neuron = Presynaptic neuron
–Target cell = Postsynaptic neuron

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Type of Synapses
Golgi –Continuous
synapse
Cajal –Contiguous
synapse

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–Gap junction
•Channel
•Connexon-formed by six connexins
–Cells are said to be “electrically coupled”
•Flow of ions from cytoplasm to cytoplasm
Electrical Synapse

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INSERT FIG. 5.1 (Yes, deliberately out of order)

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Electrical Synapse
–Very fast transmission
•Postsynaptic potentials (PSPs)
–Synaptic integration: Several PSPs occurring
simultaneously to excite a neuron (i.e. causes AP)

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Chemical Synapse

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Chemical
Synapse

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•CNS Synapses (Examples)
–Axodendritic: Axon to dendrite
–Axosomatic: Axon to cell body
–Axoaxonic: Axon to axon
–Dendrodendritic: Dendrite to dendrite
Types of Synapses

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•CNS Synapses (Examples)
–Gray’s Type I: Asymmetrical, excitatory
–Gray’s Type II: Symmetrical, inhibitory
Types of Synapses

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•The Neuromuscular Junction
(NMJ)
–Studies of NMJ established
principles of synaptic
transmission
Types of Synapses

16. An Actual Neuromuscular Synapse
Goodsell, D. S. (2009), Neuromuscular synapse.
Biochem. Mol. Biol. Educ., 37:204–210.
doi:10.1002/bmb.20297

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Principles of Chemical Synaptic
Transmission
•Basic Steps
–Neurotransmitter synthesis
–Load neurotransmitter into synaptic vesicles
–Depolarization 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

18. Synaptic Transmission at Neuromuscular
Junction

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Principles of Chemical Synaptic
Transmission
•Basic Steps
–Neurotransmitter synthesis
–Load neurotransmitter into synaptic vesicles
–Depolarization 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

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–Amino acids: Small organic molecules
Neurotransmitters

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–Amino acids: Small organic molecules
–Amines: Small organic molecules
Neurotransmitters

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–Amino acids: Small organic molecules
–Amines: Small organic molecules
–Peptides: Short amino acid chains (i.e. proteins)
stored in and released from secretory granules
Neurotransmitters

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–____ ____: Small organic molecules
•e.g., Glutamate, Glycine, GABA
–____ : Small organic molecules
•e.g., Dopamine, Acetylcholine, Histamine
–____ : Short amino acid chains (i.e. proteins) stored
in and released from secretory granules
•e.g., Dynorphin, Enkephalins
Neurotransmitters

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Neurotransmitter Synthesis and Storage
Loading Neurotransmitters

25. Dense Core Vesicles
Goodsell, D. S. (2009), Neuromuscular synapse.
Biochem. Mol. Biol. Educ., 37:204–210.
doi:10.1002/bmb.20297

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Exocytosis: Process by which vesicles release their contents
Neurotransmitter Release

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•Process of exocytosis stimulated by release of
intracellular calcium, [Ca
2+
]i
•Proteins alter conformation -activated
•Vesicle membrane incorporated into presynaptic
membrane
•Neurotransmitter released
•Vesicle membrane recovered by endocytosis
Mechanism of Neurotransmitter release
(Clathrin-mediated endocytosis:
http://biochem.web.utah.edu/iwasa/projects/clathrin.html)

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-Ionotropic: Transmitter-gated ion channels
Neurotransmitter Receptors and Post -
synaptic Response

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–Metabotropic: G-protein-coupled receptor
Neurotransmitter Receptors and Post -
synaptic Response

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•EPSP:Transient postsynaptic membrane depolarization by
presynaptic release of neurotransmitter
•IPSP: Transient hyperpolarization of postsynaptic membrane
potential caused by presynaptic release of neurotransmitter
•Reversal potential
Excitatory and Inhibitory Postsynaptic
Potentials

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–Diffusion: Away from the synapse
–Reuptake: Neurotransmitter re-enters presynaptic
axon terminal
–Enzymatic destruction inside terminal cytosol or
synaptic cleft
–Desensitization: despite continued presence of ACh,
transmitter-gated channels close
Neurotransmitter Recovery and
Degradation

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–Effect of drugs on nervous system tissue
–Receptor antagonists: Inhibitors of neurotransmitter
receptors
•Curare
–Receptor agonists: Mimic actions of naturally
occurring neurotransmitters
•Nicotine
–Defective neurotransmission: Root cause of
neurological and psychiatric disorders
Neuropharmacology

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Principles of Synaptic Integration
–Process by which multiple synaptic potentials
combine within one postsynaptic neuron

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–Synaptic vesicles: Elementary units of synaptic
transmission. Almost fixed amount of nerotransmitter
•Quantum: An indivisible unit
–Miniature postsynaptic potential (“mini”)
–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
Quantal Analysis of EPSPs

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–Allows for neurons to perform sophisticated
computations
–EPSP summation: EPSPs added together to produce
significant postsynaptic depolarization
–Spatial: EPSP generated simultaneously in different
spaces
–Temporal: EPSP generated at same synapse in rapid
succession
Synaptic Integration -EPSP Summation

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Synaptic Integration -EPSP Summation

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–Assume: Dendrite as a straight cable (~spinal motor
dendrite)
•Membrane depolarization falls off exponentially
with increasing distance
•V
x= V
o/e
x/ 
•Dendritic length constant (): at which, 37% of Vo
–In reality, dendrites are very elaborate structures
that contribute to more complex integrative
properties
The Contribution of Dendritic Properties
to Synaptic Integration

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V
x=V
o* e
-x/λ
The Contribution of Dendritic Properties
to Synaptic Integration

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–Dendrites of neurons: voltage-gated sodium,
calcium, and potassium channels
•Can act as amplifiers (vs. passive)
–Dendritic sodium channels: May carry electrical
signals in opposite direction, from soma outward
along dendrites (Cajal?)
Excitable Dendrites

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–Action of synapses to take membrane potential away
from action potential threshold
–Exerts powerful control over neuron output
Inhibition

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–Excitatory vs. inhibitory synapses: Bind different
neurotransmitters, allow different ions to pass through
channels
IPSPs and Shunting Inhibition

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–Excitatory vs. inhibitory synapses: Bind different
neurotransmitters, allow different ions to pass through
channels
–Membrane potential more negative: hyperpolarizing IPSP
–E
Cl= -65 mV ?
•Shunting Inhibition: Inhibiting current flow from soma to
axon hillock
IPSPs and Shunting Inhibition

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Shunting Inhibition

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–Excitatory synapses
•Gray’stype I morphology
•Spines: Excitatory
synapses
–Inhibitory synapses
•Gray’stype II
morphology
•Clustered on soma and
near axon hillock
The Geometry of Excitatory and
Inhibitory Synapses

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Concluding Remarks
•Chemical synaptic transmission
–Rich diversity allows for complex behavior
–Provides explanations for drug effects
–Defective transmission is the basis for many
neurological and psychiatric disorders
–Key to understanding the neural basis of learning
and memory

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Question of the
Day
How stepping on a rusty nail mayresult in
muscle spasms and even eventual death?
Hint: It involves synaptic transmission.
-In general, what molecular/cellular events
happened?Are there effective treatments?
-Does the behavior a result of (mostly) defects in
inhibitory or excitatory synapse? How do these
defects affect synaptic integration?

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Principles of Synaptic Integration
•Modulation
–Synaptic transmission that
modifies effectiveness of
EPSPs generated by other
synapses with transmitter-
gated ion channels
–Example: Activating NE β
receptor