BMS 153: Neuroscience

The chemical synapse + neurotransmitters- lectures 12-14

Dr Pen Rashbass (p.rashbass@shef.ac.uk)

THESE NOTES ARE MEANT TO BE SUPPLEMENTAL TO YOUR

LECTURES/OWN READING – THEY DO NOT REPLACE THEM
Nerves and neurons provide the means to communicate between regions of the brain.

The synapse is the point of communication between neurons – from (presynaptic) neurons to
(postsynaptic) effector cells (e.g. muscle and glandular cells).

Most synaptic communication is neurochemical and relies on neurotransmitters (NT).

(However some rare synapses rely on electrical communication via Gap junctions)

Synaptic control of neuronal activity provides the complex, Brain function has regional
elaborate, subtle and flexible mechanisms by which the brain specificity
is able to process information.
Brain function has neurochemical
When chemical synaptic transmission goes wrong, ⇒nervous (neurotransmitter) specificity.
system malfunction. Defective NT is the root cause of a large
number of neurological and psychiatric disorders
Synaptic neurotransmission is also the point at which we can
modify neuronal function with drugs. Mechanism of transmitter
release- (peptides)

Secretory granules are also Ca2+

dependant and use exocytosis- but
typically NOT at the active zone.
Usually requires a high-frequency
train of APs so that [Ca2+]
throughout the terminal can build
up to level required.
Release of peptides can take
50msec of more

Mechanism of transmitter release-(amino acid/amines)

AP arrives at the nerve terminal⇒Ca2+ influx into the terminal (↑[Ca2+ ] in local
microdomain)⇒vesicles triggered ⇒ release contents by exocytosis– occurs within a fraction of
a millisecond of AP arriving
Some neurons fire >1000x per second, releasing neurotransmitters each time.

The rapid release is possible because some of the vesicles are “docked “ to the plasma
membrane and primed for fusion.
Only a small proportion of vesicles fuse with plasma membrane in response to each AP

For nerve terminal to respond rapidly and repeatedly, vesicles need to be replenished very
quickly after discharged. Vesicles are retrieved from plasma membrane by endocytosis

(see Alberts et al: Mol Biology of the Cell: 4th ed pg 764-765)

THE MAJOR NEUROTRANSMITTERS
AMINO ACIDS AMINES PEPTIDES
Gamma- amino butyric acid (GABA) Acetylcholine (ACh) Cholecystokinin (CCK)
Glutamate (Glu) Dopamine (DA) Dynorphin
Glycine (Gly) Adrenalin (Epinephrine) Enkephalins (Enk)
Histamine N-Acetylaspartylglutamate (NAAG)
Noradrenalin (NA)/ Neuropeptide Y
(Norepinephrine (NE))
Serotonin (5-HT) Somatostatin
Substance P
Thyrotropin-releasing hormone(TRH)
Vasoactive intestinal polypeptide(VIP)

Different neurons in the brain release different NTs.

The amino acid and amine NTs are The peptide NTs are:
• small organic molecules • Large molecules
• contain a nitrogen atom • Stored in secretory granules
• stored and released from synaptic vesicles

Secretory granules and synaptic vesicles are frequently observed in the same axon terminals.
These different neurotransmitters are released under different conditions

A neurotransmitter should be Different neurotransmitters are synthesised in

• Localised in the presynaptic terminals
• Released in response to stimulation
• Able to interact with postsynaptic
receptors
• Rapidly removed from the synapse
⇒implies cellular specialisation for mechanisms
for
• synthesis and/or storage
• release
• post-synaptic recognition (receptors)
• transmitter release
• transmitter removal
different ways
• Glutamate and glycine are among the
20amino acids (protein building blocks)–
they are abundant in all cells in the body
• GABA and the amines are only made by the
neurons that release them. They require
specific enzymes to synthesize them: these are
situated locally at the axon terminal,
Once synthesised the amino acid and amine NTs
are concentrated into synaptic vesicles by
transporter proteins.
(Synaptic vesicles – specialised class of tiny
(~50nm diameter) vesicles- store amino acid and
amine NTs.)

• Peptides are formed in the rER. Secretory

Agonist- mimics normal NT function
Antagonist –blocks effect of NTs and
agonist
granules from the peptide bud off from the
Golgi apparatus and are carried to the axon
terminal by axoplasmic transport

Transmitter-gated ion channels
• specialised for rapidly converting
extracellular chemical signals into
electrical signals
• concentrated in plasma membrane of
postsynaptic cell
• open transiently in response to binding
of NT
⇒ brief permeability change in membrane
⇒change in membrane potential that are
graded according to how much NT is
released at synapse and how long it
persists there
An AP is triggered only if local membrane
potential increases enough to open
sufficient number of nearby voltage-gated
cation channels in the same target cell
membrane
Transmitter-gated ion channels differ from one another
• Highly selective binding for the NT released from the presynaptic
terminal
• Selective as the type of ions they let pass across the plasma
membrane
⇒ determines nature of postsynaptic response
Excitatory NTs open cation channels ⇒ influx of Na+ ⇒depolarises
postsynaptic membrane (excitatory post synaptic potential (EPSP))
toward the threshold potential for firing an AP
Inhibitory NTs – open either Cl- or K+ channels⇒ surpresses firing
(inhibitory post synaptic potential (IPSP)_= make it harder for
excitatory influences to depolarise postsynaptic membrane.
Inhibition is important: Strychnine – binds to glycine receptors ⇒
blocks action of glycine ⇒ muscle spasms, convulsions ⇒death
ACh, glutamate, 5-HT -usually excitatory
GABA and glycine – usually inhibitory

Transmitter-gated ion channels are major targets for psychoactive drugs

Curare- poison arrows /muscle relaxant in surgery– block ACh receptors on skeletal muscle
Barbiturates and tranquilizers e.g. diazepam (valium) – bind to GABA receptors ⇒potentiate inhibitory action of
GABA by allowing lower[GABA] to open Cl- channels
Fluozetine (Prozac)- blocks uptake of 5-HT

G-coupled receptors :
NT binds to receptors ⇒activate small G-proteins ⇒activate ‘effector’ proteins (either G-protein –gated ion
channels or 2nd messengers).
Synapses with transmitter-gated channels carry the bulk of specific information that is processed by the nervous
system. But the effectiveness of these are modified by the many synapses with G-protein coupled receptors.

The same NT can give different postsynaptic actions depending on what receptor it binds to e.g.
ACh in heart – coupled by a G -protein to a K+ channel⇒ hyperpolarises the heart muscle fibre slows heartbeat
ACh in skeletal muscle- binds to ACh-gated ion channel permeable to Na+⇒rapid depolarises skeletal
muscle⇒contraction

After neurotransmitter has been secreted it is rapidly removed- either destroyed by specific enzymes in
synaptic cleft or taken up presynaptic nerve terminal or by surrounding glial cells.

Reuptake is mediated by variety of Na+-dependent neurotransmitter carrier proteins – allows

neurotransmitter to be recycled ⇒ allows cells to keep up with high rate of release.
Rapid removal ensures
• spatial and temporal precision of synaptic signal.
• Decreases the chance of neurotransmitter influencing neighbouring cells
• Clears the synaptic cleft before next pulse is released
 Dale’s principle: A single neuron has only one NT –e.g. cholinergic, glutamatergic, GABAergic etc.
(Strictly speaking many peptide containing neurons violate this because the cells release an amino acid
or amine AND a peptide, BUT it can be used to assign most neurons to distinct overlapping classes.

Cholinergic neurons- Acetylcholine (ACh)

First identified as substance released from vagus nerve to diminish heart rate

ACh is transmitter in parasympathetic nerves, neuromuscular junction (therefore synthesised by all

motorneurons of spinal cord and brain stem) and parts of brain e.g.
1)Neurons in the basal forebrain (nucleus basalis) innervate the cortex and hippocampus etc. These are
involved in memory, coordination etc., and are lost in Alzheimer’s disease.
2) Interneurons in the striatum are involved in motor function. A side effect of the treatment of
parkinsonism with muscarinic ACh receptor antagonists (see below) is confusion.
ACh formed from readily available substrates: Choline + Acetyl-CoA → Ach. Synthesised by: Choline
acetyltransferase (ChAT) ChAT is specific to cholinergic neurons and present in neuronal terminal in excess
(i.e. enzyme is not saturated)
Choline – component of membrane lipids. Transport of choline into neuron = rate-limiting step (by altering
amount can increase/decrease Ach synthesis
AcetylCoA – intermediary metabolism, deriving from glucose

Following transmitter release, ACh is degraded by acetylcholinesterase (AChE):

ACh → choline + acetic acid
Interfering with ACh pathway eg:
1.Prevent release of ACh eg-Botulism-poisoning from Clostridium botulinum toxin or black-widow spider
venom
2.AChE inhibitors: nerve gases, insecticides (organophosphates)+ treatments for Alzheimer’s disease. Acute
effects = decrease in heart rate + BP. Irreversible inhibition of AChE results in respiratory paralysis⇒death
3.Block ACh receptors (skeletal muscle)-curare (see above)

Catecholamines
Neurotransmitters dopamine, noradrenalin and adrenalin are synthesised from the amino acid tyrosine
Catecholaminergic neurons- found in regions of nervous system involved with regulation of movement, mood,
attention and visceral function.
Tyrosine has an active transport mechanism for uptake into the brain, shared with other large neutral amino acids.

-Tyrosine →L-Dopa (L-Dihydroxyphenylalanine) → Dopamine (DA)→ Noradrenalin (NA) → adrenalin

↑ ↑
Tyrosine hydroxylase (TH) Dopa decarboxylase (DDC)
TH is the rate-determining step as it is normally saturated by substrate and is present only in neurons. DDC has high
activity and is non-specific. Therefore the amount of dopamine is dependent on the amount of Dopa available.

Removal of catecholamine neurotransmitters from synaptic cleft is by selective uptake back via Na+-dependent
transporter into presynaptic terminal axon terminals.
Amphetamine increases release of DA whilst cocaine blocks uptake – therefore both prolong DA action
In axon terminal- catecholamines may be reloaded into synaptic vesicle for reuse or enzymatically degraded by
enzymes esp. Monoamine oxidase (MAO) on outer mitochondrial membrane
MAO-A removes noradrenalin and 5-HT,
MAO-B removes dopamine
(MAO enzymes are present in the liver and gut, and provide protection from exogenous retroactive chemicals)

MAO inhibitors have been used (a) in the treatment of: Depression and Parkinson’s disease and (b) to increase levels
of NT- BUT MAO-A inhibition can cause hypertensive crisis (the “cheese effect”) due to the neuroactive effects of
dietary amines such as tyramine, found in cheese, marmite etc
Parkinson’s disease
Tremor, rigidity, akinesia (slowing of movement, postural changes. No sensory loss and cognitive function is
preserved until late stages.
• Primary pathology- progressive cell degeneration of pigmented dopaminergic cells in the substantia nigra
which innervate the striatum (The striatum can be considered as a system that inhibits motor function).
Dopamine, via its effects on D2 receptors, inhibits the cells of the striatum⇒diminishes their inhibitory
activity.
As well as output neurons and dopaminergic terminals, the striatum contains cholinergic interneurons that
have an excitatory effect (i.e. opposite to that of dopamine) on the striatum;
⇒If dopamine is lost, decreasing ACh activity will tend to restore the balance.
⇒So an antagonist at ACh receptors has similar effects to an agonist at dopamine receptors (Anticholinergic
drugs blocking muscarinic receptors (a subtype of ACh receptors) can alleviate Parkinsonian symptoms Old
treatments for Parkinson’s used anticholinergic agents (belladonna alkaloids))

Pharmacological intervention in dopamine neurotransmission

• Synthesis: L-Dopa increases dopamine synthesis
• Storage: Reserpine destroys vesicular stores of dopamine – induces Parkinsonism
• Release: Amphetamine increases dopamine release
• Reuptake: Cocaine blocks dopamine reuptake
• Metabolism MAO (B) inhibitor – selegiline – increases dopamine and used to treat Parkinson’s
disease.
• Receptors: Dopamine receptor agonists used to treat Parkinson’s disease (Dopamine D2 antagonists
induce parkinsonism)

The pathway from the subs. nigra to the striatum is only one of several important dopaminergic systems in
the brain innervating the:
• striatum (part of the basal ganglia - controlling motor function)
• cortical and limbic regions (emotion, memory, complex behaviours, addiction, psychosis)
• pituitary gland (hormonal secretion)

The antipsychotic drugs are thought to act on dopamine receptors in cortical and/or limbic regions to improve
some of the symptoms of schizophrenia. Their Parkinsonian side effects are due to antagonism of striatal
dopamine receptors. There effects on dopamine receptors in the pituitary that control prolactin secretion can
result in the overproduction of prolactin and gynaecomastia (enlarged breasts) and galactorrhoea (milk
secretion) – even in males!

5-Hydroxytryptamine (5-HT, serotonin)

Synthesis: Similar to dopamine but from tryptophan via tryptophan hydroxylase.
Availability of tryptophan is rate-determining. Controlled by binding to albumin. Removal of 5-HT by active
uptake process; MAO-A

5-HT systems:
Diffuse projection from brainstem (raphe nuclei in the reticular formation – the “reticular activating system”) to
widespread areas of forebrain, particularly the cortex.
The function of 5-HT systems include:
• Consciousness/arousal
• Circadian rhythms
• Mood
• Regulating aggression
Drugs that increase synaptic 5-HT levels are used in the treatment of depression. These include the tricyclic
antidepressants and the newer specific serotonin reuptake inhibitors (SSRIs) like fluoxetine (Prozac), that block
reuptake removal of 5-HT into the presynaptic terminal.
Tryptophan, as a precursor of 5-HT, has also been used as an antidepressant, as have MAO (A) inhibitors that
prevent 5-HT breakdown
 Amino acids, Glutamate, Glycine and GABA serve as NTs at most CNS synapses.

Gamma-amino butyric acid (GABA)

Most common inhibitory transmitter in brain.
Very efficient and specific uptake processes remove GABA from synapse, not only into neurons but also
into glia.
GABA is found in striatum – main output controlling motor function.
GABA is also found throughout the brain, and esp. the cortex, in interneurons.

Glutamate
Most common excitatory transmitter in brain.
Very efficient and specific uptake processes remove glutamate into neurons and glia.
Found throughout the brain, notably as the transmitter in large pyramidal neurons (e.g. motor
neurons) of the cortex that project to other regions of the brain or spinal cord.

As GABA and glutamate are widely distributed throughout the

brain they are therefore involved in all aspects of brain function.
Imbalance between these two transmitter systems (increased
excitatory glutamate, or decreased inhibitory GABA) occurs in
epilepsy. This can be treated by e.g. GABA agonists.

In the CNS, single neurons can receive inputs from 1000s of other neurons and can in turn synapse on
may thousands of other selves
The average motor neuron in the spinal cord has several thousand nerve terminals synapsing on its cell
body + dendrites. The motor neuron must combine information from these sources and react either by
firing APs along its axon or remaining quiet.
Any single NT can have different effects depending on what receptor it can bind to.
Divergence =The ability of one NT to activate more than one subtype of receptor and cause more than one
type of postsynaptic response. Divergence may occur at any stage in the cascade of transmitter (e.g.
which G-proteins and which effector systems are activated)
Convergence. multiple transmitters activating their own receptor type can converge on the same effector
system (again can occur at any stage in the signal cascade)
Neurons integrate divergent and convergent signalling systems

Recommended Reading:

Anatomy & Physiology: The Unity of form of function 463-468- – not extensive enough on pathways and
neurochemistry
Neuroscience Chapter 6 – admittedly a bit deep but it’s all there.
Neuroscience at a Glance 24-25, 106, 122.
Fundamentals of Psychopharmacology by Brain Leonard also has this material in Chapter 1 but the book
isn’t particularly user friendly for Level 1.
Neuroscience: exploring the brain –Chapter 5 and 6- good general overview with additional ‘facts of special
interest’