Week 3 Topic 3 - Neurotransmission defects and mental health: Focus on schizophrenia

Question 1

schizophrenia as an example of how
neurotransmission deficits can cause mental health disorders. And the aim this subtopic is to give
you an appreciation that defects in neurotransmission are associated with several mental health
problems. You will do this mainly through looking at how impairment of dopamine signalling in the
brain is implicated in schizophrenia. And you will also consider glutamate as a factor in schizophrenia.

Answer 1

Well hello, and welcome to this subtopic, which focuses on schizophrenia as an example of how
neurotransmission deficits can cause mental health disorders. And the aim this subtopic is to give
you an appreciation that defects in neurotransmission are associated with several mental health
problems. You will do this mainly through looking at how impairment of dopamine signalling in the
brain is implicated in schizophrenia. And you will also consider glutamate as a factor in schizophrenia.
Slide 5

Question 2

how deficits in neurotransmission underpin the symptoms of this disease. In this section,
we will focus on the role of dopamine, considering the evidence for the dopamine hypothesis of
schizophrenia. To do this, we first need to know something about dopamine neurochemistry.

Answer 2

Having learned something about the basic clinical features of schizophrenia, we will now go on to
consider how deficits in neurotransmission underpin the symptoms of this disease. In this section,
we will focus on the role of dopamine, considering the evidence for the dopamine hypothesis of
schizophrenia. To do this, we first need to know something about dopamine neurochemistry.

Question 3

This situation is likely more complex, still, since dopamine, glutamate, and GABA interact and regulate
each other. So how does the glutamate hypothesis work, in terms of positive symptoms? I

Answer 3

So what is the involvement of other neurotransmitters in schizophrenia? If increases in dopamine
are not present in all schizophrenia patients, then what else is going wrong at the level of
neurotransmission? We have seen that treatment-resistant patients have elevated levels of the
neurotransmitter glutamate in the frontal cortex. Atypical antipsychotic drugs also have a dual action
at dopamine and serotonin receptors. Therefore, alterations in either of these neurotransmitter
systems is likely to be implicated in schizophrenia.
This situation is likely more complex, still, since dopamine, glutamate, and GABA interact and regulate
each other.

Question 4

What are the 7 stages of

of neurotransmission?

Answer 4

1. Electrical information is received at the
   pre-synaptic neuronal terminal,
2. This information is converted to chemical information through electrically stimulated neurotransmitter release which is driven by calcium influx into the pre-synaptic terminal.
3. The released neurotransmitter then diffuses across the synaptic cleft
4. The neurotransmitter binds to an effector on
   the pre-synaptic membrane.

[This can either be a membrane-bound receptor protein or an enzyme and so on and so forth.]

5. The receptor becomes activated.
6. This will activate second messenger pathways, for example, ionic flux, and depolarisation of the post-synaptic membrane.
7. This converts the chemical information encoded by the neurotransmitter back into electrical information in the shape of action potentials, and in this way, information is propagated from one nerve cell to another.

Question 5

What happens when neurotransmission goes wrong? And how can that happen?

Answer 5

Neurotransmitters, as we have seen, are
essential for the transfer of electrical information between neurons within a functional brain network.

So it may be said that neurotransmitters modulates the flow and rate of information transfer within
a network, effectively gating synaptic plasticity.

As a consequence, this process is subject to very tight regulation at several levels.

In terms of neurotransmitter release, it’s controlled from the presynaptic terminal by autoreceptors.

Neurotransmitter sites of action are subject to regulation– for example, post-synaptic membrane receptors– the number can be increased or decreased on the membrane.

The neurotransmitter itself may be degraded either in the synaptic cleft by an enzyme– an example
of which would be acetylcholine, by uptake into the pre-synaptic terminal– for example, through a
transporter, or into surrounding glial cells.

And finally, neurotransmitter synthesis and storage can be
dynamically regulated by enzymes in the pre-synaptic terminal.

And these multiple levels of regulation
essentially ensure the correct fidelity of synaptic signalling.

Ergo, when this equilibrium is altered, the
final consequence is a disruption of the normal patterns of synaptic signalling.

These will reverberate through neuronal networks, which ultimately manifests as a behavioural consequence.

Question 6

What is Neurotransmission?

Answer 6

Neurotransmission is a fundamental brain process by which information encoded in the form of an action potential is communicated from one neuron to another within a given anatomical pathway and ultimately a neuronal network.

Question 7

What is ionic flux?

Answer 7

Flux is the net movement of ions across a specified area in a specified period of time.

Question 8

What are autoreceptors?

Answer 8

An autoreceptor is a type of receptor located in the membranes of presynaptic nerve cells. It serves as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters or hormones released by the neuron on which the autoreceptor sits. It can be anywhere in the pre-synaptic neuron.

Question 9

What is schizophrenia?

Answer 9

Schizophrenia is a severe psychiatric disorder characterised by major
disturbances in thought, emotion, and behaviour.

Question 10

How common is it?

Answer 10

It is relatively common. Schizophrenia affects approximately 1% of the UK
population.

Question 11

When does SCZ begin?

Answer 11

The onset of schizophrenia is typically in late adolescence or in early adulthood.

Question 12

How is SCZ diagnosed and what are the 3 types of symptoms?

Answer 12

There is no diagnostic pathology for schizophrenia and diagnosis is currently
based on clusters of symptoms. These are described as

1. positive,
2. negative,
3. cognitive.

Question 13

How does schizophrenia relate to other psychiatric disorders?

Answer 13

In common with other psychiatric disorders such as bipolar disorder or major depression, schizophrenia patients display cognitive impairments,

In contrast, schizophrenia is characterised by psychotic episodes consisting of both
positive and negative symptoms.

Question 14

What are the three classes of symptoms of schizophrenia?

Answer 14

1. positive,
2. negative,
3. cognitive.

Question 15

What are positive symptoms of SCZ?

Answer 15

Positive symptoms are described as additional features that are not ordinarily
present. These include

1. delusions,
2. hallucinations that maybe auditory or visual, and
3. thought disorder.

Delusions occur and 90% of patients and represent an idiosyncratic belief or impression which
is maintained despite being contradicted by reality or rational argument– for example, I’m being
watched by an alien force.

Hallucinations are generally auditory– for example, hearing voices– and occur in 70% of patients.
Patients may feel as though these voices come from the outside and they often think they’re being
criticised by them. Hallucinations may also, however, been visual or related to smell, taste, or touch.

Thought disorder may show up as disordered speech, including rapid changes of subject, the use of
invented words, or in an appropriate emotional response to other people in a particular situation.

Question 16

What are negative symptoms of SCZ?

Answer 16

Negative symptoms in contrast refer to a loss or reduction in a normal function. Examples include–

1. alogia, the function of being reduced speech;
2. affective flattening, which means a lack of emotional
   facial expression;
3. avolition, meaning a diminished ability to begin and sustain an activity which is
   related to motivation;
4. anhedonia, meaning you no longer find pleasure in something you used to
   enjoy; and
5. asociality, meaning social withdrawal.

Question 17

What are cognitive symptoms of SCZ?

Answer 17

Cognitive symptoms refer to specific impairments in certain cognitive domains and affect the
patient’s general quality of life and ability to hold down a job. These include

1. working memory,
2. spatial memory,t
3. the ability to pay attention, and
4. executive functions which may be defined as planning and
   decision making.

The combination of these symptoms make it difficult for patients to interact with other people and may severely affect their work depending on the severity of each domain.

Question 18

What are the 4 broad categories of SCZ patients?

Answer 18

Schizophrenia itself can take several courses over a patient’s lifetime. The graphs on the slide show
possible life courses following a diagnosis of schizophrenia. The x-axis represents time and the y-axis
symptom severity. Patients may fall into one of at least four broad categories.

Group 1– a single episode of psychosis which recovers with no lasting impairment,
which corresponds to about 20% of the total number of schizophrenia patients.

Group 2– show
repeated episodes of psychosis– also referred to as relapse-remit– with no lasting impairment,
accounting for approximately 35% of patients.

Group 3– show repeated episodes of psychosis
without full recovery to pre-symptomatic levels of functioning. The proportion is about 8%.

Group 4, the most serious, show repeated episodes of psychosis which increase in severity and are
associated with no recovery to pre-symptomatic levels. This is about 35% of all cases on average.

Question 19

What then are the causes of schizophrenia?

Answer 19

Epidemiological studies clearly highlight the combination
of environmental factors, but there is also evidence from genetic studies that suggest genetic risk is a
serious component of schizophrenia risk. In reality, it is the interaction between these environmental
factors and genetic factors that determine the clinical outcome in terms of symptom severity, longterm outcome, and the life course that we just heard about.

Question 20

What are some examples of environmental factors that contribute to SCZ?

Answer 20

Some examples of environmental factors include
1. obstetric complications;
2. pre-term birth;
3. hypoxia;
4. exposure to infection or inflammation, either in utero or in early post-natal life;
5. exposure to social
stress, particularly during adolescence– particularly childhood trauma is a common risk factor; and
6. drug use, particularly addictive drugs such as cannabis, particularly during vulnerable periods of
brain development have been associated with an increased risk of psychosis in the adulthood.

Question 21

What are some examples of genetic factors that contribute to SCZ?

Answer 21

On the genetic side, schizophrenia is clearly highly heritable, but the genetics are complex and they
break down into rare variants that have large effect and are highly penetrant. And examples of this
include
1. the DISC1 gene and
2. deletions of the gene known as neurexin-1,

although there are others.
More common are variants of small effect, which together interact. And this is often referred to as
the

3. polygenic score, meaning the number of these small mutations that you have in your genome.

And together, as we said at the beginning, it is the interaction of these environmental factors and the
genetic risk factors that define the clinical outcome.

Question 22

Describe the 5 stages of dopamine transmission.

Answer 22

From a dopamine-releasing neuron -

1. uptake,
2. synthesis,
3. storage,
4. release, and
5. re-uptake of dopamine.

Question 23

Which amino acid is dopamine synthesized from and how does this amino acid enter the neuron?

Answer 23

Dopamine itself is synthesised from the amino acid tyrosine, which enters the neuron by active
transport.

Question 24

What is a dopaminergic neuron?

Answer 24

a neuron that primarily synthesises

and releases dopamine

Question 25

In a dopaminergic neuron, what is tyrosine first converted into and by which enzyme? Why is this step important?

Answer 25

In the cytoplasm of a dopaminergic neuron, defined as a neuron that primarily synthesises
and releases dopamine, tyrosine is first converted to dihydroxyphenylalanine, or DOPA, by an
enzyme called tyrosine hydroxylase.

This is the rate-limiting step for dopamine synthesis and is a
useful marker of how much dopamine a cell is producing, and by proxy, releasing.

And this will be
important later on.

Question 26

What is DOPA converted into and by which amino acid? How is it transported into the presynaptic vesicles?

Answer 26

DOPA is converted to dopamine by L-amino acid decarboxylase also known as DOPA decarboxylase,
and actively transported into synaptic vesicles through vesicular monoamine transporter 2.

Question 27

What are D1 and D2?

Answer 27

D1 and D2 are two types of post-synaptic dopamine receptors.

Question 28

What happens after dopamine is released from a dopaminergic neuron?

Answer 28

Following release,

1. dopamine binds to postsynaptic dopamine receptors, which are divided into D1 and D2 subtypes.
2. Dopamine can also bind to presynaptic auto receptors that inhibit further dopamine release.
3. Dopamine in the synaptic cleft is inactivated by active transport back into the presynaptic terminal
   by the dopamine transporter, or DAT, where it is degraded or stored again in vesicles.

Question 29

Where are the two places dopamine is degraded and by which enzymes?

Answer 29

Degradation of dopamine occurs
1. presynaptically via an enzyme known as monoamine oxidase, but a small
percentage may also be degraded
2. postsynaptically by Catechol-O-Methyl Transferase, or COMT.

Question 30

Which are the three neuronal pathways in the brain that utilise dopamine as a neurotransmitter.

Answer 30

Dopamine is used by
dopaminergic neurons in three primary pathways in the human brain:

1. These are the nigrostriatal pathway, which is critical for the control of movement, and projects from
   the substantia nigra to the striatum.
2. The mesolimbic and mesocortical pathways, which project from
   the ventral tegmental area to the nucleus accumbens, amygdala, hippocampus, to the mesolimbic
   pathway, and the prefrontal cortex, the mesocortical pathway. And this pathway involved in both
   limbic and cognitive functions, such as memory, motivation and emotional response, reward and
   desire, and addiction.
3. The third pathway is the tuberoinfundibular pathway, which projects from the A8 dopaminergic
   nucleus via the hypothalamus to the pituitary gland. This is involved in hormonal regulation and
   secretion of the hormone prolactin. The mesolimbic and mesocortical pathways, as you see from
   their function and their topographical projections, are, therefore, well placed to contribute to the
   symptoms of schizophrenia.

Question 31

Which are the three neuronal pathways in the brain that utilise dopamine as a neurotransmitter.

Answer 31

Dopamine is used by
dopaminergic neurons in three primary pathways in the human brain:

1. These are the nigrostriatal pathway, which is critical for the control of movement, and projects from
   the substantia nigra to the striatum.
2. The mesolimbic and mesocortical pathways, which project from
   the ventral tegmental area to the nucleus accumbens, amygdala, hippocampus, to the mesolimbic
   pathway, and the prefrontal cortex, the mesocortical pathway. And this pathway involved in both
   limbic and cognitive functions, such as memory, motivation and emotional response, reward and
   desire, and addiction.
3. The third pathway is the tuberoinfundibular pathway, which projects from the A8 dopaminergic
   nucleus via the hypothalamus to the pituitary gland. This is involved in hormonal regulation and
   secretion of the hormone prolactin.

Question 32

What is the dopamine hypothesis of schizophrenia?

Answer 32

The basic premise of the dopamine hypothesis is that an increase in dopaminergic neurotransmission in the
mesolimbic pathway leads to abnormally high levels of dopamine in the nucleus accumbens and the
striatum, which are thought to underlie the positive symptoms of schizophrenia, as we’ve already
heard about, including hallucinations.

Question 33

Which dopamine pathways are well placed to contribute to the

symptoms of schizophrenia?

Answer 33

The mesolimbic and mesocortical pathways, as you see from
their function and their topographical projections, are, therefore, well placed to contribute to the
symptoms of schizophrenia.

Question 34

What’s the difference between the mesolimbic pathway in a normal individual and a person with SCZ?

Answer 34

As you can see on the slide, in panel A, we can see the mesolimbic pathway in a normal individual
projecting from the VTA to the nucleus accumbens. In panel B, this is what is happening in the
schizophrenic patient. Now we can see that this projection is overactive and there is a much higher
amount of dopamine in the nucleus accumbens as compared to the normal control.
In contrast, a decrease in dopamine transmission– shown in the second image– in the mesocortical
pathway leads to lower levels than normal of dopamine in the prefrontal cortex, and this is thought
to explain the negative and cognitive symptoms of schizophrenia. So again, in the diagram, in panel
A, we can see the situation in the normal brain where there is a normal equilibrium of dopamine
neurotransmission from the VTA to the prefrontal cortex. And in panel B, we see that this pathway is
reduced and there is less dopamine in these areas, leading to negative and cognitive symptoms.

Question 35

What

is the evidence for the dopamine hypothesis?

Answer 35

If we accept the dopamine hypothesis, we have to first understand the evidence underlying it.

Primarily, this comes from
1. clinical observations and
2. experiments with dopamine-releasing drugs combined with Positron Emission Tomography, or PET, a
neuroimaging method used commonly in humans, but is also possible to do in animals.

Question 36

What are the three clinical observations and experimental medicine studies which were the key pieces of evidence that led to the development of the dopamine hypothesis?

Answer 36

1. Clinical observations in the 1950s, doctors treating schizophrenia patients serendipitously observed
   that certain drugs, such as chlorpromazine, the target of which was unknown at the time, decreased
   the positive symptoms of schizophrenia. This suggested that understanding how chlorpromazine
   had this action could provide insights into the neurobiology of schizophrenia. These drugs were
   thereforafter referred to as anti-psychotic drugs.
2. In 1963, Carlsson and Lindquist subsequently showed that anti-psychotic drugs increased the amount
   of dopamine metabolites in the cerebral spinal fluid of schizophrenia patients. They hypothesised that
   this may be something to do with the brain compensating for the blockade of a dopamine receptor in
   the brain, although at this stage, dopamine receptors have not yet been identified.
3. Subsequently, in the late 1980s, early 1990s, and into the 2000s, experiments in healthy people using
   PET who were given amphetamine showed that when amphetamine is given, dopamine release is
   stimulated, and these patients displayed positive symptoms of schizophrenia, including hallucinations.
   More importantly, when schizophrenia patients were given amphetamine, their symptoms became
   much worse. Clear evidence that increasing dopamine neurotransmission induces schizophrenia-like
   symptoms in otherwise healthy people and increases the severity of symptoms in patients already
   with a diagnosis of schizophrenia.

Taken together, these clinical observations and experimental medicine studies with amphetamine
were the first key pieces of evidence that led to the development of the dopamine hypothesis.

Question 37

How do we know where in the brain the amount of dopamine could be related to the positive
symptoms of schizophrenia?

Answer 37

We can use PET to look at how much dopamine is present

in specific parts of the brain.

Question 38

What is PET?

Answer 38

PET is a technique that allows the visualisation of specific proteins, such as an enzyme or
neurotransmitter receptor with very high sensitivity, by combining a specific molecule that binds to
these proteins with a radiolabel.

Question 39

What analogue can we use in a PET to visualise

dopamine synthesis and storage pathways in a living person and why?

Answer 39

To visualise dopamine
production in the brain, we can use a radiolabeled analogue of dopamine, 18 fluorodopa, to visualise
dopamine synthesis and storage pathways in a living person, because the synapse treats this as if it
were normal dopamine.
18 fluorodopa is taken up into the presynaptic terminals, where it is metabolised by DOPA
decarboxylase This can provide a proxy measure of the rate of dopamine synthesis, otherwise
referred to as dopamine synthesis capacity, which we would expect to be higher if there is an
increased rate of dopamine release in the patient we’re studying.

Question 40

What areas of the basal ganglia have the highest density of dopaminergic terminals?

Answer 40

The areas of high signal intensity, are the caudate and putamen, which contain the highest density of dopaminergic terminals.

Question 41

What areas of the basal ganglia have the highest density of dopaminergic terminals?

Answer 41

The areas of high signal intensity, are the caudate and putamen (is this the striatum?) , which contain the highest density of dopaminergic terminals.

Question 42

What has been discovered in PET scans of individuals who have SCZ?

Answer 42

Patients with schizophrenia have been repeatedly imaged using 18 fluorodopa PET and compared
to healthy controls who do not have schizophrenia, or any other psychiatric disorder. These
experiments show that schizophrenia patients, the red dots in the graph where each patient is
represented by a dot, have a higher uptake value given by the rate constant KI on the y-axis of 18
F-DOPA in the striatum compared to the healthy controls indicated by the blue dots.
This increase in dopamine synthesis capacity correlates positively with the severity of patient positive
symptoms. Several studies greater than 50 to date have replicated these findings in different groups
of schizophrenia patients around the world, and this provides the most robust evidence of dopamine
dysfunction in schizophrenia localised to the mesolimbic pathway.

Question 43

What evidence for the dopamine hypothesis comes from studies of anti-psychotic drugs?

Answer 43

Further evidence for the dopamine hypothesis comes from studies of anti-psychotic drugs and their
binding to dopamine D2 receptors. As we’ve already heard, the finding that drugs like chlorpromazine
block the positive symptoms of schizophrenia were serendipitous, but led to the coining of the term
anti-psychotic drugs. The role of dopamine in schizophrenia was therefore strengthened by the
identification of dopamine receptors in the brain, and the subsequent finding that all anti-psychotic
drugs bind the dopamine D2 receptor.
Indeed, the efficacy of anti-psychotics, measured as a daily dose required for the treatment of
positive symptoms of schizophrenia, is closely correlated to the potency or affinity with which a
particular anti-psychotic binds to the dopamine D2 receptor, as shown in figure A.
An exception to this, however, is clozapine, which has a low affinity for the D2 receptor, but is one of
the most effective anti-psychotic drugs. The reason for this is currently unclear, but clozapine and
other anti-psychotics do bind to a number of other neurotransmitter receptors in the brain. This tells
us that changes in dopamine neurotransmission might not be the whole story behind the symptoms of
schizophrenia,

Nevertheless, subsequent PET studies found that a specific percentage of dopamine D2 receptors
must be blocked to achieve a good clinical response, defined as a reduction of positive symptoms.
These studies suggest that 60% to 80% of dopamine D2 receptors must be blocked for the maximum
therapeutic effect. This is shown in figure B.
Here on the x-axis is the percentage of occupied or blocked D2 receptors following anti-psychotic
dosing. On the y-axis is the clinical improvement in positive symptoms from none to significant
improvement. It can be seen clearly that as the percentage of dopamine D2 receptors blocked
increases to the critical window, more patients, indicated by the green dots, show recovery of their
symptoms.
We should note, however, that once the threshold of 80% dopamine D2 blockade is crossed, patients’
positive symptoms may improve, but they begin to suffer side effects, as shown by the red dots.
These are described as extrapyramidal symptoms and include dyskinesia and other movement
disorders, such as akathisia. These reflect the action of anti-psychotics on dopamine D2 receptors
in other dopamine pathways, such as the nigrostriatal pathway, which are responsible for the control
movement.
This represents an elegant description of a drug therapeutic window, defined as the range of doses in
which positive effects are seen without adverse side effects. As we can see, for anti-psychotics, this
window is quite narrow, suggesting care must be taken in dosing.

Question 44

If the dopamine hypothesis is correct, where does the excess dopamine activity comes from in SCZ patients?

Answer 44

It might be

1. that the patient produces too much dopamine,
2. doesn’t metabolise excess dopamine
   quickly enough, or
3. has D2 receptors that have been modified so they respond differently to dopamine
   binding, principally being more sensitive to dopamine.

Question 45

So how could excess dopamine come about?

Answer 45

The stress diathesis model was developed to explain this excess of
dopamine in the schizophrenic brain.

Question 46

What is the stress diathesis model?

Answer 46

The stress diathesis model suggests that an individual inherits several genes that encode
for abnormal proteins, leading defective dopamine function in the mesolimbic pathway, rendering the
pathway hyperactive and leading to the positive symptoms.

Question 47

So what is the evidence for the stress diathesis model?

Answer 47

1. The dopamine D2 receptor is one of the more significant hits
   in large scale studies of the genetics of schizophrenia.
2. This genetic risk is paired with environmental
   stresses which further modify dopamine release. For example, stress during adolescence. Perhaps
   together, these can be enough to create the symptoms leading to a diagnosis of schizophrenia.

Question 48

What evidence does not support the dopamine hypothesis model?

Answer 48

1. a significant proportion of schizophrenia patients do not
   respond to anti-psychotic drugs, and their positive symptoms do not improve.

This might suggest
that dopamine hyperactivity is only one of the causes of the onset of schizophrenia.

Question 49

Is there any
evidence that dopamine hyperactivity is only one of the causes of the onset of schizophrenia and what is the problem with this?

Answer 49

Here, we consider this possibility by looking at levels of dopamine and response to anti-psychotic
treatment to understand whether there may be subtypes of schizophrenia.

As we have just
discussed, in about 30% of cases, the positive symptoms of schizophrenia patients do not improve
following treatment with anti-psychotic drugs.

If this continues, despite switching drugs or changing
the dose, these patients may be described as treatment-resistant.

This is a very difficult clinical
problem, as essentially, there are no effective treatments for these individuals.

Question 50

What is an explanation for treatment resistance?

Answer 50

One explanation for treatment resistance could be that the patients do not have the same
abnormalities of dopamine neurotransmission as those who respond conventionally to anti-psychotic
drugs.

Question 51

Is there any evidence that there are many types of abnormalities of dopamine transmission in SCZ patients?

Answer 51

Using 18 fluoro PET scans, as we discussed earlier, recent studies have revealed that this may be the
case.

The graph in A on the slide shows that people who respond to treatment have an increased
capacity to produce dopamine. In other words, a higher dopamine synthesis capacity in the striatum,
as shown by the red dots. And these are referred to as treatment responders.

In contrast, people who are described as resistant to anti-psychotic treatment do not show an
elevation in this dopamine synthesis capacity and are indistinguishable from healthy controls.

Question 52

What difference does Magnetic Resonance

Spectroscopy find between SCA patients who respond and those who don’t to anti-psychotics?

Answer 52

Studies in the same individuals using a different neuroimaging technique called Magnetic Resonance
Spectroscopy have found that patients who respond to anti-psychotics have normal levels of
glutamate in the frontal cortex, whereas patients who are resistant have higher amounts of cortical
glutamate as compared to healthy controls and treatment responders. These data confirm that
treatment-resistant patients may not have an abnormality in dopamine synthesis capacity, but may
have defective glutamate neurotransmission instead. This suggests that other neurotransmitters,
particularly glutamate, are important for schizophrenia symptoms, not just dopamine.

Clearly, there are also implications for the treatment of schizophrenia, and it is critical to be able
to identify individuals who will or will not respond to anti-psychotic medication early such that other
alternative drugs may be tried, including glutamatergic drugs that are currently in development.

Question 53

What are the two sub-types of SCZ?

Answer 53

The dopamine and glutamate evidence that you’ve looked at is the first biological in vivo data that
demonstrates that there may be at least two subtypes of schizophrenia– one based on dopamine
and one that does not seem to involve the dopamine system.

Although these data require replication
in a larger cohort, they confirm what has been long suspected, that the symptoms of schizophrenia
cannot solely be explained by the dopamine hypothesis.

Clinical evidence would support this, suggesting anti-psychotic drugs do not effectively treat the
negative symptoms of schizophrenia. Therefore, there clearly are other transmitter systems
involved, and in the next section, we will focus on a similarly influential theory of schizophrenia, the
glutamate hypothesis.

Question 54

So how does the glutamate hypothesis work, in terms of positive symptoms?

Answer 54

in the normal brain, cortical projection neurons, indicated by 1, send
glutamatergic projections from the frontal cortex to the dopaminergic neurons in the midbrain,
where, we have already seen, is the origin of the mesolimbic pathway, indicated by 2.
The activity
of these cortical neurons is regulated by another type of neuron in the cortex which releases the
inhibitory neurotransmitter, GABA, indicated by 3.

When this circuit is functioning normally, glutamate, GABA, and dopamine are in equilibrium.

In
schizophrenia, panel B, it is hypothesised that the glutamatergic cortical projection neurons, shown
by the number 1, become overactive, due to a reduction in the activity of the GABA interneurons,
shown by 2.

This overactivity drives activation of the mesolimbic pathway, indicated by the number 3
in the figure, leading to high levels of dopamine in in the striatum and nucleus accumbens, indicated
by the number 4, and the appearance of the positive symptoms of schizophrenia.

Therefore, imbalances in glutamate and GABA systems may also give rise to dopamine imbalance.

Question 55

What evidence is there for the glutamate hypothesis of SCZ?

Answer 55

This is supported, again, by evidence from studies with drugs that block N-methyl-D-aspartate
receptors and thus lead to excess glutamate, such as ketamine, which causes the manifestation
of positive symptoms in schizophrenia in healthy individuals and exacerbates positive symptoms
in schizophrenia patients, providing clear evidence for the role of glutamate in schizophrenia
symptomatology.

Question 56

How do alterations in glutamate

explaining the negative symptoms of schizophrenia?

Answer 56

Here we see, again, the glutamate-GABA-dopamine circuitry in the normal brain, on the left, in panel
A, and the schizophrenia brain on the right, in panel B.

How do alterations in neurotransmission in
this circuit lead to the negative symptoms of schizophrenia?

Here, a cortical glutamate neuron, a
GABA interneuron and mesolimbic dopaminergic neurons interact in the same way as shown on the
previous slide.

In addition, we now highlight an additional synapse between GABA interneurons in the
midbrain and dopaminergic neurons projecting back to the cortex, the mesocortical pathway.

Under normal conditions, these cells are all in equilibrium, such that sufficient dopamine reaches
the cortex to allow normal social reward and cognitive functioning.

In schizophrenia, we think
that the overactive cortical projection neurons, following GABA deficiency in the cortex, leads to
hyperactivation of GABA interneurons in the midbrain, which in turn block the activity and firing
rate of dopaminergic mesocortical projections, which become inhibited and fire less.

Thus, the
mesocortical dopamine pathway becomes underactive and unable to supply adequate dopamine to
the frontal cortex, leading to hypofrontality and the emergence of negative and cognitive symptoms.

Here, then, we can see the complex polysynaptic nature of neurotransmitter actions in the brain
functioning as part of large and complex neuronal circuits and ultimately networks, the activity in
which defines behavioural outcomes. Whilst these are normally in balance, when neurotransmission
becomes defective the outputs of these circuits and the information flow within them are
fundamentally corrupted, leading to behavioural disturbances, as highlighted here, by example, in
the positive and negative symptoms of schizophrenia, driven by alterations in dopamine, GABA, and
glutamate neurotransmission, respectively