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Dopamine and Schizophrenia

Computational Psychiatry Seminar, ETH Zurich, 28.03.2014

Helene Haker

on 25 August 2015

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Transcript of Dopamine and Schizophrenia

Dopamine Pathology
Computational Psychiatry Seminar - 28.03.2014
Helene Haker & Sara Tomiello
The DA hypothesis of SZ v3
Multiple ‘‘hits’’ interact to result in DA dysregulation: the final common pathway to psychosis in SZ.

The locus of DA dysregulation moves from the D2 receptor level to the presynaptic dopaminergic control level.

DA dysregulation is linked to ‘‘psychosis’’ (and maybe psychosis proneness) rather than SZ.’’ SZ reflects the nature of the hits coupled with sociocultural factors and not the DA dysfunction per se.

The DA dysregulation is hypothesized to alter the appraisal of stimuli (aberrant salience).
DA and salience
unlimited, changing perceptual input
Antipsychotic action
Antipsychotics = DR2 antagonists

Not effective in all patients
not all Sz patients may have predominant dysregulation in DA (but ACh, 5-HT)

Clozapin (most effective)
also partial D1 agonist
enhances dendritic spine number and NMDAR proteins
Cellular or synaptic causes?
Abnormal interregional functional coupling because of...

impairments of structural connectivity ("DISconnection")
abnormal wiring during brain development
(inconclusive data)

impairments in synaptic plasticity ("DYSconnection")


converging evidence for the latter
Dysconnection in Sz
Starting point:

Strong evidence for dysconectivity in Sz,
i.e. abnormal functional integration of brain processes

pathophysiological mechanisms
significance for clinical symptoms
Schizophrenia: Symptoms
Fixed beliefs that are resistent to change in the light of conflicting evidence.

persecutory/paranoid (to be harmed, harrassed, ...)
referential (observations are directed to oneself)
religious (being god, jesus, etc.)
grandiose (false belief about exceptional abilities, fame)
Heterogeneous presentation
Different pathophysiological pathways may converge
predominant DA-ergic vs.
predominant cholinergic dysregulation

modulating factors that differ across patients and within time
immunologic factors
differences in the sensory experience
Neurochemical imaging:
PET in psychosis
aberrant salience and psychosis
Psychosis prodromal
emotional and sensory overload
a sense that things and events have a hidden important meaning
a sense that the world has changed in some way

Manifest psychosis
delusions emerge out of this context
the patient becomes convinced of an explanation for this distressing experience
the individual’s interpretation of the experience will reflect their own prior beliefs and experience
the content of delusions varies according to culture
hyperrelease of DA (midbrain to the striatum)
Shifting the D1/D2 activation balance toward D2
over time NMDAR hypofunction due to D2-evoked dampening of NMDAR-dependent plasticity

Keatamin (Glu antagonist at the NMDAR)
buildup of cognitive deficits with incrasing doses
psychotic symptoms only at higher doses
DA and PE in Sz
DA ...
increases the synaptic gain by modulation of the NMDAR
encodes the precision of a PE
the precision weights the influence of the PE on inference

Increased DA activity in Sz leads to an incorrect, increased weighting of PEs

false PE are propagated upwards the hierarchy

change the internal model of the world in an inaccurate way
to explain away the predicition error
to make sense of abnormal senory experiences
(bizarre) delusions
What goes wrong in Sz
main abnormalities are seen in cortical pyramidal cells
in areas responsible for high hierarchical processing (prefrontal cortex)

postsynaptic gain of these neurons encodes the precision of prediction errors
postsynaptic gain is dependent on DAergic neuromodulation of NMDAR
(... in pyramidal neurons in prefrontal cortex input layers)

consistent with chronic NMDAR hypofunction:

NMDAR are potent promotors of dendritic spine formation and dendritic growth
Evidence for disturbed synaptic plasticity in Sz
MMN (dependent on synaptic plasticity) is reduced in Sz and in ketamin psychosis

NMDA antagonists, DA agonists (D2), and 5-HT agonists can induce psychosis

reductions in dendritic field size and dendritic spines of cortical neurons
as a consequence of impaired synaptic plasticity: one of the most important promoters of dendritic growth and dendritic spine formation is activation of NMDARs.

a majority of the currently strongest candidate genes for schizophrenia, as determined by linkage and association studies, play an important role in NMDAR-dependent signaling and plasticity and its regulation by DA and ACh

(migrant status, older fathers, Toxoplasmosis antibodies, prenatal famine, obstetrical complications, urban ruring, winter or spring birth, lifetime cannabis use)

NMDAR dependent synaptic plasticity is affected by
immunological (e.g. viral infections during pregnancy)
hormonal factors (e.g. cortisol levels due to stress)

Cannabis: perturbation of endocannabinoid-mediated plasticity (CB1 receptor)
Bayesian inference
NMDAR-dependent plasticity
... can be controlled by modulatory transmitters through the following mechanisms:

Trafficking/insertion/endocytosis of NMDAR (DA, ACh)

Conductance properties of NMDARs (DA, 5-HT)

Relative expression of different NMDAR subunits (electrophysiological properties) (ACh, 5-HT)
Dual role of neuromodulatory transmitters:

short-term synaptic plasticity
changing postsynaptic responses

long-term synaptic plasticity
lasting reconfiguration of neuronal connections

... of different importance in different subgroups of patients
A hierarchy of prediction
and model building
Models of the world have a hierarchical structure

they are formed through PEs
PEs emitted by a lower level = input for a higher level
Feedbacks from a higher level = prior belief for the lower level

if adjustments on one level do not resolve a repeated PE, adjustments on higher levels are needed


Formal thought disorders

Abnormal motor behavior

Negative symptoms
Positive symptoms
= Psychosis
Perception-like experiences that occur without an external stimulus in any sensory modality.

In the case of Schizophrenia mostly voices.
Formal thought disordes
Disorganized thinking - inferred usually from speech.

loose associations
switching from one topic to another
answers are not exactly directed to the question
thoughts cannot be followed
word salad
completely incomprehensible speech
Abnormal motor behavior
Problems in any form of goal directed behavior
marked decrease in reactivity to the environment
Catatonic excitement
purposeless and excessive motor activity without obvious cause
Negative Symptoms
Accounts for a substantial portion of the morbidity

Diminished emotional expression
decrease in motivation for self-initiated purposeful activities
social withdrawal

CPS Fall 2014
Clinical aspects
Established facts & Hypotheses explaining these facts
The Dopamine hypotheses
The dysconnection hypothesis
1. Heterogenous presentation

2. Age of onset and sex differences

3. Heritability

4. Antipsychotic action

5. Environmental risk factors

6. Medication response lag

7. Psychomimetic effects of DA ...
8. and Glu agonists

9. Reduced dendritic spine density

10. reduced G67 levels

1. Schizophrenia has a heterogeneous presentation, with disorganized, positive, and negative symptoms having different levels of prominence across time and across individuals.
2. Schizophrenia has a peak of onset in young adulthood and is rare before adolescence or after middle age. Onset also interacts with sex, such that men are likely to become ill earlier in life than women. Prevalence is greater in men throughout most of adulthood but is equal by the end of the risk period.
3. Liability to schizophrenia is highly heritable (about 0.81), and concordance between identical twins is almost 50%, suggesting a role for environmental or stochastic influences as well.
4. All drugs with established antipsychotic effects block DA D2-like receptors, but antipsychotic drugs are not effective for all schizophrenia symptoms. Among available agents, the atypical antipsychotic Clozapin is the most effective; however, it carries unique risks for some.
5. Several early neurological insults, later life stressors and nonhereditary genetic risk factors confer additional risk. These include (in order of impact) migrant status, older fathers, Toxoplasmosis gondii antibodies, prenatal famine, lifetime cannabis use, obstetrical complications, urban rearing, and winter or spring birth.
6. While antipsychotics can lead to immediate improvement for some individuals, the time course of medication effects varies widely with some patients showing responses to medication more than a month after beginning treatment.
7. Exposure to amphetamine, a DA agonist, can result in schizophrenia-like symptoms in some individuals. This effect may interact with liability, such that a single dose can trigger relapse in patients, but more chronic use is usually needed to induce psychosis in low-risk populations.
8. A single exposure to phencycline and other NMDA receptor antagonists (such as ketamine) can result in schizophrenia-like symptoms in some individuals.
9. In postmortem studies, pyramidal neurons in input layers of prefrontal cortex have a reduced dendritic spine density, whereas hippocampal neurons appear to be abnormally oriented with signs of arrested migration.
10. GAD65 and 67, the rate-limiting enzymes that convert glutamate to GABA, are reduced in schizophrenia patients. Reelin, an important factor involved in synaptic plasticity that colocalizes to GABAergic inter-neurons, is also reduced.
GAD65 and 67: convert Glu to GABA

Reduced Glu conversion
Enhanced Glu activation of DA neurons in the midbrain
version 1, 1970s (e.g. Seeman & Lee, Science 1975)
"The dopamine receptor hypothesis"
hyperdopaminergia (excess transmission at DA receptors)

version 2, 1991 (Davis et al., Am J Psychiatry 1991)
"A modified dopamine hypothesis of schizophrenia"
subcortical hyperdopaminergia with prefrontal hypodopaminergia

version 3, 2009 (Howes & Kapur, Schizophr Bull 2009)
"a dopamine hypothesis of psychosis-in-schizophrenia"
a framework that links environmental risk factors and genes, to increased presynaptic striatal dopaminergic function

synapse-level / cognitive and computational level

reviewed in Winton-Brown et al. 2013 TINS
DA synthesis
DA release into the synapse
Synaptic DA levels at rest
D2/D3 availability
DA (reuptake) transporter
radiolabelled L-Dopa
elevated DA synthesis capacity in SZ (large effect size)
change in radiotracer binding after a DA challenge (e.g. ampetamine)
greater radiotracer displacement in SZ, related to transient worsening of psychotic symptoms
same finding to a standard psychosocial stress challenge
hyper-responsive DA system
most apparent in acutely psychotic patients, less marked in stable remitted patients
D2/D3 a availability is elevated in SZ (small effect size)
unaltered in SZ
no compensatory increase in the capacity to buffer elevated DA levels
depleting presynaptic DA stores
elevated baseline occupancy of D2/D3 receptors in SZ, suggesting elevated extracellular DA concentrations
Prodromal psychosis:

People at genetic risk:

People with long-term subclinical symptoms:
elevated DA synthesys capacity and stress-induced DA release
increase dopamine synthesis capacity at onset of psychosis

inconsistent findings

no elevated DA synthesis capacity
limited cognitive and motor resources
prioritisation based on salience,
mediated by DA
internal factors
external factors
The Dysconnection hypothesis' answer to Fact 1
Age of onset and sex differences
NMDA dep. synaptic plasticity is altered by
estrogens (enhance LTP, improvements in e.g. memory)

Estrogens: protective effect on NMDAR-dependent synaptic plasticity
delay the onset of schizophrenia in genetically predisposed females
not males: earlier onset of schizophrenia in men
The Dysconnection hypothesis' answer to Fact 2
Highly heritable liability
but only 50% concordance in mc twins
suggest gene x environment interaction:

Most candidate genes for Sz are related to glutamatergic signaling

the functional expression of syn. plast. rests on the exchange with the environment and the resulting sensory experiences
The Dysconnection hypothesis' answer to Fact 3
The Dysconnection hypothesis' answer to Fact 4
Environmental risk factors
The Dysconnection hypothesis' answer to Fact 5
Medication response lag
The Dysconnection hypothesis' answer to Fact 6
Psychomimetic effects of
DA and Glu
The Dysconnection hypothesis' answer to Facts 7 and 8
Reduced dendritic spine density
The Dysconnection hypothesis' answer to Fact 9
Reduced G67 levels
The Dysconnection hypothesis' answer to Fact 10
The computational anatomy of psychosis
posterior belief
is biased towards the
or the
sensory evidence
in proportion to their relative precision.
Explaining the positive symptoms of Sz
Abnormal perception

loss of distinction between relevant and irrelevant stimuli
rendering everything surprising and salient
attribution of meaning to (irrelevant) stimuli
(delusional mood)

failure to ignore self-generated stimuli
deficit in corollary discharge
misattribution of self-generated actions to others
passivity experiences
misattribution of self-generated thoughts to others
hearing voices (auditory hallucinations)

enhanced precision of prediction errors / loss of top down predictions
Perceiving is believing
Strong false beliefs
held against contradictory evidence

Problems in probabilistic reasoning
jumping to conclusion
less evidence
more confidence
abnormal bias against disconfirmatory evidence
Abnormal beliefs
linking neuropathology
and neurocomputation
Stephan et al. 2006
reduced prefrontal NMDAR function
reduced stim. of
reduced DA backprojections
to prefrontal D1R
(reduced cortical precision)
increased hippocampal
drive to the VTA
disinhibition of DA N in VTA that
project to the striatum
increased DA release
from the SNc
inhibition of striatal GABA N
inhibition of ACh
reduced Glu release from cortico-striatal N
The Dysconnection Hypothesis of Sz
The central pathomechanism in schizophrenia is

aberrant NMDAR-mediated synaptic plasticity

due to abnormal regulation of NMDARs by neuromodulatory transmitters like
Stephan et al. 2006 / 2009
Take home: Schizophrenia
Positive symptoms
Negative symptoms
(abnormal perception)
(abormal beliefs)

(i.e. learning)
Synaptic plasticity


Dysconnection Hypothesis
DSM-5 (Diagnostic and Statistic Manual)
Winton-Brown et al. 2013
Adams et al. 2013
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