Basic Science of Schizophrenia

Question 1

What aspects of SZ can be modelled in animals?

Answer 1

Increase in locomotor activity (psychomotor agitation)
Sensory gating abnormalities, lack of pre-pulse inhibition of acoustic startle
Impaired social interactions
Alteration in nT level or action
Changes in cellular morphology or function (e.g. parvalbumin-positive interneurons)

Question 2

What are some examples of SZ symptoms that cannot be modelled in animals?

Answer 2

Speech abnormalities; loose associations; preservation; rhyming words

Action; difficulty starting or finishing tasks, bizarre behaviour, unpredictable or inappropriate emotional responses

Question 3

Is there a connection between SZ and the PFC?

Answer 3

Theory that hypofrontality and impaired executive function lead to disorganisation of speech and action
fMRI studies reveal task dependent abnormalities (increase or decrease) in PFC

Question 4

Is SZ considered a neurodevelopmental disorder?

Answer 4

Yes; growing evidnece that genetic and environmental influences during development play a large role in SZ

Question 5

What genes are thought to be involved with SZ?

Answer 5

DISC1:
Translocation between 1 and 11 - confers with susceptibility in several genes for psychiatric illness

This translocation truncates and inactivates the DISC1 gene.

Affected members have a higher risk for SZ, MDD, BAD

However, vast majority of those diagnosed with SZ do not have DISC1

Question 6

What is the function of DISC1?

Answer 6

Progenitor proliferation 
Neuronal migration 
Spine regulation 
Neuronal signalling 
== Neurodevelopment 

Example: necessary for pyramidal (CA1) cell migration

Question 7

What is the relevance of DISC1 to SZ?

Answer 7

DISC1 -/- mice; abnormal social behaviour and reduced parvalbumin staining and intraneuronal activity

Inducible expression of mutant DISC1; hyperactivity, abnormal social behaviour, enlargement of ventricles, reduced gamma synchrony

Question 8

What is the neurodevelopmental hypothesis of SZ?

Answer 8

Hyperconnectivity - synaptic connections between neurons that would not usually be present
Synaptic pruning failure
Aberrant neuronal migration
Synaptic changes

Question 9

What is an endophenotype?

Answer 9

Intermediate between a gene that is implicated (DISC1) and symptoms of SZ itself
They are simple, quantifiable, heritable biological traits that segregate with an illness

In combo with environmental RF and developmental stage combine to increase susceptibility to SZ

Question 10

Describe the traits of an endophenotype

Answer 10

Heritable with robust deficits in patients and some unaffected family members

Stable across symptom state to reflect the trait of the disorder

Easily and rapidly measured

Excellent in terms of test-retest reliability

Representative of a discrete neurobiological mechanism that is relevant to the pathology of the disorder.

Question 11

Describe some environmental RF for SZ??

Answer 11

Neuronal differentiation/ migration:
Intrauterine stress
Perinatal infection

Glutamergic synapse density, dendritic arborization, mesocortical dopaminergic projections:

Urban city
Cannabis

Question 12

What is the evidence for developmental oxidative stress in SZ pathogenesis?

Answer 12

Oxidative stress in interneurons
Imbalance in inhibition
Specifically parvalbumin interneuron
Loss of these cells results in a change of inhibition to principal neurons - altered oscillations in EEG

Question 13

Describe the anomalies in perceptual processing in SZ

Answer 13

Difficulties in filtering out relevant stimuli 
Attention deficits
Impairments in language processing 
Changes in auditory cortex
NOT DIAGNOSTIC OF SZ

Question 14

What occurs when an auditory stimulus reaches the brain?

Answer 14

Low level automatic process to high level processes

Event related potential (ERP); electrical activity aligned with auditory stimulus

Question 15

Describe the p50 wave on the ERP signalling

Answer 15

Described as the sensory gating of stimuli

Relevant to SZ; unable to filter out repetitive sensory stimuli

Question 16

How can the “sensory gating” failure in SZ be tested?

Answer 16

Paired-click paradigm
2 auditory stimuli around 500 milliseconds apart.
Cortical ERP corresponding to each one are measured. Specifically; the p50 amplitude and the corresponding negative trough that follows it.

In normal subjects; the second click’s p50 wave is much smaller than the first. This suggests an automatic mechanism for filtering out repetitive sounds

In SZ patients; the p50 response to the second click is the same as the first response. This suggests an abnormality in the filtering out of repetitive sensory stimuli. Failure of sensory gating

Question 17

Is a failure of sensory gating a diagnostic test?

Answer 17

No
For example; when looking at the p50 response to the stimulus; a ratio of >0.5 response after the second click is seen in 90% of people with SZ but 8% of non-schizophrenic patients

Therefore; this test does not pick up everyone with SZ, and will identify health subjects

Question 18

Is there a genetic link to sensory gating abnormalities?

Answer 18

Yes; links to the alpha 7 nicotinic receptor on chromosome 15

Question 19

Describe the pre-pulse inhibition of an acoustic startle

Answer 19

In terms of a reaction to a loud noise; the startle response (in healthy subjects) is reduced if there is a smaller pre-pulse stimulus
This is measured using EEG of the extraocular muscles

In those with SZ (like sensory gating and paired click paradigm), the PPI deficits are reduced

Question 20

Is there an effect of antipsychotic drugs on PPI response?

Answer 20

Haloperidol (dopamine D2 antagonist) reverses the impairment in PPI caused by stimulant drug (amphetamine) administration

Question 21

Describe mismatch negativity

Answer 21

Event-related brain potential that is sensitive to stimulus deviation from a repetitive pattern.
Reflects activity of sensory memory; such as attention.
Deficits are seen in patients with SZ

Question 22

Does MMN vary with symptomatic progression?

Answer 22

Yes; the size of MMN wave is altered (progressively less) in healthy patients, at risk patients, first episode and chronic SZ

Question 23

Describe the P300 wave

Answer 23

Associated with oddball detection (like MMN) or target identification
Modulated by attention, measure of the extent of attention paid to the stimulus and subsequent oddball

This is reduced in SZ; attentional processing of oddball stimulus

Question 24

Summarize the neurophysiological measures of sensory processing

Answer 24

p50 (paired click), MMN and p30 all show heritable and robust deficits in SZ pts

P3 and MMN show state dependence = they vary with disease severity due to demands on attention

All components combine basic perceptual processes with perceptual memory

Represent basic neural processes that underpin the more complex cognitive operations that are impaired in SZ

Question 25

Describe the dopamine hypothesis in SZ

Answer 25

Evidence;
Antipsychotics block D2 receptors

Drugs such as amphetamines that increase brain DA levels can cause psychosis

Post mortem studies have shown increased D2 receptor levels

Question 26

Is there any evidence against the DA hypothesis of SZ?

Answer 26

Yes;
DA inhibiting drugs modify
DA levels within minutes but take much longer to be as effective as antipsychotics

Abnormalities in other systems e.g. GABA and glutamate

Question 27

What is probably the most convincing piece of evidence for DA hypothesis in SZ?

Answer 27

The effective antipsychotic dose is typically inversely related for affinity to D2 receptors
The higher the affinity of the drug; the less required for the desired effect

Clozapine bucks the rule; has other actions and higher affinity for D4 receptors

Question 28

Describe the mesolimbic vs mesocortical DA projections in SZ?

Answer 28

Mesolimbic hyperactivity (dorsal and ventral striatum and VTA) = positive symptoms 
Prefrontal (mesocortical) hypoactivity = negative symptoms 

THEREFORE; antidopaminergic drugs can worsen negative symptoms

Question 29

Describe the pharmacological stimulant model of SZ

Answer 29

Stimulant induced hyperactivity = psychosis
Antipsychotics = suppression

Lack of specificity; hyperactivity is not only observed in SZ; also mania and ADHD

Doesn’t capture developmental aspects of disease

More informative about mechanism of action of a drug than the disease process

Question 30

Is the cholinergic system implicated in SZ?

Answer 30

Yes; arise from basal forebrain and project to large amount of cortex

In SZ human and animal models; tx with agonists of alpha 7 nicotinic receptor can cause an improvement in working memory and attention symptoms

Certain variants of genes that are linked to alpha 7 nicotinic receptors are assoc with abnormalities in sensory gating

Post mortem; decrease in alpha 7 nicotinic receptors in the frontal cortex

Question 31

Describe the link between smoking and SZ?

Answer 31

Around 80% of those with SZ smoke, compared to 20% of general population

Alpha 7 nicotinic receptors (downregulated in SZ) activation enhances sensory gating and may improve attention and sensory filtering

It may actually improve schizophrenic symptoms

Question 32

Are glutamate levels altered in SZ?

Answer 32

Yes;

Glutamate levels are reduced in CSF of SZ patients (post mortem) in the hippocampus and PFC

Question 33

Are there alterations with glutamate receptors in SZ?

Answer 33

Yes; SZ assoc mutations in genes coding for post-synaptic density proteins and components of the NMDA receptor signalling complex

Question 34

Does NMDA abnormalities in SZ contribute to the symptoms seen?

Answer 34

Yes; studies have shown ketamine and PCP to cause schizophrenic like symptoms

Ketamine administration causes pathological changes in interneurons (e.g. loss of parvalbumin staining in mice)

Transgenic mice under expressing NMDA GluN1 subunits show social isolation, hyperactivity and motor stereotypies which are reversed by antipsychotics `

Question 35

Describe the role of ketamine in SZ pathogenesis as a adjunct to NMDA hypofunction

Answer 35

Ketamine is particularly effective in neurons with high spontaneous activity such as interneurons (fire at higher rates than excitatory cells)

Question 36

Describe the role of the parvalbumin positive interneuron in SZ pathogenesis

Answer 36

Reduction in NMDAr mediated excitation of parvalbumin positive interneurons of the hippocampus and PFC may play a role in altered gamma activity and synchrony

If this activity is reduced; the inhibition provided by these neurons is reduced

Question 37

What is a parvalbumin positive interneuron?

Answer 37

Situated in the hippocampus of the brain close to the pyramidal (CA1) soma.
Make synaptic connections to inhibit the excitation of these neurons

Particularly affected by NMDA receptor antagonists

Question 38

Describe the GABAergic hypothesis of SZ

Answer 38

Post mortem abnormalities in parvalbumin containing interneurons e.g. reduced synthesis and reuptake of GABA

Repeated ketamine causes a reduction in parvalbumin staining in hippocampus of rats

Question 39

What is the link between gamma frequency and long range synchrony and SZ?

Answer 39

Decreased in SZ

Question 40

What is interhemispheric synchronization?

Answer 40

Auditory verbal hallucinations that are associated with reduced gamma synchrony between left and right auditory cortices

Question 41

What is gamma frequency?

Answer 41

Between 30-60 Hz

All to do with neuronal firing

Question 42

Is there a link between DISC 1 overexpression and gamma frequency?

Answer 42

Yes; DISC 1 overexpression (linked with translocation of genes that correlated with SZ) causes abnormal hippocampal gamma frequency synchronisation

Question 43

What is one of the major roles of gamma oscillations?

Answer 43

Feature binding; shape,
position and colour of objects for example

Cells representing different attributes fire in synchrony

They play a role in synaptic transmission and processing

Question 44

What drives gamma oscillations?

Answer 44

Cycles of mutual excitation and inhibition
Excitatory neuron fires AP, will also fire a collateral onto the interneuron
The interneuron will inhibit the pyramidal cell; feedback reduction in excitation in the interneuron

Question 45

Describe the role of abnormal gamma synchrony the PFC and its link to SZ

Answer 45

Disinhibition of excitatory neurons like pyramidal cells
Abnormal cortical output leading to cognitive dysfunction
Abnrmal generation and synchronization of gamma oscillations
Breakdown in gamma coordinated activity causing disorganization in PFC and other areas of the brain