SZ - Basic Science

Question 1

Which NIMH research domains is SZ studied under?

Answer 1

Cognitive impairment

Anhedonia

Question 2

Which aspects of SZ can be modelled in rodents?

Answer 2

Locomotor changes
Psychomotor agitation 
Sensory gating abnormality 
Alteration in NTM levels 
Changes in cellular function

Question 3

Describe the speech abnormalities in SZ

Answer 3

Word salad and knights move thinking
Perseveration
Rhyming

Question 4

What abnormalities in action are seen in SZ?

Answer 4

Difficulty starting or finishing tasks
Bizarre behaviours with lack of purpose
Unpredictable emotional response

Question 5

Describe frontal lobe activity in SZ?

Answer 5

Low

Question 6

What is the DISC-1 mutation?

Answer 6

Translocation between chromosome 1 and 11 which truncates and activates the DISC-1 gene

Question 7

What does the DISC-1 mutation put you at risk of?

Answer 7

SZ, bipolar and depression

Question 8

What is the normal function of DISC-1?

Answer 8

Required for pyramidal cell migration

Tomita et al 2011

Question 9

What is observed in DISC-1 KO mice?

Answer 9

Abnormal social behaviour
Reduced staining and abnormal interneuron activity

Pletnikov et al 2008

Question 10

What does an inducible expression of DISC-1 in mice show?

Answer 10

Hyperactivity
Abnormal social behaviour
Ventricular enlargement
Reduced gamma synchrony

Pletnikov 2008

Question 11

Give a brief outline of the neurodevelopmental hypothesis of SZ

Answer 11

There is hyperconnectivity between some neurons, and hypoconnectivity between others
Due to the aberrant neuronal migration (seen with the DISC-1 mutation)
This causes synaptic change

Question 12

Outline the schizophrenia hypothesis of developmental oxidative stress

Answer 12

Oxidative stress damages cortical interneurons
Causing altered parvalbumin staining in the prodromal phase
This leads to E/Iimbalance
Then causing EEG alterations and cognitive defects

Question 13

What is observed when monitoring rats with early hippocampal lesions?

Answer 13

Hyperactivity
Hypersensitivity to stress
Working memory deficits
Reduced PPI 
Reduced parvalbumin staining 
Developmental changes in DA 
Altered E/I balance

Question 14

What are endophenotypes?

Answer 14

Simple, quantifiable and heritable biological or behavioural traits
Which segregates an illness

Question 15

What do endophenotypes need to be?

Answer 15

Heritable
Stable across symptom state
Easily and rapidly measured
Reliable

Question 16

What risk factor at age 15/16 can greatly contribute to SZ onset? How?

Answer 16

Cannabis consumption

Greatly decreases the density of glutamatergic synapses

Question 17

Where are the defects which lead to abnormal sensory gating?

Answer 17

Near the alpha 7 nicotinic receptor on chromosome 15

Question 18

What does the P50 wave abnormality on EEG mean?

Answer 18

SZ patients cannot filter out repetitive sensory stimuli

Clock ticking, etc

Question 19

Which other group of people is the P50 Wave defect seen in?

Answer 19

Relatives of SZ patients who don’t have SZ

Question 20

Which abnormal wave form in SZ in associated with “oddball detection”?

Answer 20

p300 wave

Question 21

What is pre-pulse inhibition?

Answer 21

When a prior stimuli gives a warning of a secondary event

There should be less of a startle response to the secondary event

Question 22

Describe PPI and startle inhibition in SZ

Answer 22

Both deficient

Unable to reduce the startle response

Question 23

Why do we think that dopamine is relevant to PPI?

Answer 23

Haloperidol is a d2 receptor antagonist
This reverses the PPI impairment in rodents
Implies too much dopamine is the cause

Question 24

Explain the dopamine hypothesis

Answer 24

Antipsychotics seem effective and they block d2 receptors
Elevated number of d2
receptors in SZ post-mortem
DA administration causes psychosis

Question 25

What evidence goes against dopamine being the only pathology in SZ?

Answer 25

DA altering drugs (ie haloperidol) can take minutes/hours to modify the DA levels But weeks to become effective as antipsychotics

Question 26

Which other systems may be abnormal in SZ?

Answer 26

GABA and GLU

Question 27

Abnormalities in the mesolimbic system are responsible for which group of symptoms?

Answer 27

Positive

Question 28

Abnormalities in the PFC account for which group of symptoms?

Answer 28

Negative

Question 29

What evidence is there that cholinergic pathways are involved in SZ?

Answer 29

Treatment with alpha-7 agonists improves memory and attention Defects in sensory gating are in the gene locus of the alpha 7 receptor Post-mortem studies show reduced alpha 7 recs in the PFC Increased smoking levels in SZ

Question 30

Outline the glutamate hypothesis in

Answer 30

GLU reduced in CSF in SZ Mutations found in genes which code for GLU postsynaptic density proteins Under-expression of GluN1 shows social isolation, motor problems and hyperactivity which is reversed by antipsychotics (Bear et al 2016)

Question 31

What evidence is there that NMDAR is involved in SZ?

Answer 31

Reduced NMDAR-mediated excitation of parvalbumin-positive interneurons Ketamine also causes reduced staining (ket is an NMDAR antag) (Keilhoff et al 2004)

Question 32

Explain the GABA hypothesis of SZ

Answer 32

Reduced GABA synthesis and reuptake in parvalbumin positive interneurons

Question 33

What other environmental factors affect schizophrenia risk?

Answer 33

Intrauterine stress Perinatal infection City living

Question 34

What does mismatch negativity mean in terms of SZ?

Answer 34

SZ patients have no EEG pattern to suggest they are aware of an "odd one out" of a group ie a tone with a higher pitch than others

Question 35

How does mismatch negativity error correlate to clinical disease?

Answer 35

There is more error (ie wave is less negative) with the symptom progression (Control, at risk, recent onset, chronic) (Rissling and Light 2010)

Question 36

Why is the pharmacological stimulant model of SZ not perfect?

Answer 36

Stimulant induced hyperactivity as this causes psychosis in humans Antipsychotics suppres this hyperactivity not specific to SZ thought (its seen in mania and ADHD) And doesn't develop, SZ is progressive like Probs more info about drugs

Question 37

How can hyperactivity be measured in rodent models?

Answer 37

Open field activity | Intellicage