SZ - Basic Science Flashcards
Which NIMH research domains is SZ studied under?
Cognitive impairment
Anhedonia
Which aspects of SZ can be modelled in rodents?
Locomotor changes Psychomotor agitation Sensory gating abnormality Alteration in NTM levels Changes in cellular function
Describe the speech abnormalities in SZ
Word salad and knights move thinking
Perseveration
Rhyming
What abnormalities in action are seen in SZ?
Difficulty starting or finishing tasks
Bizarre behaviours with lack of purpose
Unpredictable emotional response
Describe frontal lobe activity in SZ?
Low
What is the DISC-1 mutation?
Translocation between chromosome 1 and 11 which truncates and activates the DISC-1 gene
What does the DISC-1 mutation put you at risk of?
SZ, bipolar and depression
What is the normal function of DISC-1?
Required for pyramidal cell migration
Tomita et al 2011
What is observed in DISC-1 KO mice?
Abnormal social behaviour
Reduced staining and abnormal interneuron activity
Pletnikov et al 2008
What does an inducible expression of DISC-1 in mice show?
Hyperactivity
Abnormal social behaviour
Ventricular enlargement
Reduced gamma synchrony
Pletnikov 2008
Give a brief outline of the neurodevelopmental hypothesis of SZ
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
Outline the schizophrenia hypothesis of developmental oxidative stress
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
What is observed when monitoring rats with early hippocampal lesions?
Hyperactivity Hypersensitivity to stress Working memory deficits Reduced PPI Reduced parvalbumin staining Developmental changes in DA Altered E/I balance
What are endophenotypes?
Simple, quantifiable and heritable biological or behavioural traits
Which segregates an illness
What do endophenotypes need to be?
Heritable
Stable across symptom state
Easily and rapidly measured
Reliable
What risk factor at age 15/16 can greatly contribute to SZ onset? How?
Cannabis consumption
Greatly decreases the density of glutamatergic synapses
Where are the defects which lead to abnormal sensory gating?
Near the alpha 7 nicotinic receptor on chromosome 15
What does the P50 wave abnormality on EEG mean?
SZ patients cannot filter out repetitive sensory stimuli
Clock ticking, etc
Which other group of people is the P50 Wave defect seen in?
Relatives of SZ patients who don’t have SZ
Which abnormal wave form in SZ in associated with “oddball detection”?
p300 wave
What is pre-pulse inhibition?
When a prior stimuli gives a warning of a secondary event
There should be less of a startle response to the secondary event
Describe PPI and startle inhibition in SZ
Both deficient
Unable to reduce the startle response
Why do we think that dopamine is relevant to PPI?
Haloperidol is a d2 receptor antagonist
This reverses the PPI impairment in rodents
Implies too much dopamine is the cause
Explain the dopamine hypothesis
Antipsychotics seem effective and they block d2 receptors
Elevated number of d2
receptors in SZ post-mortem
DA administration causes psychosis
What evidence goes against dopamine being the only pathology in SZ?
DA altering drugs (ie haloperidol) can take minutes/hours to modify the DA levels
But weeks to become effective as antipsychotics
Which other systems may be abnormal in SZ?
GABA and GLU
Abnormalities in the mesolimbic system are responsible for which group of symptoms?
Positive
Abnormalities in the PFC account for which group of symptoms?
Negative
What evidence is there that cholinergic pathways are involved in SZ?
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
Outline the glutamate hypothesis in
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)
What evidence is there that NMDAR is involved in SZ?
Reduced NMDAR-mediated excitation of parvalbumin-positive interneurons
Ketamine also causes reduced staining (ket is an NMDAR antag) (Keilhoff et al 2004)
Explain the GABA hypothesis of SZ
Reduced GABA synthesis and reuptake in parvalbumin positive interneurons
What other environmental factors affect schizophrenia risk?
Intrauterine stress
Perinatal infection
City living
What does mismatch negativity mean in terms of SZ?
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
How does mismatch negativity error correlate to clinical disease?
There is more error (ie wave is less negative) with the symptom progression
(Control, at risk, recent onset, chronic)
(Rissling and Light 2010)
Why is the pharmacological stimulant model of SZ not perfect?
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
How can hyperactivity be measured in rodent models?
Open field activity
Intellicage
