Basic science of schizophrenia

Question 1

What are some aspects of schizophrenia that can be modelled in animals?

Answer 1

Locomotor changes, sensory gating abnormalities, impaired social interactions, alterations in neurotransmitter levels or actions, changes in cellular morphology or function

Question 2

What can happen to speech in people with SZ?

Answer 2

• Loose associations - rapidly shifting between unrelated topics
• Perseveration - repeating the same things over and over again
• Use of rhyming words without reason

Question 3

What actions can be affected in people with SZ?

Answer 3

• Difficulty starting or finishing tasks
• Behaviours that appear bizarre or lack purpose
• Unpredictable or inappropriate emotional responses

Question 4

What impairment in SZ predicts language disturbances?

Answer 4

• Working memory and executive function are impaired in SZ
• fMRI studies reveal task dependent abnormalities in prefrontal activity

Question 5

What is the link between the DISC1 gene and SZ?

Answer 5

• Located in a chromosomal region that contains susceptibiltiy genes for psychiatric illness in several populations
• Truncates (and inactivates) a gene called DISC1
• Affected members have greatly increased risk of psychiatric disorders including SZ but also depression and bipolar

Question 6

What is the function of DISC1?

Answer 6

The DISC1 gene is necessary for pyramidal cell migration

Question 7

What do subjects with induced expression of mutant human DISC1 show?

Answer 7

Hyperactivity, abnormal social behaviour, ventricular enlargement and reduced gamma synchrony

Question 8

What are the features of the neurodevelopmental hypothesis of schizophrenia?

Answer 8

Hyperconnectivity, synaptic pruning failure, aberrant neuronal migration and synaptic changes

Question 9

What are endophenotypes?

Answer 9

Simple, quantifiable and heritable biological or behavioural traits that segregate with an illness

Question 10

What is the role of developmental oxidative stress in SZ?

Answer 10

Oxidative stress in cortical neurons causes altered parvalbumin interneurons which causes an excitation-inhibition imbalance, leading to altered EEG oscillations and cognitive deficits

Question 11

Neonatal hippocampal lesions in rats causes what in adolescence?

Answer 11

Hyperactivity, hypersensitivity to stress, working memory deficits, reduced pre-pulse inhibition (PPI), reduced parvalbumin staining, changes in DA activity, altered cortical E/I balance

Question 12

SZ is associated with abnormal early processing of sensory information, particularly auditory. What could this be related to?

Answer 12

• Difficulties in filtering out irrelevant stimuli
• Attentional deficits Impairments in language processing

Question 13

What is sensory gating?

Answer 13

Neurological processes of filtering out redundant or unnecessary stimuli in the brain from all possible environmental stimuli

Question 14

What proportion of people with SZ and people without SZ showed problems with sensory gating?

Answer 14

• 90% of people with SZ
• 8% of people without SZ

Question 15

What is pre-pulse inhibition (PPI)?

Answer 15

Neurological phenomenon in which a weaker pre-stimulus (pre-pulse) inhibits the reaction to a subsequent strong reflex-eliciting stimulus (pulse), often using the startle reflex

Question 16

What drug has been shown to reverse the impairment in PPI in rodents?

Answer 16

Haloperidol (DA D2 antagonist)

Question 17

What is the problem with reduced PPI in SZ?

Answer 17

It is not specific to SZ, PPI deficits are seen in HD as well

Question 18

What is mismatch negativity?

Answer 18

Mismatch negativity is a negative component of the event-related response in an EEG signal, elicited by any perceptible change in some repetitive aspect of an auditory stimulation e.g. stimulus pitch

Question 19

How is mismatch negativity affected in SZ?

Answer 19

• Reduced in SZ
• Varies with symptom progression, i.e. chronic SZ there will be greater reduction in MMN compared to recent onset SZ

Question 20

What is the P300 wave?

Answer 20

• The P300 wave is an event-related potential (ERP) component elicited in the process of decision making.
• It is considered to be an endogenous potential, as its occurrence links not to the physical attributes of a stimulus, but to a person’s reaction to it.
• It is modulated by attention

Question 21

How is the P300 wave affected in SZ?

Answer 21

Reduced in SZ

Question 22

What kind of drugs can cause psychosis via dopamine pathways?

Answer 22

Amphetamines can elevate brain DA levels and cause psychosis (positive symptoms of SZ)

Question 23

What is some of the evidence for and against the DA hypothesis of SZ?

Answer 23

Evidence for:

• Anti-psychotics block D2 receptors
• Drugs such as amphetamines elevate brain DA levels and cause psychosis
• Elevated D2 receptor levels in people with SZ

Evidence against:

• DA-inhibiting drugs modify DA levels within minutes but can take much longer to be effective as anti-psychotics
• Abnormalities in other systems e.g. GABA and glutamate

Question 24

What is thought to underlie the positive symptoms of SZ?

Answer 24

Hyperactivation of both the mesolimbic and nigrostriatal pathways

Question 25

What is thought to underlie the negative and cognitive symptoms of SZ?

Answer 25

Hypoactivation of the mesocortical pathway

Question 26

What is wrong with the pharmacological stimulant model of SZ?

Answer 26

Hyperactivity is not only observed in SZ - seen in mania and ADHD

Question 27

What is the link between cholinergic pathways and schizophrenia?

Answer 27

• In both animal models and patients with SZ, treatment with alpha7 agonists resulted in improvements in working memory and attention
• Postmortem studies of patients with SZ show a decreased expression of alpha7 receptors in the frontal cortex

Question 28

What is the link between smoking and schizophrenia?

Answer 28

• Around 80% of people with SZ smoke compared to around 20% of the general population
• Alpha 7 nicotinic receptor activation enhances sensory gating
• May improve attention and sensory filtering

Question 29

What is the glutamate hypothesis of SZ?

Answer 29

• Glutamate levels are reduced in the CSF of SZ patients in the hippocampus and PFC
• Genomic studies have revealed SZ-associated mutations in genes coding for post-synaptic density proteins and components of the NMDA receptor signalling complex
• Non-competitive NMDAR antagonists such as ketamine cause SZ like symptoms in humans and animals

Question 30

What evidence is there to back up the glutamate hypothesis?

Answer 30

• Ketamine administration causes a loss of parvalbumin staining in mice
• Transgenic mice underexpressing NMDA GluN1 subunits show social isolation, hyperactivity and motor stereotypes - effects reversed by anti-psychotics

Question 31

What happens to power and synchronisation of hippocampal gamma oscillations in SZ?

Answer 31

• Gamma-frequency power and long-range synchrony are reduced in SZ
• Inter-hemispheric synchronisation - auditory verbal hallucinations are associated with reduced gamma synchrony between left and right auditory cortex

Question 32

What has DISC1 overexpression in mice been shown to do to gamma frequency synchronisation?

Answer 32

DISC1 overexpression in mice causes abnormal hippocampal gamma-frequency synchronisation