Basic Science of Schizophrenia Flashcards
What aspects of SZ can be modelled in animals?
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)
What are some examples of SZ symptoms that cannot be modelled in animals?
Speech abnormalities; loose associations; preservation; rhyming words
Action; difficulty starting or finishing tasks, bizarre behaviour, unpredictable or inappropriate emotional responses
Is there a connection between SZ and the PFC?
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
Is SZ considered a neurodevelopmental disorder?
Yes; growing evidnece that genetic and environmental influences during development play a large role in SZ
What genes are thought to be involved with SZ?
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
What is the function of DISC1?
Progenitor proliferation Neuronal migration Spine regulation Neuronal signalling == Neurodevelopment
Example: necessary for pyramidal (CA1) cell migration
What is the relevance of DISC1 to SZ?
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
What is the neurodevelopmental hypothesis of SZ?
Hyperconnectivity - synaptic connections between neurons that would not usually be present
Synaptic pruning failure
Aberrant neuronal migration
Synaptic changes
What is an endophenotype?
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
Describe the traits of an endophenotype
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.
Describe some environmental RF for SZ??
Neuronal differentiation/ migration:
Intrauterine stress
Perinatal infection
Glutamergic synapse density, dendritic arborization, mesocortical dopaminergic projections:
Urban city
Cannabis
What is the evidence for developmental oxidative stress in SZ pathogenesis?
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
Describe the anomalies in perceptual processing in SZ
Difficulties in filtering out relevant stimuli Attention deficits Impairments in language processing Changes in auditory cortex NOT DIAGNOSTIC OF SZ
What occurs when an auditory stimulus reaches the brain?
Low level automatic process to high level processes
Event related potential (ERP); electrical activity aligned with auditory stimulus
Describe the p50 wave on the ERP signalling
Described as the sensory gating of stimuli
Relevant to SZ; unable to filter out repetitive sensory stimuli
How can the “sensory gating” failure in SZ be tested?
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
Is a failure of sensory gating a diagnostic test?
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
Is there a genetic link to sensory gating abnormalities?
Yes; links to the alpha 7 nicotinic receptor on chromosome 15
Describe the pre-pulse inhibition of an acoustic startle
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
Is there an effect of antipsychotic drugs on PPI response?
Haloperidol (dopamine D2 antagonist) reverses the impairment in PPI caused by stimulant drug (amphetamine) administration
Describe mismatch negativity
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
Does MMN vary with symptomatic progression?
Yes; the size of MMN wave is altered (progressively less) in healthy patients, at risk patients, first episode and chronic SZ
Describe the P300 wave
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
Summarize the neurophysiological measures of sensory processing
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
Describe the dopamine hypothesis in SZ
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
Is there any evidence against the DA hypothesis of SZ?
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
What is probably the most convincing piece of evidence for DA hypothesis in SZ?
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
Describe the mesolimbic vs mesocortical DA projections in SZ?
Mesolimbic hyperactivity (dorsal and ventral striatum and VTA) = positive symptoms Prefrontal (mesocortical) hypoactivity = negative symptoms
THEREFORE; antidopaminergic drugs can worsen negative symptoms
Describe the pharmacological stimulant model of SZ
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
Is the cholinergic system implicated in SZ?
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
Describe the link between smoking and SZ?
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
Are glutamate levels altered in SZ?
Yes;
Glutamate levels are reduced in CSF of SZ patients (post mortem) in the hippocampus and PFC
Are there alterations with glutamate receptors in SZ?
Yes; SZ assoc mutations in genes coding for post-synaptic density proteins and components of the NMDA receptor signalling complex
Does NMDA abnormalities in SZ contribute to the symptoms seen?
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 `
Describe the role of ketamine in SZ pathogenesis as a adjunct to NMDA hypofunction
Ketamine is particularly effective in neurons with high spontaneous activity such as interneurons (fire at higher rates than excitatory cells)
Describe the role of the parvalbumin positive interneuron in SZ pathogenesis
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
What is a parvalbumin positive interneuron?
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
Describe the GABAergic hypothesis of SZ
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
What is the link between gamma frequency and long range synchrony and SZ?
Decreased in SZ
What is interhemispheric synchronization?
Auditory verbal hallucinations that are associated with reduced gamma synchrony between left and right auditory cortices
What is gamma frequency?
Between 30-60 Hz
All to do with neuronal firing
Is there a link between DISC 1 overexpression and gamma frequency?
Yes; DISC 1 overexpression (linked with translocation of genes that correlated with SZ) causes abnormal hippocampal gamma frequency synchronisation
What is one of the major roles of gamma oscillations?
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
What drives gamma oscillations?
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
Describe the role of abnormal gamma synchrony the PFC and its link to SZ
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
