Animal Models of Schizophrenia Flashcards
What are the animal endophenotypes of positive symptoms?
amphetamine-induced locomotion
sensory gating impairment
What are the animal endophenotypes of negative symptoms?
locomotion tests
social tests
sustained attention tasks
reward/pleasure tests
cognitive tests
What are the ongoing controversies in psychiatry?
validation crisis: only publishing positive outcomes
sensitivity to placebo effect: MDD
DSM-5 controversies
disorder heterogeneity: categorization used in diagnostics and research has hindered progress
What is research domain criteria (RDoC)?
developing initiative to provide a biologically-relevant framework for the understanding of mental disorders
proposed alternative to the DSM-V for both clinicians and researchers
proposes to modernize psychiatric illness by moving away from strictly symptom-based diagnostics
What are RDoC domains?
dimensional - ranges from normal to abnormal
inclusive of clinical symptoms
informed by genetic, cell, circuit, molecular, physiological, and system-level insights
“agnostic” to existing categories of illness
What are examples of RDoC domains?
negative valence: stress, fear, anxiety, loss
positive valence: motivation, reward learning, reward valuation
cognitive systems: attention, perception, working memory, cognitive control
social processing: attachment formation, social communication, perception of self, affiliation
arousal/modulatory: arousal, circadian rhythm, sleep and wakefulness
What is the negative valence domain in schizophrenia?
30-85% comorbidity with anxiety symptoms
30-41.5% comorbidity with anxiety disorder
comorbid stress/anxiety severity dependent on incidence of positive symptoms (hallucination, delusions)
What is the positive valence domain in schizophrenia?
motivational deficits: mediate abnormal cognition, social cognition
anhedonia
impaired reward representation, reward-learning, motivation for incentives: mesocorticolimbic and mesostriatal dopaminergic pathways
What is the cognitive valence domain in schizophrenia?
attentional deficits: impact on social function, anxiety, gating
working memory impairments: PFC and hippocampal circuits
impaired sensory gating mechanism: mesolimbic DA pathway
What is the social processing domain in schizophrenia?
decreased social drive: social withdrawal, decreased social interest
longitudinal studies show early social deficits: poor socialization before age 10 in 60% of individuals who later developed SCZ, early socialization deficits associated with increased risk of developing psychosis before 17
What is the pre-pulse inhibition test (PPI)?
test of sensory gating: proxy for positive symptoms
startle response recorded in response to auditory tone
low intensity (3-12 dB) pre-pulse (30-500 ms) results in inhibition of startle response (PPI)
SCZ patients (and unaffected relatives) have impaired PPI at 60 ms
What is PPI measurement in rodents?
PPI is readily reproduced in rodents
PPI deficits induced by: DA-receptor agonists, 5-HT2 receptor agonists
What is the CANTAB battery?
Cambridge neuropsychological test automated battery
developed at Cambridge in the 80’s
recently adapted for rodents
22 touch-screen based tests examining:
general memory and learning
working memory and executive function
visual memory
attention and reaction time
semantic/verbal memory
decision making and response control
What are amphetamine-induced locomotion tests?
amphetamines induce rapid DA release and cause locomotor hyperactivity: increased DA tone in the nigrostriatal pathway
antipsychotics acting at DA receptors can inhibit the locomotor effects
widely used for drug screening (biased towards DA receptor antagonists)
predictive validity, but lacking any face or construct validity
What is the psychedelic-induced head-twitch response?
hallucinogenic drugs (5HT2A receptor agonists, i.e., LSD) induce a head-twitch response in rodents
LSD was once considered to be a psychotomimetic drug in humans: hallucinations considered to be vastly different and lacking as model of psychosis
atypical antipsychotics having action at 5HT2A receptor will block the head-twitch response
some predictive validity for atypical antipsychotics
What are the models of schizophrenia in rodents?
genetic: DBA/2J mice, db/db mice, PSD-93/Dlg2 mice
environmental: maternal protein malnutrition, maternal immune activation
pharmacological: phencyclidine (PCP)
What are DBA/2J mice?
the oldest inbred mouse strain: mouse inbreeding uses sibling-sibling crosses to reach effective genetic homogeneity
compares with C57BL/6J in popularity and variability of use
spontaneously develops SCZ-like symptoms
What is negative valence in DBA/2J mice?
increased stress and anxiety-like behaviors
avoidance of open-field
decreased exploration of elevated plus maze
increased latency, fewer entries in light/dark box
lack of preference for novel objects
immobility in FST
What is positive valence in DBA/2J mice?
impaired sucrose preference
insensitivity to ethanol, nicotine, amphetamine, morphine
measurable differences in mesolimbic dopamine system
What is the cognitive domain in DBA/2J mice?
impaired auditory PPI: PPI restored with typical or atypical antipsychotic treatment
complete absence of tactile PPI
lack of contextual blocking in fear conditioning
poor performance in learning and memory tasks
hippocampal and amygdala structural alterations
What is the social processing domain in DBA/2J mice?
no differences from C57BL/6J
What is the arousal domain in DBA/2J mice?
poor studied
What are db/db mice?
leptin receptor-deficient mouse strain
leptin is an adipose-derived hormone controlling satiety
spontaneous mutant on the C57BL/6 line
common model for obesity and diabetes
What is the negative domain in db/db mice?
increased anxiety
susceptible to learned helplessness
increased immobility in FST
What is the positive domain in db/db mice?
poorly studied
decreased preference for voluntary ethanol consumption
What is the cognitive domain in db/db mice?
age-dependent decreased PPI emerging after puberty
impaired spatial learning
normal object recognition
impaired LTP/LTD in hippocampal CA1
What are the phenotypes of db/db mice?
arousal domain changes
no social deficits
obesity confounds locomotor tasks
predictive validity not established
What are PSD-93/Dlg2 mice?
PSD93 is a membrane associated guanylate kinase
analog of PSD95
formation of NMDAR-associated signaling complexes in the post-synaptic density
polymorphisms identified in human SCZ patients
increased transcript, decreased protein expression reported in PFC and ACC in post-mortem SCZ tissues
What is the limited behavioral characterization in PSD-93/Dlg2 mice?
negative domain, positive domain, arousal domain, social domain
one of the first demonstration of deficits induced by an identified SCZ polymorphisms
What is the cognitive domain in PSD-93/Dlg2 mice?
impaired visual discrimination
impaired cognitive flexibility
impaired visuo-spatial learning and memory
correlations between CANTAB test battery (SCZ humans) and CANTAB-based touchscreen operant behavioral assay (mice)
What is the maternal protein malnutrition model?
models adverse early environmental events seen as risk in SCZ
prenatal protein malnutrition leads to increased anxiety-like behaviors
coupled with elevated corticosterone response
What are the positive domains of the maternal protein malnutrition model?
decreased motivation to earn reward
decreased sucrose preference
What are the cognitive domains of the maternal protein malnutrition model?
age-dependent decreased PPI
increased striatal NMDAR binding
impaired memory acquisition in operant conditioning
impaired hippocampal DG LTP
What is phencyclidine (PCP)?
NMDAR antagonist
inhibits hippocampal and cerebellar activity
cortical hyperactivity
dissociative and hallucinogenic
What are the effects of PCP in humans?
induces both positive and negative symptoms
psychosis, hallucinations, paranoia
emotional withdrawal, motor retardation
formal thought disorder and neuropsychological deficits
What are the negative domains of PCP phenotypes?
hyperlocomotion - (anxiety?)
inconsistent changes in anxiety tasks
learned helplessness in FST
What are the positive domains of PCP phenotypes?
decreased sucrose preference
decreased conditioned food-reward
possibly confounded by attention deficits
What are the cognitive domains of PCP phenotypes?
impairments: attentional set shifting, cognitive flexibility, processing speed, novel-object recognition, spatial learning, episodic memory, sensorimotor gating (PPI)
PFC and hippocampal deficits implicated
increased startle response
What are the social domains of PCP phenotypes?
attenuated social interaction
