Research Models of Autism

Question 1

What are the phenotypes of ASD?

Answer 1

social deficits

social communication: language deficits

intellectual disability

restricted, repetitive behaviors

Question 2

What are the animal endophenotypes of ASD?

Answer 2

social behavior: social recognition, reciprocal social interactions, social interactions, social approach, social preference

vocalization alteration: atypical ultrasonic vocalizations

cognition: cognitive flexibility

repetitive behavior: hyperactivity, stereotypies

Question 3

What are the animal models of autism?

Answer 3

genetic models involve genes proposed to contribute to ASD (causal models, construct validity) or in systems associated with ASD (associative models, face validity)

environmental models involve known causal risks for ASD (construct validity)

phenotype models reproduce phenotypes of ASD (face validity)

Question 4

What are the genetic models of autism?

Answer 4

FMR1 KO mice

OTR KO mice

OT KO mice

CD38 KO mice

Question 5

What are the environmental models of autism?

Answer 5

prenatal valproic acid

neonatal borna disease virus infection

maternal immune activation (MIA)

Question 6

What are the phenotype models of autism?

Answer 6

BTBRT+TF/J mice

BALB/C mice

microtine rodents

Question 7

Why is predictive validity difficult to establish in ASD models?

Answer 7

no current pharmacology treats core symptoms of ASD

antidepressants (depression, anxiety), psychostimulants (attention deficits, impulsivity), and antipsychotics (aggressive, repetitive, and self-injurious behaviors) are used to treat comorbidities and difficult behaviors

anticonvulsants used to treat comorbid seizures

Question 8

How can behavioral therapy be translated to animal models?

Answer 8

individuals with autism are responsive to speech, language, and occupational therapy, predictable environmental enrichment, adherence to routine, and multi-sensory stimulation

animal models are amenable to such manipulations (especially predictable enrichment and multi-modal sensory stimulation paradigms) but are rarely tested

Question 9

What is the social recognition tests for social behavior in rodents?

Answer 9

measure of social memory

rodent introduced to familiar and novel conspecifics and time spent in olfactory investigation measured

decreased time investigating familiar is indicative of memory

Question 10

What is the social preference test for social behavior in rodents?

Answer 10

degree of preference for novel vs. familiar individual

measured by time spent in proximity to novel or familiar rodent in adjacent chambers

preference for social novelty indicative of social motivation

Question 11

What is the partner preference test for social behavior in rodents?

Answer 11

measures bonding between rodents

preference for bonded conspecific measured by time spent in huddle with novel vs. familiar

Question 12

What is the ultrasonic vocalizations test for communication deficits in rodents?

Answer 12

ultrasonic vocalizations are a normal response to acute isolation in pups

indicative of social anxiety

decreased vocalizations is proposed to parallel social communication deficits in ASD

Question 13

How is oxytocin (OXT) involved in autism?

Answer 13

hypophyseal peptide hormone released into the posterior pituitary

normal roles in reproduction, labor, and lactation

recent work recognizes role for oxytocin in pro-social behavior

OXT is a putative pharmacotherapeutic for social deficits in ASD

Question 14

What are putative OXT therapeutics?

Answer 14

as a peptide hormone, OXT administration is challenging due to rapid catabolism and low BBB permeability (half-life of 3 minutes in blood)

intranasal OXT: allows rapid access and moderate permeability across BBB, multiple ongoing trials

non-peptide agonists: BBB permeable agonists for the OXT receptor

OXT releasers: agonists to stimulate OXT releasing neurons

P-LAP inhibitors: antagonists of placental leucine aminopeptidase, the enzyme responsible for degradation of OXT

Question 15

What are BTBR T+TF/J and BALB/C mice?

Answer 15

inbred mouse strains screened for variations in social behavior

BALB/C and BTBR mice showed reduced social behaviors

decreased vocalizations

decreased scent marking

BTBR show altered OTR system

but BTBR pups show increased isolation-induced vocalization

variation in inbred strains arose through independent selection: low construct validity, but high face validity

Question 16

What are microtine rodents?

Answer 16

voles of the genus Microtus show interesting patterns of social behavior

prairie voles (Microtus ochrogaster) lives in colonies and form life-long monogamous bonds

share huddles, grooming, nesting, and pup-rearing responsibilities

the closely related meadow or montane voles inhabit solitary burrows and lacks any of these bonding characteristics

Question 17

What is the difference between montane and prairie voles?

Answer 17

prairie vole and the related montane vole show high variability in social behavior

prairie vole is highly affiliative and socially monogamous

montane and meadow voles are asocial and non-monogamous

differences in developmental and neurological bases of social behavior have been applied to ASD

general model for social behavior

no construct validity for ASD

Question 18

What are the limitations of Microtine rodents?

Answer 18

no construct validity

limited predictive validity

limited face validity

useful model for studying general neurological correlates of social behavior

Question 19

How do early life social interactions impact oxytocin?

Answer 19

maternal care is associated with increased oxytocin (OXT) function/release

maternal separation decreases the expression of OXT, particularly in female offspring

in humans early childhood neglect correlates with decreased OXT levels in urine, and adult women exposed to abuse as a child have decreased OXT in CSF

human infants with high parent-infant synchrony (i.e. enhanced capacity to respond to infant’s socio-affective signals) have increased OXT levels in saliva compared with low parent-infant synchrony

effects seem to be cross-generational

human parents with high parent-infant synchrony also shown increased salivary OXT

Question 20

How do early life social interactions affect adult social behaviors?

Answer 20

early social deprivation induces changes in social behaviors that persist into adulthood in animal models: impaired maternal care, increased/decreased aggression (species-specific), impaired social recognition

female offspring of low-licking/grooming dams (rats) show earlier sexual receptivity

male offspring of low-licking/grooming dams show increased dominant play-fighting behaviors

early social deprivation and enhancement lead to correlations in OXT system function and social behaviors: current studies are investigating causality in animal models

Question 21

What are the three common OXT KO mice models?

Answer 21

OXT KO: prevents release of OT

OTR receptor KO: prevents activity of OT

CD38 KO: inducer of OT release

Question 22

What are oxytocin KO mice?

Answer 22

OXT, OTR, and Cd38 KO all block recognition of familiar conspecifics in social recognition tests

normal sensory and non-social learning and memory

normal habituation to non-social odors

Question 23

What are the specific findings of OTR KO mice?

Answer 23

forebrain-specific OTR KO mice show deficits in social recognition selective to strain background

failure to recognize familiarity of same strain of mice but can discriminate mice of a difficult background

suggestive of OXT involvement in “fine” social discrimination

Question 24

how do OXT and OXT receptor KO mice produce social deficits?

Answer 24

decreased social memory: failure to recognize conspecifics in social recognition tests, normal sensory/olfactory function and non-social learning and memory

decreased isolation anxiety: decreased ultrasonic vocalizations after maternal separation of pups

Question 25

What are OXT system KO mice?

Answer 25

OXT, OTR, CD38 KO mice show decreased vocalizations after isolation from dam and other pups

decreased isolation anxiety and locomotion (attempts to reunite with dam across barrier)

pups show a general increase in locomotion and exploration: thought to reflect decreased anxiety

children with high-function ASD show reduced social stress in Trier social stress test

BUT OXT is anxiolytic and proposed to act in ASD by reducing social anxiety

Question 26

What is predictive validity of KO models?

Answer 26

OXT, OTR, and CD38 KO mice recover social deficits by a single intracerebroventricular injection of OXT

deficits recover if OXT delivered before, but not after initial social exposure

suggests OXT involvement in encoding but not recall of social information

possible role in enhancing saliency of social information

Question 27

How does intranasal OXT affect human social behaviors?

Answer 27

in-OXT improves social function in autism and schizophrenia: increases gaze-fixing on faces, improves social recognition and cognition, improves affective recognition and retention of affective speech, some studies show decreases in repetitive behavior

but limited evidence for role of OXT in heritable cases of autism: deletion of OTR gene in some families, evidence for methylation differences in OTR (epigenetics)

Question 28

How does intranasal OXT alters behavior in healthy controls?

Answer 28

OXT is now being investigated experimentally in a number of human studies looking at specific behaviors

IN-OXT increases social cognition in healthy controls: increased gaze-fixation, increased socio-affective processing

IN-OXT decreases emotional processing: in fMRI studies, OXT groups show decreased activation of the amygdala while viewing frightful faces or threatening scenes

Question 29

What are the limitations of OXT models?

Answer 29

limited evidence of OXT system dysfunction in ASD: low construct validity

OXT enhances social capability in “normal” rodents and humans

possible compensatory mechanism to OXT action rather than direct rescue of ASD deficits

unknown if OXT has impact on other phenotypes of ASD outside social domain

Question 30

What are the environmental models of ASD?

Answer 30

prenatal exposure to valproic acid (anti-convulsant) is a known risk for development of ASD

prenatal exposure in rodents produces behaviors consistent with ASD

decreased social interactions

decreased sensitivity to pain: increased sensitivity to non-painful stimuli

repetitive/stereotypic-like activity

increased anxiety

long-lasting fear memories - difficult to extinguish

altered isolation-induced vocalization

Question 31

What is the VPA model of autism?

Answer 31

decreased spine density and increased dendrite length: suggestive of hypo- and hyper-connectivity phenotypes

behavioral interventions reverse VPA phenotypes: environmental enrichment, multi-sensory stimulation

environmental enrichment and multi-sensorimotor stimulation shown to ameliorate some symptoms in autistic children

Question 32

How is maternal infection related to autism?

Answer 32

maternal infection is associated with an increased risk of developing autism

evidence of inflammation in ASD children that persists into adulthood

elevated cytokines and pathology of microgliosis and astrogliosis in post-mortem ASD brain

elevated cytokines in CSF of ASD children (3-10)

dysregulation of immune genes in autistic brain in microarray studies

Question 33

How is neonatal borna disease virus infection associated with autism?

Answer 33

major human risk for ASD (rubella) is a human-specific infection

BDV is a persistent neurotropic virus capable of infecting humans, rodents, horses, sheep, cattle, and birds

causes persistent, non-lethal infection of neural cells

analogous to in utero rubella infection

first rodent model used to investigate prenatal risk of ASD

Question 34

What is the BDV model of ASD?

Answer 34

rats infected at birth - neonatal period

neuroanatomical deficits: cerebellum, limbic

behavioral deficits: hyperreactivity, circadian rhythm disturbance, social-play deficits, cognitive deficits, chronic anxiety

Question 35

What are the limits of the BDV model of ASD?

Answer 35

persistent infection - not seen in ASD

timing of insult - neonatal (3rd trimester) does not match risk of viral infection in ASD

may reflect the specific neurotoxic effects of infection rather than the maternal immune activation

largely supplanted by MIA models for ASD: POLYI:C model is the preferred system

Question 36

What is maternal immune activation?

Answer 36

POLYI:C effects are moderated indirectly through placental transmission of inflammation

key role for IL-6 in placental transmission of inflammation