Download Developmental - Schizophrenia Research Forum

7/20/2016
Schizophrenia Research Forum: Animal Models
Print this page
Animal Models: Developmental
NAME
DA-RELATED
BEHAVIOR
GATING
COGNITIVE BEHAVIOR
SOCIAL BEHAVIOR
MOLECULAR AND/OR
MORPHOLOGICAL
SIGNATURE
RESPONSE TO APD
24-Hour Maternal
Deprivation on
Postnatal Day 9, Rat
Disrupted PPI, Effect
develops after puberty.
Males only: neuronal
degeneration and increased
GFAP+ cells in cerebellum;
neuronal degeneration and
increased astrocytes in
hippocampus Both sexes:
altered cannabinoid receptor
expression in hippocampus;
increased plasma
glucocorticoid levels;
increased levels of 5- HT in
the prefrontal cortex,
hippocampus, and striatum
(some changes sex
dependent); increased levels
of DA in the prefrontal cortex
and striatum
Haloperidol reverses PPI
deficit.
Antimitotic Agent
(MAM or AraC), Rat
Enhanced response to
amphetamine and MK801 (post-puberty)
Disrupted PPI (postpuberty)
Learning deficits in
Morris water maze,
object recognition, and
attentional set-shifting;
no change in 5-choice
serial reaction time task
Decreased social
interaction (deficit
present prior to puberty)
Reduced hippocampal
volume; alterations of NMDAR
protein levels and function in
the hippocampus; increased
neuron density in prefrontal
cortex; enhanced NAc DA
release to amphetamine;
increased firing of
dopaminergic neurons;
enlarged lateral and third
ventricles
Increased response to MK801 was attenuated by
risperidone, haloperidol, and
clozapine
Fetal Irradiation,
Monkey
Impaired working
memory
Mid-gestational irradiation
decreases both gray and
white matter in frontal cortex.
Isolation Rearing, Rat
Enhanced
amphetamine-induced
locomotion and DA
release (straindependent)
Disrupted PPI (straindependent)
Performance on Morris
water maze and T-maze
appears normal
Impaired novel object
recognition, attentional
set-shifting, and
performance on Morris
water maze
Increased social
interaction and
aggression (males);
impaired social
recognition
Reduced PFC volume (neuron
# unchanged) and GAT-1
expression; altered accumbal
protein expression (some
correlated with PPI deficits);
reduced accumbal dendritic
length and spine density;
altered NMDA receptor mRNA
and protein expression in the
hippocampus and prefrontal
cortex; enhanced amplitudes
of hippocampal voltagedependent transient outward
K+ currents
Raclopride reversed PPI
deficit
Maternal Malnutrition,
Rat
Enhanced
amphetamine- but not
MK-801-induced
locomotion and
apomorphine-induced
stereotopy; (females
only with post-pubertal
onset)
Disrupted PPI (females
only with post-pubertal
onset)
Increases in NMDA receptor
binding (sex- and regionspecific); increased DA
receptor binding and
decreased DA transporter
binding in striatum (females
only)
Neonatal Immune
Challenge: Borna
Disease Virus, Rat
Enhanced novelty
induced locomotor
activity in Fisher rats;
enhanced
amphetamine-induced
locomotion
Disrupted PPI in Fisher
rats
Reduced social
interaction
Impairs BDNF
synaptogenesis; prefrontal
cortex thinning; loss of
cerebellar Purkinje neurons;
increased norepinephrine and
5-HT levels in cortex and
cerebellum (post-pubertal)
Placental
Insufficiency/Birth
Insults, Rat
Enhanced
amphetamine-induced
locomotion and
accumbal dopamine
release
Disrupted PPI (postpubertal onset)
Performance on Morris
water maze and T-maze
appears normal
Reduced DA release in PFC,
increased DAT in NAc (basal),
decreased DA receptor
expression; reduced dentate
granule cells; region- and agespecific alterations in dendritic
spine development; altered
expression of presynaptic
genes; decreased caudateputamen volume
PPI deficits reversed by
clozapine
Prenatal Immune
Challenge: Human
Decreased open field
exploration
Impaired PPI
Impaired social
interaction
Reduced reelin expression in
cortex layer 1; increased
Clozapine and
chlorpromazine increase
http://www.schizophreniaforum.org/res/animal/defaultprint.asp?modelType=44
1/3
7/20/2016
Schizophrenia Research Forum: Animal Models
Influenza Virus
pyramidal cell density; cortical
and callosal atrophy; reduced
5-HT levels in cerebellum
atrophy; altered expression of
myelination genes in the
cerebellum; reduced 5-HT
levels in cerebellum;
increased 5-HT2A receptor
expression in frontal cortex
PPI – hyper-reversal of PPI
deficit
Prenatal Immune
Challenge: LPS, Rat
Increased
amphetamine-induced
locomotion
Enhanced acoustic
startle; disrupted PPI
(worse in males)
Impaired object
recognition (postpuberty)
Reduced social
interaction, possibly due
to increased anxiety
Reduced dendritic complexity
in PFC and hippocampus;
increased accumbal DA and
striatal DOPAC; elevated
serum and fetal brain cytokine
levels; altered frontal
synaptophysin expression;
reduced parvalbuminexpressing neurons in the
hippocampus; down regulated
expression of several genes
involved in neurogenesis and
neuronal migration; (direction
of some changes are agedependent)
PPI deficit and elevated
serum cytokines both
reversed by haloperidol
Prenatal Immune
Challenge: PolyI:C
(Delivery Timing
Varies)
No change in total
distance traveled in
open field but reduced
center exploration;
increased response to
amphetamine and MK801 (emerges after
puberty; not rescued by
cross-fostering)
Disrupted PPI (postpuberty; deficits not
rescued by crossfostering)
Reduced escape
latency in Morris water
maze; impairment in
novel object recognition
memory; deficits in
latent inhibition (postpuberty; deficits not
rescued by crossfostering);
electrophysiology:
reduced theta oscillation
generated in the CA1
area of the
hippocampus
Reduced social
interaction
Increased DA turnover and
reduced binding to D2
receptors in striatum; reduced
reelin- and parvalbuminexpressing neurons in PFC;
reduced DA levels and D1
receptors in PFC; increased
TH expression in striatum;
reduced density of cerebellar
Purkinje cells; delayed
myelination of hippocampus;
reduced parvalbuminexpressing neurons in the
hippocampus; enlargement of
lateral ventricles; impaired
synaptic development of
upper-layer neurons
Disrupted PPI was improved
by clozapine and
chlorpromazine; deficits in
latent inhibition and novel
object recognition memory
were improved by clozapine
but not haloperidol; deficits
in Morris water maze were
improve by clozapine
Prenatal Immune
Challenge: PolyI:C
(Delivery Timing
Varies), Rat
Increased response to
amphetamine (emerges
after puberty); in moms
that lost or gained little
weight offspring showed
attenuated hyperactivity
in response to MK-801
Disrupted PPI (possibly
sex dependent)
Disrupted latent
inhibition (post-puberty);
impaired novel object
recognition; classical
fear conditioning, active
avoidance, water maze
and discrimination
learning appear normal
Amphetamine-induced DA
release increased; increased
hippocampal pyknotic cells
Deficit in latent inhibition
was improved by clozapine
and haloperidol; altered
response to amphetamine
was attenuated by
adolescent treatment with
fluoxetine and aripiprazole
Prenatal Restraint
Stress
Increased novelty
induced locomotor
activity; enhanced MK801induced locomotion
Impaired PPI
Deficits in object
recognition memory and
contextual fear
conditioning
Reduced social
interaction
Abnormal Purkinje cell growth
and dendritic atrophy; glial
deficits in the hippocampus
(female specific); overexpression of DNMTs mRNA
in the frontal cortex;
decreased GAD67, reelin, and
mGlu2 and mGlu3 receptor
protein levels in the frontal
cortex; altered neuronal
migration
Clozapine reversed deficits
in PPI and social interaction;
increased locomotive
response to MK-801 was
attenuated by clozapine;
phenotypic rescue with
mGluR2/3 agonist or
valproic acid
Prenatal Restraint
Stress, Rat
Increased novelty
induced locomotor
activity
No disruption in PPI
Memory deficits during
Y maze and radial arm
maze; no apparent
deficits in latent
inhibition, may or may
not show spatial
memory defict in water
maze task
Increased expression of D2like and NMDA receptors in
the frontal cortex and
hippocampus; prolonged
corticosterone stress
response and decreased
expression of central
corticosteroid receptors
(sensitive to cross-fostering);
increased basal dopamine
and decreased noradrenaline
output in the nucleus
accumbens; decreased basal
noradrenaline output in the
prefrontal cortex; apical
dendritic atrophy and altered
spine density in the
hippocampus; decrease
neurogenesis in hippocampus
Maternal fluoxetine
treatment improves
hippocampal neurogenesis
and reverses anxiety
behaviors in stressed
offspring
Prenatal Variable
Stress (GD1-7)
Altered learning and
memory during a
modified Barnes maze
task (sex specific;
timing specific)
Increased plasma
glucocorticoid levels following
stress; altered expression of
glucocorticoid receptor
expression in the
hippocampus;
dysmasculinization of
offspring and second
generation offspring (paternal
http://www.schizophreniaforum.org/res/animal/defaultprint.asp?modelType=44
2/3
7/20/2016
Schizophrenia Research Forum: Animal Models
stress lineage) via epigenetic
programming
Prenatal Variable
Stress, Rat
Increased response to
amphetamine and PCP
with post-pubertal onset
Disrupted PPI and N40
Impaired object and
social recognition;
deficits in Morris water
maze; impaired cued
and contextual fear
conditioning;
impairment in sustained
attention and inhibitory
response control
Impaired social
interaction present in
adolescent and adult
rats; reversal by
oxytocin; no effect of
cross-fostering
NMDA, GABAergic and
presynaptic protein
dysregulation; reduced
hippocampal neurogenesis
and hippocampal volume;
decreased BDNF protein
expression in the
hippocampus (strain
dependent); altered pattern of
apical dendritic maturation of
pyramidal neurons (males
only)
Social interaction deficit not
improved by haloperidol
Prenatal Vitamin D
Insufficiency, Rat
Enhanced MK801induced locomotion;
enhanced
amphetamine-induced
locomotion (females
only)
No disruption in PPI
No deficit in social
behavior
Enlarged lateral ventricles;
thinned cortex; altered brain
expression of proteins
involved in mitochondrial
function, calcium
homeostasis, and synaptic
plasticity; decreased
neurogenesis
Haloperidol ameliorated
effects on neurogenesis
http://www.schizophreniaforum.org/res/animal/defaultprint.asp?modelType=44
3/3