realistic expectations of prepulse inhibition in translational ......review realistic expectations...

REVIEW

Realistic expectations of prepulse inhibition in translationalmodels for schizophrenia research

Neal R. Swerdlow & Martin Weber & Ying Qu &Gregory A. Light & David L. Braff

Received: 17 September 2007 /Accepted: 3 January 2008 / Published online: 21 June 2008# Springer-Verlag 2008

AbstractIntroduction Under specific conditions, a weak lead stim-ulus, or “prepulse”, can inhibit the startling effects of asubsequent intense abrupt stimulus. This startle-inhibitingeffect of the prepulse, termed “prepulse inhibition” (PPI), iswidely used in translational models to understand thebiology of brain based inhibitory mechanisms and theirdeficiency in neuropsychiatric disorders. In 1981, fourpublished reports with “prepulse inhibition” as an indexterm were listed on Medline; over the past 5 years, newpublished Medline reports with “prepulse inhibition” as anindex term have appeared at a rate exceeding once every2.7 days (n=678). Most of these reports focus on the use ofPPI in translational models of impaired sensorimotor gatingin schizophrenia. This rapid expansion and broad applica-tion of PPI as a tool for understanding schizophrenia has, attimes, outpaced critical thinking and falsifiable hypothesesabout the relative strengths vs. limitations of this measure.Objectives This review enumerates the realistic expect-ations for PPI in translational models for schizophreniaresearch, and provides cautionary notes for the futureapplications of this important research tool.Conclusion In humans, PPI is not “diagnostic”; levels ofPPI do not predict clinical course, specific symptoms, orindividual medication responses. In preclinical studies, PPI

is valuable for evaluating models or model organismsrelevant to schizophrenia, “mapping” neural substrates ofdeficient PPI in schizophrenia, and advancing the discoveryand development of novel therapeutics. Across species, PPIis a reliable, robust quantitative phenotype that is useful forprobing the neurobiology and genetics of gating deficits inschizophrenia.

Keywords Animal models . Antipsychotic . Dopamine .

Prepulse inhibition . Schizophrenia . Sensorimotor gating .

Startle

Introduction

Among the paths to understanding the neurobiology ofschizophrenia, one heavily traveled, has been the studythrough preclinical and clinical models of sensorimotorgating and its neural and genetic substrates. A laboratoryparadigm frequently used to operationally measure senso-rimotor gating is prepulse inhibition of the startle reflex(PPI). Medline lists over 1400 published reports utilizingthe key word “prepulse inhibition” and over 580 that alsoinclude the key word “schizophrenia”. Research using PPIto probe the neural and genetic bases of schizophrenia hascrossed every level of the “top down” and “bottom up”investigations of this disorder—from studies of thepsychological implications of PPI to those assessingthe control of PPI by signal transduction pathways andthe genes that regulate them. Arising implicitly andexplicitly from such a broad application of the PPIparadigm have been assumptions and expectations thatwe hope to examine critically in this review. In so doing,we hope to offer some perspectives on both potentiallyproductive directions of this work, and the degree to

Psychopharmacology (2008) 199:331–388DOI 10.1007/s00213-008-1072-4

Neal R. Swerdlow and Martin Weber contributed equally to this work.

N. R. Swerdlow :M. Weber :Y. Qu :G. A. Light :D. L. BraffDepartment of Psychiatry, UCSD School of Medicine,La Jolla, CA 92093-0804, USA

N. R. Swerdlow (*)Department of Psychiatry, University of California, San Diego,9500 Gilman Drive,La Jolla, CA 92093, USAe-mail: [email protected]

which some assumptions and expectations may, or maynot, be reasonable.

Historical overview

The popularity of PPI as an experimental paradigm for under-standing schizophrenia comes from its conceptual linkage toclinical observations that schizophrenia patients are unable tooptimally filter or “gate” irrelevant, intrusive sensory stimuli(Bleuler 1911; Kraepelin and Robertson 1919; McGhie andChapman 1961; Venables 1964). These clinical observationsled to the formulation of a construct—“gating deficits” inschizophrenia—that has been extended to refer to deficientinhibition of both sensory and cognitive information. The PPIparadigm was developed as a measure of automatic or pre-conscious inhibition in normal comparison subjects, as onevariant of numerous paired-pulse paradigms in which thepresentation of a lead stimulus led to the reduced perceptualor motor response to a second stimulus (Peak 1939; Graham1975) (Fig. 1). Braff et al. (1978) first merged the constructand its operational measurement by identifying PPI deficitsin schizophrenia patients, a finding that has since beenreplicated by many independent groups and [as reviewedpreviously (Braff et al. 2001b) and below], has becomeamong the most influential paradigms in the field ofschizophrenia psychophysiology. A comprehensive reviewthrough the year 2000 of all reports linking PPI deficits toschizophrenia in clinical populations is found in Braff et al.(2001b); reports subsequent to this date are listed in Table 1.Animal studies first linked this finding to a neurochemical(DA) and anatomical (ventral striatum) substrate (Sorensonand Swerdlow 1982; Swerdlow et al. 1986), and subsequentreports centered these substrates within an extended forebrainand pontine circuit that regulates PPI in rodents (Koch andSchnitzler 1997; Swerdlow et al. 1992, 2000a; see Table 4).Animal studies have identified developmental (Geyer et al.1993; Lipska et al. 1995; see Table 3) and genetic (Carter etal. 1999; Ralph et al. 1999; Geyer et al. 2002; see Table 3)influences on PPI and have led to predictive models forantipsychotic development (Swerdlow et al. 1994) that havebeen modified and widely applied towards antipsychoticdiscovery. A comprehensive review through theyear 2000 of all reports using PPI in models predictingantipsychotic properties is found in Geyer et al. (2001);reports subsequent to this date are listed in Table 2.

This quantitative physiological abnormality in schizo-phrenia patients, conceptually linked to an intuitive clinicalconstruct and neurochemical, anatomical, developmental,and genetic substrates, has provided a powerful focus forscientific developments. With the rapid expansion andbroad application of variations of PPI measures, newexpectations for its use to inform us about the biology of

schizophrenia have at times outpaced critical thinking andfalsifiable hypotheses about the relative strengths vslimitations of these complex studies. Here, we hope toenumerate some of these expectations and the futurepromises and potential limitations of PPI studies.

Human studies: What can our field realistically expectto learn about schizophrenia based on studies of PPIin humans?

Diagnosis

As an isolated measure, PPI is not a “diagnostic instru-ment”. There is substantial variability and significantoverlap in PPI distributions among normal and disorderedpopulations. In addition, there are many different disorders

Fig. 1 Schematic representation, adapted from Swerdlow et al.(1994), of stimuli used to elicit PPI in laboratory measures (a). bshows superimposed tracings of electromyography of the rightorbicularis oculi in an adult male subject, from sequential trials thatincluded either a prepulse [20 ms noise burst 4 dB over a 70-dB(A)background] followed 100 ms later by a 118-dB(A) 40 ms startle noisepulse (solid black area), or the startle pulse alone (open area).Tracings in (b) begin at pulse onset. The amount of inhibitiongenerated by the prepulse can be appreciated visually by subtractingthe solid area from the open area

332 Psychopharmacology (2008) 199:331–388

Tab

le1

Studies

ofPPIin

schizoph

reniapatientsandrelatedgrou

ps,ca.20

01–2

007a

I.Studies

repo

rtingPPIdeficitsin

schizoph

reniapatients

II.Studies

repo

rtingPPIdeficitsin

subg

roup

sof

schizoph

reniapatients

III.Studies

repo

rtingPPIdeficitsin

schizoph

reniapatientsun

derspecific

experimentalcond

ition

sIV.Studies

repo

rtingPPIdeficitsin

schizoph

reniapatients

V.Studies

repo

rtingPPIdeficitsin

popu

latio

nsconceptually

linkedto

schizoph

renia

Reference

Sex,medications,n,

othercharacteristics

PPIdeficitscompared

tono

rmal

comparison

subjects(N

CS)?

Other

measuresor

factorsexam

ined

inrelatio

nto

PPIb

Eye

side

Backg

roun

dDBc

Startle

stim

uli

Prepu

lsestim

uli

Prepu

lse

interval

(ms)

I.StudiesreportingPPIdeficitsin

schizop

hrenia

patients

Braffet

al.20

05F,

MED

(n=25

)Yes

R70

40ms115dB

WN

20ms78and86

dBWN

30,12

0Cadenhead

etal.20

02M/F

10/11,

MED

(n=4),UNMED

(n=17

)33

%of

PTS<1SD

ofPPIof

NCS

Medication,

clinical

characteristics,

P50

,AS

R,L

7040

ms115dB

WN

20ms86

dBWN

30,12

0

Dun

canet

al.20

03a

M,MED

(n=27

),UNMED

(n=14

)Yes

Medication

R70

40ms116dB

1KHz

20ms85

dB1KHz

30–1

20

Dun

canet

al.20

03b

M,stud

y1:

pre-

and

post-m

edication(n=16

);stud

y2:

MED

(n=43

),UNMED

(n=21

)

Yes,independ

ent

ofmedicationstatus

Medication

R70

40ms116dB

1KHz

20msdB

1KHz

30–1

20

Heresco-Levyetal.2

007

M/F

18/12,

MED

Yes

Clin

ical

characteristics,

serum

glycineand

glutam

atelevels

R70

40ms115dB

1KHz

20ms84

dB1KHz

30–1

20

Hon

get

al.20

07M/F

46/13,

MED

Yes

Medication,

P50

R70

40ms116dB

WN

20ms80

dBWN

30–5

00Kum

ariet

al.20

03a

M,MED

(n=7).

Trend

towards

lower

PPI

fMRI

RNon

e40

msairpuff30

psi

20msairpuff10

psi

100

Kum

ariet

al.20

05a

M,MED

(n=23

)Yes

Medication,

violence

ratin

gs,clinical

characteristics,

illness

duratio

n

R70

40ms115dB

WN

20ms85

dBWN

30–1

50

Kum

ariet

al.20

05b

Study

1:M,MED

(n=35–3

9);stud

y2:

M/F

23/12,

MED

Yes

Medication,

clinical

characteristics,AS

R70

40ms115dB

WN

20ms85

dBWN

30–1

20

Kum

ariet

al.20

07B

M/F

17/3,UNMED

Yes

R,L

7040

ms115dB

WN

20ms85

dBWN

30–1

20Lud

ewig

and

Vollenw

eider20

02M/F

49/18,

MED

Yes

Medication,

clinical

characteristics

R70

40ms115dB

WN

20ms86

dBWN

30–2

000

Lud

ewig

etal.20

02M/F

15/4,MED

Yes

R70

40ms115dB

20ms86

dB30–2

000

Lud

ewig

etal.20

03M,UNMED

(n=24

)Yes

Clin

ical

characteristics

R70

40ms115dB

WN

20ms86

dBWN

30–2

000

Mackepranget

al.20

02M/F

14/6,MED

Yes

independ

entof

medicationstatus

Medication

R70

40ms116dB

85dB

30–1

20

Perry

etal.20

02M

andF(n=41

);M/F

25/16,

MED

(n=20

),UNMED

(n=21

)

Yes

Medication

R70

40ms115dB

WN

20ms95

dBWN

30–1

20

Psychopharmacology (2008) 199:331–388 333

Tab

le1

(con

tinued)

Reference

Sex,medications,n,


PPIdeficitscompared

tono

rmal

comparison

subjects(N

CS)?

Other

measuresor

factorsexam

ined

inrelatio

nto

PPIb

Eye

side

Backg

roun

dDBc

Startle

stim

uli

Prepu

lsestim

uli

Prepu

lse

interval

(ms)

Perry

etal.20

04M/F

8/6,

MED

Yes

Sex

R70

40ms115dB

WN

20ms85

dBWN

30–1

20Swerdlow

etal.

2006

fM/F

72/31,

MED

(n=94

),UNMED

(n=9)

Yes

Medication,

sex,

clinical

characteristics,

neurocog

nitiv

eand

functio

nal

measures,

smok

ing

R,L

7040

ms115dB

WN

20ms85

dBWN

20–1

20

II.StudiesreportingPPIdeficitsin

subgrou

psof

schizop

hrenia

patients

Kum

ariet

al.20

04M/F

27/15,

MED

Yes

inmen,bu

tno

tin

wom

enMedication,

sex,

clinical

characteristics,PPF

R70

40ms115dB

WN

20ms78

or85

dBWN

30–1

50

Leumannet

al.20

02M/F

25/8,MED

Yes

with

typicalbu

tno

tatyp

ical

APs

Medication,

LI

R70

40ms115dB

20ms86

dB30–2

000

Meincke

etal.20

04M/F

22/14,

MED

Yes

during

acute,

butno

tremitted

clinical

state

Clin

ical

characteristics,

psycho

patholog

ical

symptom

s

R65

20ms115dB

WN

20ms73

dBWN

30,10

0

Minassian

etal.20

07M/F

16/7,admission

:MED

(n=15

),UNMED

(n=8),

2weeks

later:MED

(n=23

),UNMED

(n=1)

Yes

atho

spitaladmission

,bu

tno

t2weeks

later

Medication,

clinical

characteristics

R70

40ms115dB

WN

20ms85

dBWN

30–1

20

Oranjeet

al.20

02M/F

31/13,

MED

Yes

inPTSwith

typical

butno

twith

atyp

ical

APs

Medication

RNS

30ms115dB

1KHz

30ms80

dB1.5KHz

120

Quedn

owet

al.20

06M/F

19/9,pre-stud

y:MED

(n=9),UNMED

(n=16

),po

st-rando

mization:

typicalAPs(n=12

),atyp

ical

APs(n=16

)

Yes

during

baselin

esession

infirstweekof

treatm

ent,

butno

tafterprolon

ged

treatm

ent

Num

berof

previous

episod

es,clinical

characteristics,

therapeutic

success

R70

40ms116dB

20ms86

dB12

0

III.StudiesreportingPPIdeficitsin

schizop

hrenia

patients

under

specific

experim

entalconditions

Georgeet

al.20

06M/F

9/6,

smok

ers,MED

Smok

ingabstinence:

↓PPI;sm

oking

reinstatem

ent:↑P

PI

Smok

ing

NS

7040

ms115dB

WN

20ms85

dBWN

30–1

20

Hazlettet

al.20

03M/F

14/4,UNMED

PTS

with

schizotypical

person

ality

disorder

Greater

PPIduring

attended

vs.ignored

prepulsesin

NCS,

butnotinPT

S

PPF

R45

40ms10

4dB

WN

5or

8s70

dB0.8

or1KHz

120,

240

Kedzior

and

Martin

-Iverson

2007

M/F

7/1,

MED

deficitsin

“attend

”cond

ition

only

Smok

ing

Ld

6050

ms10

0dB

WN

20ms70

dB5KHz

20–2

00

Kum

ariet

al.20

02M,MED

(n=30

)Yes

inPTStreatedwith

typicalAPsbu

tno

twith

RIS

Medication,

clinical

characteristics,

duratio

nof

illness

R70

40ms115dB

WN

20ms85

dBWN

30–1

20


Tab

le1

(con

tinued)

Reference

Sex,medications,n,


PPIdeficitscompared

tono

rmal

comparison

subjects(N

CS)?

Other

measuresor

factorsexam

ined

inrelatio

nto

PPIb

Eye

side

Backg

roun

dDBc

Startle

stim

uli

Prepu

lsestim

uli

Prepu

lse

interval

(ms)

Kum

ariet

al.20

03b

M/F

7/4,

MED

(n=11)

↓PPIin

respon

seto

procyclid

ine

R70

40ms115dB

WN

20ms78

or85

dBWN

30–120

Wyn

net

al.20

04PTS:M/F

74/2,MED

(typ

ical

APs(n=22

),atyp

ical

APs(n=43

),mixed

orun

know

n(n=11),un

affected

siblings:M/F

17/19

NoPPIdeficitsin

PTSor

unaffected

siblings

Medication,

PPF,

sex,

clinical

characteristics

LNon

e50

ms10

5dB

WN

20ms75

dBWN

120

IV.StudiesreportingnoPPIdeficitsin

schizop

hrenia

patients

Dun

canet

al.20

06a

M,MED

(n=52

),UNMED

(n=21

)No

Medication,

clinical

characteristics

R70

40ms116dB

1KHz

20ms85

dB1KHz

30–120

Postm

aet

al.20

06M,MED

(n=9)

No.

Smok

ingenhanced

PPIin

PTSandNCS

fMRI

RNon

e40

msairpuff30

psi

20msairairpuff

10psi

30–120

Volzet

al.20

03M/F

23/26,

MED

(n=42

),UNMED

(n=7)

No

LNS

50ms10

0dB

WN

Picturespresented

for6s

150–

3,80

0

V.StudiesreportingPPIdeficitsin

pop

ulation

sconceptually

linked

toschizop

hrenia

Kum

ariet

al.20

05d

M/F

4/15

,un

affected

siblings

ofSZPTS

Reduced

PPIin

siblings

ofSZPTSwith

binaural

stim

ulus

presentatio

n

Schizotyp

yratin

gsR

7040

ms115dB

WN

20ms85

dBWN

30–120

Sob

inet

al.20

05a

M/F

11/14,

child

ren

with

22q11DS

Yes

Sex,age,

clinical

characteristics,

latency

redu

ction,

attention

networktest,

reactio

ntim

e

R50

50ms10

4dB

WN

40ms70

dBWN

100

Sob

inet

al.20

05b

M/F

13/12,

child

ren

with

22q11DS

Yes

Sex,age,

clinical

characteristics,

symptom

severity,

subsyn

drom

alsymptom

sof

other

disorders

R56

50ms10

4dB

WN

30ms70

dBWN

100

Weike

etal.20

01Ss“believe

inextraordinary

phenom

ena”

(n=16

,M/F=5/11)or

not

(n=16

,M/F=10

/6)

PPIno

tdifferentbetween

believers

and

non-believers

Sex,age,

schizotypal

person

ality,magical

ideatio

n/perceptual

aberratio

nscales

LNS

50ms10

5dB

WN

20ms10

00Hz

30–480

APsAntipsychotics,ASanti-saccademeasures,Ffemale,fM

RIfunctio

nalmagnetic

resonanceim

aging,

Lleft,L

Ilatent

inhibitio

n,M

male,MED

medicated,N

CSno

rmalcomparisonsubjects,N

Sno

tspecified,

P50

P50

event-relatedpo

tentialsupp

ression,

PPFprepulse

facilitation,

PPIprepulse

inhibitio

n,PTSpatients,

Rrigh

t,RIS

risperidon

e,Ss

subjects,SZ

schizoph

renia,

UNMED

unmedicated,WNwhite

noise,

↓redu

ced,

↑increased

aAlltables

arepreceded

byou

tlinesdescribing

theirorganizatio

nalstructure.

Indistillingthissubstantialliteratureinto

tabu

larform

,asubstantialam

ount

ofinform

ationislost.The

abbreviated

descriptions

herein

cann

otdo

justiceto

thewealth

ofdata

andinterpretatio

nsfoun

din

theoriginal

repo

rts.Referencesareprov

ided

togu

idereadersto

thesource

material.

bDem

ograph

icsrepo

rted

asindepend

entmeasuresin

moststud

ies

cAlldB

Ascaleun

less

notspecifiedin

text;stim

ulidescribedin

KHzarepu

retones.

dRight

eye,

n=1


in which affected individuals are characterized by reducedPPI, on average, compared to a normal comparisonpopulation (cf. Braff et al. 2001b). The reason for the“non-pathognomonic” nature of PPI deficits is simple: theamount of PPI exhibited by any organism at any givenmoment reflects activity at many different levels ofintegrated cortico–striato–pallido–thalamic (CSPT) circuit-ry and its output via the pontine tegmentum. Low levels ofPPI can result from normal variations at several levels ofthis circuitry; alternatively, disease processes can impactdifferent levels of this circuit, with synergistic effects onpontine activity that mediates PPI. Conceivably, diseaseprocesses might even impact this circuitry in such a way asto bias it towards elevated levels of PPI, and compensatoryor allostatic changes within feedback or downstreamelements of the circuitry might offset the effects ofotherwise PPI-disruptive disease processes. Thus, absolutelevels of PPI—either low or high—are neither diagnosti-cally nor neurophysiologically specific.

A corollary of this fact—that PPI is not “diagnostic”—isthat no simple qualitative value of “normal” or “deficient”can accurately be applied to any particular level of PPI,particularly among clinically normal individuals. It iscommon in the literature (including our own reports) todescribe relatively low levels of PPI as “deficient”,“impaired”, or “poor”. In fact, we know of no clearadaptive or functional advantage of higher vs. lower levelsof PPI among clinically normal individuals. Perhaps, thisidea is most easily conveyed in the comparison betweenclinically normal men and women: on average, underspecific stimulus conditions (e.g., 20 ms white noiseprepulses, 10 dB over a 70-dB(A) white nose background,100 ms before a 115-dB(A) 40 white noise pulse), menexhibit more PPI than do women (Swerdlow et al. 1993b,2006f; Kumari et al. 2004; Aasen et al. 2005). Furthermore,there is some evidence that among normal women, PPIshifts across the menstrual cycle (Swerdlow et al. 1997;Jovanovic et al. 2004). Clearly, there is no basis fordescribing PPI in women vs. men as “deficient”, nor fordescribing luteal- vs. follicular-phase PPI as “impaired”.Similarly, drugs that increase PPI in normals cannot beaccurately claimed to “improve” PPI.

At a more basic level, at any given moment in time,individuals are not characterized by a single “PPI” value, inthe same manner in which they might be characterized byother quantitative traits such as height, Q–T interval, orfasting glucose level. One of PPI’s strengths as anexperimental measure is its exquisite sensitivity to stimulusparameters and test conditions [as described for the startlereflex by Davis 1984]. The inhibition generated byprepulses under different stimulus conditions likely reflectsdifferent underlying physiological substrates. Thus, under avariety of test/stimulus conditions, the same clinical

population might conceivably exhibit PPI levels that arereduced, equal to, or elevated, compared to normalcomparison subjects. An instructive example from preclin-ical studies of PPI is found in the report that inbred BrownNorway (BN) rats exhibit “deficient” PPI compared tooutbred Sprague Dawley (SD) rats, based on measurementswith 100 ms prepulse intervals (Palmer et al. 2000).Subsequent studies reproduced this finding, but alsodemonstrated that at shorter prepulse intervals, the oppositerelationship existed: BN rats exhibited significantly morePPI compared to SD rats (Swerdlow et al. 2006a, 2008).Thus, depending on the stimulus parameters, populationscan exhibit either relatively reduced or excessive PPI.

PPI is also highly sensitive to state variables andinfluences, such as medications (Table 1), cigarette smok-ing (Table 1), fatigue (van der Linden et al. 2006), stress(Grillon et al. 1998), and hormonal status (Swerdlow et al.1997; Jovanovic et al. 2004). While some of these variablesand influences can be controlled under experimentalconditions, the notion of using such a sensitive measurein isolation as a diagnostic tool is not realistic. This beingsaid, one potentially valuable strategy in the characteriza-tion of clinical populations is the use of PPI in combinationwith multiple other measures of forebrain inhibitoryfunction, such as P50 event-related potential (ERP) sup-pression (“P50 gating”; Adler et al. 1982) and antisaccadedeficits (Radant et al. 2007), to identify multiple measuresand patterns of normal vs. deficient function (Cadenhead etal. 2002; Braff et al. 2008; Sugar et al. 2007). PPI and P50gating are both deficient but correlate weakly, if at all, inschizophrenia patients (Braff et al. 2007b); similarly, PPIand antisaccade performance are both deficient but do notcorrelate significantly in schizophrenia patients (Kumari etal. 2005b). Thus, these measures apparently assess fore-brain inhibitory processes that are dissociable and nonre-dundant. More importantly, there are patients who exhibitnormal levels of some but not other gating measures (andpresumably normal function within brain circuitry regulat-ing some but not other measures), and subpopulations ofpatients who exhibit different profiles in these deficits(Kumari et al. 2005b; Swerdlow et al. 2006f; Braff et al.2007b). These subpopulations may reflect different patternsof brain dysfunction and conceivably distinct geneticsubstrates and treatment sensitivities (Braff et al. 2007a).

Symptoms, course, and outcome

Can we predict the clinical course or even clinical features ofschizophrenia based on PPI levels? There is no compellingdata to suggest that among schizophrenia patients, levels ofPPI predict clinical course, nor are there consistent robustrelationships between lower levels of PPI and higher levelsof specific symptoms of schizophrenia, or cumulative


Tab

le2

Examples

ofstud

iesusingPPIto

assess

orpredictantip

sychotic

prop

erties,ca.20

01–2

007

I.Anti-dopaminergics

VII.Cannabino

idmechanism

A.D2/mixed

receptor

antago

nists

A.CB1-antago

nists

B.D3-preferentialantago

nists

B.End

ocannabino

idtransportinhibitor

C.D4-preferentialantago

nists

C.Cannabidiol

II.Glutamatergicmechanism

sVII.Neuropeptidemechanism

sA.mGLUR

A.Neurotensin

agon

ists

B.NMDA

B.Opioids

C.GLY

C.CCK

III.Seroton

ergicmechanism

sIX

.Adeno

sine

mechanism

sIV.Noradrenergic

mechanism

sX.GABA

agonists

V.Cho

linergicmechanism

sXI.GABA

agon

ists

A.Nicotinic

agon

ists

XII.Hormon

esB.Muscarinicagon

ists

XIII.Secon

d-messeng

erinhibitors

C.AChE

inhibitors

A.Nitric

oxidesynthase

inhibitors

VI.Histaminergicmechanism

sB.Guany

late

cyclase+

NOSinhibitors

C.PDE-inh

ibito

rsXIV.Miscellaneou

s

References

Species,strain,sex

PPIdeficitindu

cedby

Primaryd

rug/mechanism

tested

Effects

Other

drug

typestested

I.Anti-dop

aminergics

A.D2/mixed

receptoran

tago

nists

Rats

Bastet

al.20

01WI,M

Intra-VHPC

NMDA

infusion

HALD2family

antago

nist

∅NMDA

CLO

(∅NMDA)

Ciliaet

al.20

07SD,M

KET

HAL

∅KET,

notpo

tentiatedby

mGLUR5antago

nist

MPEP

CLO,RIS,lamotrigine,SB-271

046-A

(allsimilareffectsto

HAL)

Con

tiet

al.20

05WKY,M;BN,M

ICV

CRFinfusion

HAL

↓CRFin

WKY

rats,∅CRF

inBN

rats

CLO

(↓CRFin

WKY

rats,

overcompensationof

PPI-deficit

inBN

rats)

vandenBuu

seandGog

os20

07SD,M

8OHDPA

THAL

↓8OHDPA

T(at10

0msPP

interval)

RAC,ARI,BUS(all↓8-O

HDPA

T),

CLO,OLA,RIS,AMI,

MDL73

,005

EF(partial

5-HT1Aagon

ist)(all∅8-OHDPA

T)

allat

100msPPinterval

Rats+mice

Metzger

etal.20

07Mice,

C57

;Rats,

SD,M

AMPor

APO

HAL(implantedHAL

polymer,or

acuteHAL)

HALim

plants:↓A

MPin

mice,

↓APO

inratsAcute

HAL:↓A

PO

inrats

Mice

Russiget

al.20

04C57

,M

APO

HAL

↓APO

CLO

(∅APO)


Tab

le2

(con

tinued)

References

Species,strain,sex

PPIdeficitindu

cedby

Primaryd

rug/mechanism

tested

Effects

Other

drug

typestested

Human

subgrou

ps(+rats)

Vollenw

eideretal.2

006

Hum

ans(“low

vs.

high

gaters”)

Basal

PPI,differencesbetween

subg

roup

sCLO

D1<4/5-H

T2/α

1/

muscarinicantago

nist

↑PPIin

“low

gaters”(atsho

rtPPintervals),∅PPIin

“highgaters”

Swerdlow

etal.

2006

aHum

ans(“low

vs.

high

gaters”),

M;rats,SD,

M;rats,BN,M

Basal

PPI,differencesbetween

human

subgroupsor

ratstrains

QuetiapineD1<2/5-HT2/α1/H1/

muscarinicantagonist

↑PPIin

human

low

gaters

andSD

rats(atshortPP

intervals),↑P

PIin

BN

rats

CLO

(↑PPIat

shortPPintervals),

HAL(∅

PPI)in

SD

rats

Primates

Linnet

al.20

03Capuchinmon

keys,F

PCP

CLO

↓PCP

HAL(∅

PCP)

Rats

Erhardt

etal.20

04SD,M

↑End

ogenou

sKYNA

byky

nurine

orPNU

1565

61A

CLO

↓KYNA

HAL(↓KYNA)

LePenandMoreau2002

SD,M

nHPClesion

CLO

↑PPI

OLA

(↑PPI),R

IS(↑PPI),HAL(∅

PPI)

Depoortereet

al.2007b

SD,M

APO

F15

063D2/D

3-A

ntagon

ist,

D4-partialagon

ist,

5-HT1A-ago

nist

↓APO

Depoortere

etal.2

007a

SD,M

Basal

PPI

F15

063

∅PPI

Barret

al.20

06SD,M

IRvs.indu

ctionof

PPIdeficitsby

APO,PCP,

orCIR

inSRrats

Ilop

eridon

eDA/5-H

AT/

NA

antago

nist

∅PPIin

IRrats,bu

t↓A

PO,

↓PCP,

↓CIR

inSRrats

Ellenb

roek

etal.20

01WI,M

Basal

PPI,APO,or

AMP

JL13

Predo

minantD1/5-H

T2

bind

ing

↑PPI(basal),↓A

PO,↓A

MP

HAL,CLO

(both,

∅PPI(basal),

↓APO,↓A

MP)

Ojim

aet

al.20

04SD,M

Basal

PPI

Perospiron

eD2/5-H

T2A/

5-HT1Aantago

nist

↑PPI

HAL(∅

PPI),RIS

(↑PPI

(relativeto

HAL))

Rueteret

al.20

04SD,M

nVHPC

lesion

Risperidon

eD2/5-H

T2/α

antago

nist(chron

iclow-dosetreatm

ent)

↑PPI

CLO

(↑PPI)

Bub

enikov

aet

al.20

05WI,M

DIZ

ZotepineD1/D

2/D3/5-H

T2A/

5-HT2C5-HT6/5-H

T7/α

1/H

1/

NET-affinity

∅DIZ

RIS

(∅DIZ),CLO,OLA

(both

↓DIZ,bu

t↓P

PIrelativ

eto

vehicle(noDIZ))

Mice

Fejginet

al.20

07NMRI,M

Basal

PPIor

PCP

Aripiprazole

partialagon

ist

atD2/5-H

T1Aandantago

nist

at5-HT2A

↑PPI(basal),↓P

CP

CLO

(↑PPI(trend

),∅PCP),OLA,

(∅PPI,∅PCP),HAL(↑PPI,∅PCP)

Breaet

al.20

06Swiss,M

APO

orDOI

QF20

04BD1<4/5-H

T1A,2A,2C/

α1,2/M

1,2/H

1-binding

↓APO,↓D

OI

CLO,HAL(both↓A

PO,↓D

OI)

Flood

etal.20

08DBA/2NCrl,

DBA/2J,2N

Hsd,

2NTac1,

2NTac2,

C57

BL/6Tac,

129S

6/SvE

vTac

Basal

PPI

OlanzapineD1/D

2/5-H

T2/α

1/

muscarinic/H1antago

nist

ReversalofPP

Ideficit(tested

onlyinDBA/2NCrlmice)

ARI(reversalof

PPIdeficit),

β-CD(reversalofP

PIdeficitcompared

toH2O

)in

DBA/2NCrlmice;both

drugswerenottested

inotherstrains


Tab

le2

(con

tinued)

References

Species,strain,sex

PPIdeficitindu

cedby

Primarydrug

/mechanism

tested

Effects

Other

drug

typestested

B.D3-preferential

antago

nists Rats

Zhang

etal.20

07b

WI,M

PD12

8907

(D3agon

ist),or

APO

A-691

990

↓PD12

8907

,∅APO

HAL(∅

PD12

8907

,↓A

PO),RAC

(∅PD12

8907

),CLO,RIS

(both:

↓PD12

8907

,↓A

PO),SB

2770

11(↓PD12

8907

,∅APO)

Mice

Zhang

etal.20

06DBA,M

Basal

PPIor

nVHPClesion

A-437

203

↑PPIin

unlesion

edanim

als,

but∅PPIafternV

HPC

lesion

)

Intact

mice:

HAL(↑PPI),RIS

(↑PPI),SB27

7011

(D3antago

nist,

↑PPI),AVE59

97(D

3antago

nist,

∅PPI);nV

HPC

lesion

:HAL(↑PPI),

AVE59

97(∅

PPI);BP89

7(preferentialD3/D2antago

nist,

↑PPIin

lesion

edandintact

mice)

Parket

al.20

05ICR,M

APO

KKHA76

1↓A

PO

C.D4-preferential

antago

nists

Boeckleret

al.20

04Rats,WI,M

FAUC

213

↓APO

II.Glutamatergicmechan

isms

A.mGLUR

Rats

Kinneyet

al.20

05SD,M

AMP

CDPPB

MetabotropicGLU

5allosteric

potentiator

↓AMP

Mice

Galiciet

al.20

05C57

,M

AMPor

PCP

LY48

7379

Metabotropic

GLU

2allosteric

potentiator

↓AMP,

∅PCP

LY37

9268

(GLU

2/3agon

ist;

∅AMP,

∅PCP)

B.NMDA

Rats

Zajaczkow

skietal.2003

WI,M

DIZ

CGP40

116Com

petitive

NMDA

antago

nist

↓DIZ

C.GLY

Rats

LePen

etal.20

03SD,M

nVHPC

lesion

Glycine

↑PPI

ORG

2459

8(G

LYT1inhibitor,↑P

PI)

Mice

Adage

etal.20

07C57

,M

PCP

AS05

7278

DAAO

inhibitor;

DAAO

istheenzymewhich

oxidizes

D<serine

(→see

below)

↓PCP

CLO

(↓PCP)

Depoo

rtereet

al.20

05DBA,M

Basal

PPI

SSR55

0473

4GLY

Tantago

nist

↑PPI

Kinneyet

al.20

03DBA,M

Basal

PPI

NFPSGLY

T1antago

nist

↑PPI

CLO

(↑PPI)

Lipinaet

al.20

05C57

,M

Basal

PPIor

DIZ

D-Serinemod

ulator

ofthe

GLY

site

oftheNMDA

receptor

↑PPI(basal

PPI),∅DIZ

L-Serine(∅

PPI),ALX

5407

(GLY

T1

inhibitor,↓P

PI,↓D

IZ),CLO

(↑PPI,

↓DIZ)


Tab

le2

(con

tinued)

References

Species,strain,sex

PPIdeficitindu

cedby

Primarydrug

/mechanism

tested

Effects

Other

drug

typestested

III.Seroton

ergicmechan

isms

5<HT1

Rats

Auclairet

al.20

06SD,M

APO

SSR18

1507

5-HT1A

agon

ist,

partialD2agon

ist

∅APO

↓APO

(when

co-adm

inisteredwith

WAY10

0635

)

SLV313(similartoSS

R81507),

sarizotan

(∅APO

),bifeprunox,H

AL,

ARI,RIS,O

LA,Q

UE,Z

IP(all↓A

PO)

Auclairet

al.20

07SD,M

Basal

PPI

SSR18

1507

↓PPI(reversedby

WAY10

0,63

5)Sarizotan,bifeprun

ox,8-OHDPA

T,(all↓P

PI),HAL,ARI,RIS,OLA,

QUE,ZIP

(all∅PPI)

Krebs-Tho

mson

etal.20

065-MeO

-DMT(hallucino

gen)

Way

100,63

55-HT1A

antago

nist

↓5MeO

-DMT

M10

0907

(5-H

T2Aantago

nist,

∅5-MeO

-DMT),SER-082

(5-H

T2Cantago

nist↓5

-MeO

-DMT)

Mice

Sakaueet

al.20

03dd

Y,M

IR,APO

orDIZ

MC-242

5-HT1Aagon

ist

↑PPI(inIR

mice,antago

nized

byWay10

0,63

5),∅

APO

(inSRmice),∅

DIZ

(inSRmice)

RIS

(↑PPIin

IRmice,

↓APO

inSR

mice)

5<HT2

Rats

Vanov

eret

al.20

06SD,M

DOI

ACP-103

5-HT2Ainverse

agon

ist

↓DOI

Siuciak

etal.20

07WI,M

APO

CP-809

,101

5-HT2Cagon

ist

↓APO

HAL(↓APO)

Ouagazzaletal.2001a,b

SD,M

LSD

(hallucino

gen)

M10

0907

↓LSD

SB

2420

84(5-H

T2Cantago

nist),

SDZSER08

2(5-H

T2b/ 2C

antago

nist),RO

04-679

0(5-H

T6

antago

nist),HAL(all∅LSD)

Mice

Barret

al.20

04DAT-KO,M

Basal

PPI

M10

0907

5-HT2Aantago

nist

↑PPI

Marqu

iset

al.20

07DBA/2N,M

Basal

PPI,DIZ,or

DOI

WAY

1639

095-HT2Cagon

ist

↑PPI,↓D

IZ,↓D

OI,↑A

MP

5-HT6

Pou

zetet

al.20

02a

Rats,WI,M

AMPor

PCP

SB-271

0465-HT6antago

nist

↓AMP,

∅PCP

CLO

(↓AMP,

∅PCP)

5-HT7

Rats(+

mice)

Pou

zetet

al.20

02b

WI,M

AMPor

PCP

SB-258

7415-HT7antago

nist

∅AMP,

↓PCP

RIS

(↓AMP,

↓PCP)

Rats+mice

Sem

enov

aet

al.20

085-HT7K

O,M;

Mice,

C57

,M;

Rats,SD,M

APO,AMP,

orPCP

SB-269

9705-HT7antago

nist

NoSB-269

970:

↓PCPin

KO

vs.WTmice;

↓APO

and↓A

MPin

both

KO

and

WT.

SB-269

970:

∅PCPin

C57

miceandSD

rats


Tab

le2

(con

tinued)

References

Species,strain,sex

PPIdeficitindu

cedby

Primarydrug

/mechanism

tested

Effects

Other

drug

typestested

IV.Norad

renergicmechan

isms Rats

Ballm

aier

etal.2001a

SD,M

Coapp

licationof

Idazox

anα2

antago

nist)+RAC

(D2/D3

antago

nist)

↓APO,bu

tno

additio

nal

impact

ofidazox

anov

erRAC

Sallin

enet

al.20

07SD,M;WI,M

PCP

JP-130

2α2Cantago

nist

↓PCPin

both

strains

Atip

amezole(α

2antago

nist,∅PCP)

V.Cholinergicmechan

isms

A.Nicotinic

agon

ists

Rats

Ciliaet

al.20

05LH,M

IRCom

pou

ndA

α7-agon

ist

↑PPI

Suemaruet

al.20

04WI,M

APO

orPCP

Nicotine

∅PPI,↓A

PO

(elim

inated

bymecam

ylam

ine,

butno

thexametho

nium

),∅PCP

Methy

llycaconitin

e(α

7antago

nist),

dihy

dro-beta-ertho

idine(α

4β2

antago

nist),bo

th∅PPI,HAL

(↓APO,∅PCP),CLO

(↓PCP)

Mice

And

reasen

etal.20

06BALB,M;

NMRI,M

PCP

Nicotine

↓PCPin

BALBmice,

∅PCPin

NMRImice

CLO

(sim

ilarpattern

than

nicotin

e),

RIS

(∅PCPin

either

strain)

Spielew

oyand

Marko

u20

04DBA,C3H

,C57BL

or129,

allM

PCP

Nicotine

∅PPIin

allstrains,↓P

CP

inDBA

andC3H

(trend

),∅PCPin

C57

and12

9mice

B.Muscarinic

agon

ists

Rats

Joneset

al.20

05SD,M

APO

orSCO

Xan

omelineM1/M4

muscarinicagon

ist

↓APO,↓S

CO

BuT

AC(M

2/4-preferring

agon

ist,

↓APO),ox

otremorine,

RS86

,pilocarpine,milameline,sabcom

eline

(allmuscarinicagon

ists,all↓A

PO),

HAL(↓APO,↓

SCO),OLA(↓APO),

SCH23

390(∅

CLO)

Stanh

opeet

al.20

01SD,M

APO

Xan

omeline

∅PPI,↓A

PO

HAL(∅

PPI,↓A

PO),pilocarpine

(↓PPI,∅APO),MUS(↓PPI),SCO

(↓PPI),methy

oscopo

lamine(∅

PPI)

C.AChE-inhibitors

Rats

Hoh

nadelet

al.20

07WI,M

APO,DIZ,or

SCO

Don

epezil

↓APO,∅DIZ,↓S

CO

Galantamine(↓APO,↓D

IZ,↓S

CO)

Ballm

aier

etal.20

02SD,M

Immun

olesioning

ofcholinergic

neuron

sin

nucleusbasalis

Rivastigm

ine

↑PPI

VI.Histaminergicmechan

isms

Roegg

eet

al.20

07Rats,SD,M

DIZ

Pyrila

mineH1antago

nist

↓DIZ

Mice

Fox

etal.20

05DBA,M

Basal

PPI

ABT-239

H3receptor

antago

nist

↑PPI

RIS

(↑PPI)


Tab

le2

(con

tinued)

References

Species,strain,sex

PPIdeficitindu

cedby

Primaryd

rug/mechanism

tested

Effects

Other

drug

typestested

Ligneau

etal.20

07Swiss,M

APO

BF2.64

9H3receptor

antago

nist/in

verseagon

ist

↓APO

Browman

etal.20

04DBA,M;C57

,M

Basal

PPIa,(b)

Thioperam

ideH3receptor

antago

nist/in

verseagon

ist

↑PPIin

DBA,∅PPIin

C57

mice

Ciproxifan(↑PPIin

DBA

andC57

(trend

),RIS

(↑PPIin

both

strains)

VII.Can

nab

inoidmechan

isms

A.CB1an

tago

nists

Rats

Ballm

aier

etal.20

07SD,M

PCP,

DIZ,APO

AM25

1↓P

CP,

↓DIZ,↓A

PO

Rim

onabant(↓APO,↓DIZ,

↓PCP),CLO

(↓PCP)

Mice

Malon

eet

al.20

04Swiss,M

APO

SR

1417

16↓A

PO

Nagai

etal.20

06dd

Y,M

Δ9-THC

SR

1417

16↓T

HC

HAL(↓THC),RIS

(↓THC)

B.Endocan

nab

inoidtran

sportinhibitor

Bortolato

etal.20

06Rats,SD,M

Basal

PPI

AM40

4∅PPI

Win55

,212

(∅PPI),APO

(↓PPI),

DIZ

(↓PPI)

C.Can

nab

idiol

Lon

get

al.20

06Mice,

Swiss,M

DIZ

Non

-psychoa

ctive

constituentof

theCan

nab

issativa

plant,agon

istof

the

TRPreceptor

VAN1,

inhibitorof

anandamide-

uptake

↓DIZ,∅DIZ

(ifpretreated

with

TRPagon

ist

capsazepine)

CLO

(↓DIZ)

VIII.Neuropeptidemechan

isms

A.Neurotensinag

onists

Rats

Shilling

etal.20

04SD,M

DOIor

CIR

NT69

L↓D

OI,↓C

IRPD14

9163

(NTantago

nist,↓C

IR)

Shilling

etal.20

03SD,M

AMPor

DIZ

NT69

L↑P

PI,↓A

MP,

↓DIZ

B.Opioids

Bortolato

etal.20

05Rats,SD,M

U50

488kapp

a-op

ioid

agon

ist

Nor-BNIKappa-opioid

antago

nist

↓U50

488,

but∅APO,∅DIZ

CLO

(↓U50

488),HAL(∅

U50

488)

UkaiandOku

da20

03Mice,

ddY,M

APO

Endom

orphin-1

End

ogenou

smuop

ioid

agon

ist(ICV-infusion)

∅PPI,↓A

PO

(antagon

ized

bythemu1

antago

nist

naloxo

nazine,bu

tno

tby

ICV-infusion

ofthemuantago

nist

β-fun

altrexam

ine)

Nalox

onazine(∅

APO)

C.CCK

Shilling

andFeifel20

02Rats,SD,M

AMP,

DIZ

orDOI

SR14

6131

CCKAantago

nist

∅AMP,

↓DIZ,↓D

OI


Tab

le2

(con

tinued)

References

Species,strain,sex

PPIdeficitindu

cedby

Primaryd

rug/mechanism

tested

Effects

Other

drug

typestested

IX.Adenosine

Wardaset

al.20

03Rats,WI,M

PCP

CGS21

680Adeno

sine

A2

agon

ist

↓PCP

X.GABA

agon

ists

Bortolato

etal.20

04Rats,SD,M

PPI,APO

orDIZ

Baclofen

∅PPI,∅APO,↓DIZ,

(prevented

bySCH50

911)

Bortolato

etal.20

07Juvenile

mice:

DBA,M;C57

,M

Basal

PPIin

DBA

(and

C57

)Baclofen

↑PPI(prevented

bySCH50

911)

inDBA,∅PPI

inC57

mice

CLO

(↑PPIin

DBA,∅PPIin

C57

),HAL(∅

PPIin

both

strains)

XI.Anticonvu

lsan

ts/m

oodstab

ilizers

Rats

Frauet

al.20

07SD,M

Basal

PPI,APO

orDIZ

Top

iram

ateGABAAagon

ist,

voltage

Tab

le2

(con

tinued)

References

Species,strain,sex

PPIdeficitindu

cedby

Primarydrug

/mechanism

tested

Effects

Other

drug

typestested

B61

29SF2

(ctrl),M

Klamer

etal.20

04b

NMRI,M

PCP

N-propyl-arginine

↓PCP

B.Guan

ylatecyclase+nos

inhibitors

Klamer

etal.20

04a

Mice,

NMRI,M

PCP

Methyleneblue

↓PCP

C.PDE-inhibitors

Kanes

etal.20

07Mice,

C57

,M

PPIor

AMP

Rolipram

Pho

spho

diesterase

(PDE)4

inhibitor

↑PPI,↓A

MP

HAL(↑PPI)

XIV.Miscella

neous

Rats

Wanget

al.20

03a

SD,

Perinatal

PCP(3

applications)

M40

403Sup

erox

ide

Dismustase

Mim

etic

↓PCP(bybo

thshortand

long

-term

treatm

ent

with

M40

403)

Mice

Palsson

etal.20

07NMRI,M

PCP

L-Lysine(sub

chronic;

L-artininetransportinhibitor)

↓PCP

Zhang

etal.20

07a

Std:ddy,M

DIZ

Minocyclin

eSecon

dgeneratio

nantib

iotic

↓DIZ

AChE

acetylcholinesterase,AMPam

phetam

ine,APO

apom

orph

ine,ARIaripipazole,BNBrownNorway,B

RO

brom

ocriptine,CBcann

abinoidreceptor,β

-CD

(2-hdrox

ypropy

l)-beta-cyclod

extrin,

CIR

cirazolin

e,CLO

clozapine,

CORTcorticosterone,DAAO

D-aminoacidox

idase,

DAdo

pamine,

DATdo

paminetransporter,DIZ

dizocilpine,

Ffemale,

GLU

glutam

ate,

GLY

glycine,

GLY

Tglycinetransporter,HALhaloperido

l,ICVintracerebroventricular,IR

isolationrearing,

KETketamine,KYNAky

nuricacid,L

ELon

gEvans,L

HListerho

oded,L

SDlysergicacid

dyethy

lamide,M

male,MPEP2-methy

l-t-(pheny

lethny

l)-pyridine,MUSmuscarine,N

Eno

repineph

rine,NETno

repineph

rine

transporter,nH

PCneon

atalhipp

ocam

pus,NOSnitric

oxyd

esynthase,NTneurotensin,

OLAolanzapine,O

VXov

ariectom

ized,p

pmpartspermillion,

PNDpo

stnatald

ay,P

Pprepulse,Q

UEqu

etiapine,Q

UIqu

inpirole,R

ACraclop

ride,R

ISrisperidon

e,Rxtreatm

ent,SC

Oscop

olam

ine,

SDSprague

Daw

ley,

SRsocial

rearing,

THC

tetrahyd

racann

abinol,TRP

transientreceptor

potentialchannel,V

ventral,VA

Nvanillo

id,WIWistar,WKYsWistarKyo

to,WTwild

type,ZIP

ziprasidon

e,↓X

YZredu

ctionof

effect

XYZ,↑X

YZenhancem

entof

effect

XYZ,∅XYZno

change

ofeffect

XYZ


Tab

le3

Mod

elorganism

s,ca.20

01–2

007

I.Low

andhigh

baselin

ePPIlevels

II.Sub

-strains

selected

bydrug

sensitivity

IV.Develop

mentalmod

els

III.Genetically

engineered

organism

s,basedon

genes

A.Isolation/Deprivatio

n/Stress-related

relatedto:

1.Isolationrearing

A.Vulnerabilityforschizoph

renia

2.Maternaldeprivation

B.Dop

amine

3.Develop

mentalstressors

C.Glutamate

4.Im

mun

e-related

D.Noradrenalin

eB.Develop

mentaldrug

expo

sure

E.Histamine

C.Develop

mentalhy

poxia

F.Catecho

lamines

(general)

D.Develop

mentalnu

trition

aldeprivation

G.Acetylcho

line

E.Neonatallesion

sH.GABA

V.Drug-relatedmod

els

I.Secon

dMesseng

erSystems

A.Drugwith

draw

alJ.Neuropeptides

B.Tox

inexpo

sure

K.Other

VI.Other

L.Mod

elsforspecific

disorders

Superscriptdesign

ates

stud

y-specificfin

ding

s

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

I.Low

andhighbaselinePPIlevels Human

sBitsioset

al.20

051;

Swerdlow

etal.20

06a2;

Vollenw

eideret

al.20

063

MBasal

PPIdifferences

betweensubg

roup

s(“low

vs.high

gaters”)

∅PER,∅AMA1in

low

gaters

↓PER1,↓A

MA1in

high

gaters

QUE(↑PPI2),CLO

(↑PPI3),

both

atshortPPintervalsand

inlow

gaters;∅PPI3

inhigh

gaters

Rats

FeifelandPriebe20

011;

Feifelet

al.20

042

BB,M

Basal

PPIdeficits

↓PPI1,2

CLO

andPD

14916

3(a

neurotensinmim

etic;

both

↑PPI),bu

tHAL

(∅PPI)1,2;subchron

icHAL(↑PPI)1

Fergu

sonandCada20

041;

vandenBuu

se20

042

SHRvs.SD

and

WKY,M,F

SHRratsdisplay

behavioral

abno

rmalities

thou

ghtto

mod

elclinical

symptom

s

↓PA1,2,↓P

PIrelativ

eto

SD

andWKY1;↓P

PI

relativ

eto

SD

(trend

only)2,bu

t∅PPI

relativ

eto

WKY

rats2

AMP(↓PPIin

SHRandWKY,

but∅PPIin

SD

rats)2;APO

(↓PPIin

SD,bu

t∅PPIin

SHR

andWKY

rats)2;DIZ

,8-

OHDPA

T(both↓P

PIin

SHR,

WKY,andSD)2

Freud

enberg

etal.20

07Former

WI,M

Selectiv

ebreeding

ofrats

with

high

vs.low

PPI

Fujiwaraet

al.20

06LECandWI,M

Apu

tativ

eanim

almod

elof

WD

↓PPIin

LECrats

CU

(↓PPIin

both

LEC

andWIrats)


Tab

le3

(con

tinued)

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

II.Sub-strainsselected

bydrugsensitivity

Rats

APO

Susceptibility

Son

taget

al.20

031;

vanderElstet

al.

2006

2,20

073

APO-SUSand

APO-U

NSUS,M

APO-SUSandAPO-U

NSUS

ratswereselectivelybred

toachievehigh

(SUS)vs.low

APO

(UNSUS)susceptib

ility

↓PPIin

APO-SUSvs.

APO-U

NSUSrats1,3

(not

apparent

in2)

Sensitiv

ityto

thePPI-disrup

tive

effectsof

COC2or

AMP3

(APO-SUS>APO-

UNSUS)2,3

Rem

oval

ofisolationstress:

↑PPIin

APO-SUS,bu

t↓P

PI

inAPO-U

NSUSrats1;R

EMO

(↓AMPin

APO-SUS,

but∅AMPin

APO

-UNSU

S)3 ;

aMpT

(depletedcytosolic

DA,

∅PP

Iin

both

strains,∅AMP

inAPO

-SUS,

↓AMPin

APO

-UNSU

S)3 ,RES(∅

PPI

inboth

strains,∅AMPin

both

strains)3 ;Testsin

APO

SUSonly:REMO

(∅PP

I,↓C

OC)2,PR

AZ(↑PP

I,↓C

OC)2,KETS(↑PP

I,∅COC)2,aM

pT+RES

(↓AMP)

3

Alcoh

olpreference

Bellet

al.20

031;

Ehlerset

al.20

072

F,M

Selectiv

ebreeding

offemale

ratsor

selectionof

malerats

with

high

(P)vs.low

(NP)

alcoho

lpreference

∅PPIafterselective

breeding

;↑PPIinP

rats2;

↓PPIin

Pratsho

used

inisolation2

Adu

ltrats:AMP(↓PPIin

P,bu

t↑P

PIin

NPrats);

Ado

lescentrats:AMP(↓PPI

inP,

but∅PPIin

NPrats)

III.Genetically

engineeredorga

nisms,based

ongenes

relatedto:

A.Vulnerab

ility

forschizop

hreniaMice

Clapcoteet

al.20

07Missensemutations

inexon

2of

the

DISC1gene

DISC1isaprop

osed

schizoph

renia

susceptib

ility

gene

↓PPIin

micewith

missensemutationat

residu

es31

Lor

100P

CLO,HAL,BUP,

Rolipram

(PDE4inhibitor;all↑P

PI;

reversalof

PPIwas

depend

ent

onthespecific

type

ofmissensemutation)

Barret

al.20

07KO

forreelin

receptorsVLDLR

orAPOER2,

M,F

Reelin

isrepo

rtedly

redu

ced

inbrains

ofschizoph

renia

patients

∅acou

stic

PPIin

both

KO,↓crossm

odal

PPI

inVLDLRmice,

↑crossmod

alPPIin

APOER2mice

PPI-disrup

tiveeffectsof

PCP:KO>WT

Pod

hornaandDidriksen

2004

Heterozyg

ous,

reeler

mutants,M,F

Reelermicehave

amutation

inthegene

forreelin

and

have

been

sugg

estedas

ananim

almod

elfor

schizoph

renia

↓PPIon

lyin

fully

adult

F(trend

only)


Tab

le3

(con

tinued)

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

Bou

cher

etal.20

07Heterozyg

ous

NRG1KO,M

NRG1isaprop

osed

schizoph

renia

susceptib

ility

gene

∅PPI

PPI-disrup

tiveeffectsof

THC:KO>WT

Muk

aiet

al.20

04ZDHH8-KO,M,F

ZDHH8isaprop

osed

schizoph

renia

susceptib

ility

gene

↓PPIin

F,bu

t∅PPIin

M

B.Dop

amine

DA

receptors

Mice

Ralph

-Williamset

al.20

02D1-KO,o

rD2-KO,M

,F∅PPIin

D1-KO,but

↓PPI

inD2-KO

APO,S

KF82

958(both∅PPIin

D1-KO,bu

t↓P

PIin

WT;

↓PPIin

D2-KO

andWT);

AMP(↓PPIin

D1-KO

and

WT,

∅PPIin

D2-KO,bu

t↓P

PIin

WT);DIZ

(↓PPIin

D1-KO,D2-KO,andWT)

Holmes

etal.20

01DA

D5nu

llmutants,

M,F

∅PPI

SKF81

297(∅

PPIin

mutants,

but↓P

PIin

WT)

DAT

Mice

Barret

al.20

041;

Yam

ashita

etal.20

062

DAT-KO,M

Increase

dopamineactiv

ityhasbeen

prop

osed

inschizoph

renia

↓PPI1,2

COC,M

ETP(both↑P

PIin

KO,

but↓P

PIin

WT)2

M10

0907

(5-H

T2Aantago

nist,

↑PPIin

KO,bu

t∅PPIin

WT)1;FLX,NSX

(aNET

inhibitor,bo

th↑P

PIin

KO,

but∅PPIin

WT)2,CIT

(∅PPIin

KO

andWT)2

Ralph

-Williamset

al.20

03b

DAT-kn

ock-do

wns,M

,F∅PPI

Other

Dop

aminerelated

Eellset

al.20

06Mice,

nuclearreceptor

Nurr1

nullmutants

Nurr1

isim

portantfor

developm

entof

DA

neuron

s;earlypo

stnatalisolation

↓PPIafterpo

stnatal

isolationin

Nurr1

+/−

mice

C.Glutamate

NR1

Rats

Inadaet

al.20

03WI,M

Antisense

knock-do

wnof

HPC

NR1by

HPJ-lip

osom

evector

↓PPI

Mice

Bickelet

al.20

081;Dun

can

etal.20

042,20

06a3;

Moy

etal.20

064

TG

with

redu

ced

expression

ofNR1,

M,F

NMDA

receptor

sign

alingmay

beredu

cedin

schizoph

renia.

Microtubu

lestabilizatio

nin

neuron

sdepend

son

STOP

↑PA1,2,3,4,↓P

PI1,2,3,4

Sensitiv

ityto

PPI-disrup

tive

effectsof

AMP:TG>WT4

HAL,CLO,RIS

(all↑P

PIin

both

TG

andcontrols)3

Fradley

etal.20

05TG

with

redu

ced

expression

ofNR1

orSTOP-K

O,M,F

↓PPI(inbo

thmou

setypes)

CLO

(∅PPIin

both

mou

setypes)


Tab

le3

(con

tinued)

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

NR2

Mice

Boy

ce-RustayandHolmes

2006

1;Sp

oorenetal.2

0042

NR2A

-KO,M,F

∅PPI1,2

Ro63

-190

8(a

selective

NR2B

receptor

antago

nist,↓PPI)2

Takeuchiet

al.20

01NR2A

,NR2B

,N2C

,N2D

,or

GLURδ2

mutants

NR2A

-Darekn

ownsubu

nits

oftheNMDA

receptor

channel.GLURδ2

isa

relativ

elyno

velGLU

receptor

subu

nit

↑PA

inNR2A

,B,Cand

Dmutants,∅PA

inGLURδ2

,↑P

PIin

NR2B

andGLURδ2,

∅PPIin

NR2A

,Cand

DNR3

Brody

etal.20

05MiceNR3A

-KO

orTG

NR3A

overexpressors,M,F

↑PPIat

3–4weeks

old

M,bu

t∅PPIin

FKO;

∅PPIin

TG

AMPA

Wiedh

olzet

al.20

08Mice,

AMPA

GLUR1-

KO,M,F

The

gene

encoding

GLUR1

lieswith

inachromosom

alregion

that

isassociated

with

schizoph

renia

↓PPI

mGLU

Mice

Brody

etal.20

03a,

bmGLU1-KO,M

Reduced

glutam

atefunctio

nhasbeen

prop

osed

inschizoph

renia

↓PPI1,2,3

PCP(↓PPIin

KO

andWT)

RAC(∅

PPIin

KO

andWT),

LAM

(↑PPIin

KO

andWT)

Brody

andGeyer

2004

b1;

Brody

etal.20

04a2;

Lipinaet

al.20

073

mGLU5-KO,M,F

↓PPI

PPIdeficitof

KO

micecould

notbe

mim

ickedin

WTmice

with

themGLU5antago

nist

MPEP1,no

furtherdisrup

tion

ofPPIby

DIZ

inKO3

RAC,CLO,LAM

(all∅PPI)2,

CX54

6andARIR

(positive

mod

ulatorsof

AMPA

,bo

th↑P

PI(lesspron

ounced

with

ARIR))3

Other

glutamaterelated

Mice

Szumlin

skiet

al.20

05Hom

er1-KO

orHom

er2-KO,M,F

Hom

erproteins

interact

with

mGLU,andmod

ifythe

morph

olog

yof

GLU

synapses.A

SNPin

Hom

er1

was

associated

with

schizoph

renia

↓PPIin

Hom

er1-KO,

but∅PPIin

Hom

er2-

KO

HAL(↑PPIin

Hom

er1-KO)

Tsaiet

al.20

04Heterozyg

ous

GLY

T-KO,M

GLY

isaco-ago

nistat

the

NMDA-receptorwith

presum

edsub-saturatin

gconcentrations

atthereceptor

∅PPI

Sensitiv

ityto

thePPI-

disrup

tingeffectsof

AMP

(KO

<WT)or

DIZ

(KO

>WT)


Tab

le3

(con

tinued)

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

Wolfet

al.20

07CPB-K

vs.Balb,

MCPB-K

micedisplaylow

levelsof

NMDA

receptors

↑PA,↓P

PIrelativ

eto

BalbC

mice

Acute

orsubchron

icCLO

(∅PPI)

D.Norad

renaline

Lahdesm

akiet

al.20

04Mice,

adrenergic

α2A-

KO,M,F

Adrenergicα2Areceptors

mod

ulatetransm

itter

release

ofDA

and5-HTneuron

s

↑PPI

AMP(↓PPIin

KO,andWT;

greatersensitivity

toAMPin

KO),DEXM

(anα2agon

ist,

∅PPI,↓A

MPin

KO,bu

tno

tWT)

ATI(anα2antago

nist,∅PPI,

∅AMP)

E.Histamine

Dai

etal.20

05Mice,

H1-KO,M

Histaminic

abno

rmalities

have

been

implicated

inthe

pathop

hysiolog

yof

schizoph

renia

↓PPIin

WT,

but∅PPI

inKO

afterIR

Sensitizationto

METH

enhanced

effectsof

IRon

PPI

inWT,

butno

tin

KO

mice

F.Cathecholam

ines

(General)

Klejbor

etal.20

06Mice,

FGFR1-TG,M,F

FGFR1-TG

expressa

dominant-negativ

emutant

from

thecatecholam

inergic,

neuron

-specificTH

prom

oter

↑PA,↓P

PI

FLUP(a

DA

antago

nist,↑P

PI)

G.Acethylcholine(A

Ch)

Nicotinic

Mice

Bow

erset

al.20

05Nicotinic

α7-KO,M

Evidencesugg

estsredu

cedα7

expression

inschizoph

renia

patients

∅PPI

PPI-disrup

tiveeffectsof

EtOH:KO=WT

Cui

etal.20

03Nicotinic

β3-KO,M,F

β3-subu

nitof

thenA

CH

ishigh

lyexpressedin

DA

neuron

sof

theSN

andVTA

↓PPI

Muscarinic

Tho

msenet

al.20

07Mice,

M5-KO,M,F

The

M5muscarinicACh

receptor

hasbeen

implicated

insusceptib

ility

toschizoph

renia

↓PPI

AMP(↓PPIin

KO

andWT)

CLO(↑PP

Iin

KO,but

∅PP

Iin

WT;∅

AMPin

both

KOand

WT),HAL(↑PP

Iin

KOand

WT;↓

APO

inboth

KOand

WT)

H.GABA

GABAA

Mice

Hauseret

al.20

05GABAAα5mutants,

M,F

The

α5subu

nitof

theGABAA

channelisstrong

lyexpressed

intheHPC

↓PPI

Yee

etal.20

05GABAAα3-KO,M,F

The

α3-GABAAreceptor

isthemainreceptor

subtyp

eexpressedby

GABA-ergic

neuron

sinvo

lved

incontrolling

monoaminergic

neuron

s

↓PPI

HAL(↑PPI)


Tab

le3

(con

tinued)

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

Other

GABA

related

Mice

Chiuet

al.20

05GAT1-KO,M,F

GAT1-KOsdisplaybehavioral

abno

rmalities

prop

osed

tomod

elsomeaspectsof

psycho

patholog

y

↓PPI

Heldt

etal.20

04GAD65

-KO,M,F

GAD65

isaGABA

synthesizing

enzyme

↓PPI

CLO

reversed

thePPIdeficit

ofKO

I.Secon

dmessengersystem

sMice

Gou

ldet

al.20

041;

Kelly

etal.20

072

TGwith

aconstituitiv

ely

activ

eGsα

orTG

with

R(A

B),or

Gsα

xPKA

doub

leTG

mice,

M,F

R(A

B)TG

expressaPKA

type

inhibitor.G-protein

sign

aling

relatedto

thecA

MP/PKA

pathway

may

beabno

rmal

inschizoph

renia

↓PPIin

Gsα

TG,bu

t∅PPIin

PKATG1,2

andGsα

xR(A

B)

doub

leTG2

HAL(↑PPIin

Gsα

TG,bu

t∅PPIin

R(A

B)TG),ROL

(↑PPIin

Gsα

TG)2

Harrisonet

al.20

03LAP1,

M,F

LAP1isaG-protein

coup

led

receptor

with

developm

ental

expression

sugg

estin

garole

inpsycho

patholog

y

↓PPI

Koh

etal.20

08PLCβ1-KO,M,F

PLCβ1may

bealteredin

brains

ofschizoph

renia

patients

↓PPI

HAL(↑PPIin

KO,bu

t∅PPI

inWT)

Shu

met

al.20

05CaM

KIV-K

O,M

CaM

KIV

isthou

ghtto

beinvo

lved

inneurop

lasticity

andaspectsem

otional

behavior

↓PPI(and

↓PA)

vandenBuu

seet

al.20

05a

Gzα-K

O,M

Gzα

isaG-protein

oftheGi

type

andassociated

with

DA

D2-receptors

∅PPI

Sensitiv

ityto

thePPIdisrup

tive

effectsof

AMP,

APO

(both:

KO>WT)or

DIZ

(KO=WT)

J.Neuropeptides

Neurotensin

Rats

Cacedaet

al.20

05M

Virally

mediatedov

erexpression

ofNT1in

the

NAC

∅PPI

↓AMP,

↓DIZ

Mice

Kinkead

etal.20

05NTnu

llmutants,M,F

NTisprop

osed

tohave

“end

ogenou

santip

sychotic”

prop

erties

↑PA,↓P

PI

AMP(∅

PPIin

mutants,

but↓P

PIin

WT)

HAL,QUET(both∅PPIin

mutants,bu

t↑P

PIin

WT),

CLO

(↑PPIin

mutantsand

WT),OLA

(∅PPIin

mutants

amdWT)


Tab

le3

(con

tinued)

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

CRF

Mice

Dirks

etal.20

021,20

032;

Groeninket

al.20

083

TG

CRF1

overexpressors,M

CRFabno

rmalities

may

play

arole

inpsycho

patholog

y↓P

PI1,2,3

CRF1antago

nists(↑PPIin

TG,

but∅PPIin

WT),GR

antago

nists(∅

PPIin

TG

and

WT),adrenelectom

y(∅

PPIin

TG

andWT)3;HAL,CLO,

RIS,bu

tno

tCDPallredu

cePPIdeficitof

TG

relativ

eto

WT

Risbrou

ghet

al.20

04CRF1-KO,M

∅PPI

CRF(↑PPIin

KO,bu

t↓P

PI

(and

↑PA)in

WT)

ArginineVasop

ressin

Egashiraet

al.20

05Mice,

V1b

-KO,M

V1b

playsarole

inregu

latio

nof

theph

ysiological

respon

seto

stress

↑PA,↓P

PI

CLO,RIS

(both↑P

PI),bu

tHAL(∅

PPI)

Gastrin

vandenBuu

seet

al.20

05b

Gastrin-K

O,M

Gastrin

isapeptideho

rmon

e.Itisalso

prod

uced

inthe

brainandbind

sto

theCCK

receptor.CCK

interacts

with

DA

inthebrain

∅PPI

Sensitiv

ityto

thePPI-disrup

tive

effectsof

AMP(K

O<WT),

butforAPO,D

IZ,8-OHDPA

T(allKO=WT)

Neurexin

Beglopo

ulos

etal.20

05Mice,

Nxp

h3-K

O,M

Nxp

h3isalig

andof

synaptic

α-neurexins

↑PA,↓P

PI

PACAP

Tanakaet

al.20

06Mice,

Adcyap1

-mutants

Adcyap1

mutantslack

the

gene

encoding

forPA

CAP

anddisplaymarked

behavioral

abno

rmalities

includ

inghy

perlocom

otion

andjumping

behavior

↓PPI

AMP(↑PPI)

HAL(∅

PPI)

K.Other

Wanget

al.20

03a,

bMice,

adenosine

A2-K

O,M

Adeno

sine

may

influence

PPIby

interactingwith

the

DA

system

ofthebrain

↓PA,↓P

PI

AMP(∅

PPIin

KO

andWT

(slig

httrendtowards

↓PPIin

KO,bu

t↑P

PIin

WT);DIZ

(↓PPIin

KO

andsomew

hat

morepron

ounced

inWT)

Wolinskyet

al.20

07Mice,

TA1-KO,M

Trace

amines

have

been

implicated

inschizoph

renia

↓PPI

Mice

Gog

oset

al.20

061;

vandenBuu

seet

al.20

032

Aro-K

O,M,M

(castrated),F

Genderdifferencesin

psychiatricdisease;

arom

ataseconv

erts

testosterone

into

estrog

en

∅PPIin

M,castrated

M,

andF1;age-depend

ent

↓PPIin

M,bu

t∅PPI

inF(slig

httrends

only)2

PPI-disrup

tiveeffect

of8-

OHDPA

T(F

K0=FWT;

MKO>M

WT;enhanced

incastratedM

WT,

but

notin

KO)1


Tab

le3

(con

tinued)

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

Weilet

al.20

06MT1-KO,M,F

Melaton

inhasbeen

implicated

inpsychiatricdisease

↓PPI

Mice

Petittoet

al.20

02a

Dou

bledeletio

nof

IL2/IL15

Rβ-dou

ble-

KO,M,F

IL2andIL15

arecytokinesthat

shareacommon

β-receptor

subu

nit,which

isessential

forintracellularsign

aling.

Exp

ressionlevelsarehigh

inHPCandlim

bicregion

s

↓PA,↓P

PI

Petittoet

al.20

02b

MRL-lpr

substrain,

MMRL-lpr

micedeveloplupus-

likeautoim

munedisease,but

also

reducedIL2production.

Schizophreniamay

involve

immuneprocessesof

theCNS

∅PPIin

pre-disease

MRL-lpr,bu

t↓P

PI

with

evidence

ofautoim

mun

edisease

Mice

Irintchevet

al.20

04L1or

CHL1,

M,F

The

cell-adhesion

moleculeL1

andits

closeho

molog

ueCHL1may

belin

kedto

schizoph

renia

↓PPI

Jaworskiet

al.20

05TIM

P-2-K

Oor

knock-

down,

M,F

TIM

Pinfluenceextracellular

matrixmolecules

andmay

beinvo

lved

inbrain

plasticity

andpo

ssibly

braindevelopm

ent

↓PPIin

KO

when

comparedto

heterozygous,butnot

knock-downorW

Tanimals

Pillai-N

airet

al.20

05NCAM-TG,M,F

NCAM

iselevated

inbrains

from

schizoph

reniapatients

↓PPI

CLO

(↑PPI),HAL(∅

PPI)

Mice

Brunskillet

al.20

051;

Erbel-Sieleret

al.20

042

Npas1-K

O,Npas3-

KO,M,F

Npasisatranscriptionfactor

high

lyexpressedin

developing

neuroepithelium

↓PPIin

Npas1

2and

Npas3

1,2-K

O

Burne

etal.20

05Vitamin

Dreceptor

KO,M,F

Vitamin

Dcontribu

testo

norm

albraindevelopm

ent.

↓PPIat

long

PP

intervals

Cao

andLi20

02Emx1

mutants,M,F

Emx1

isim

plicated

inforebrain

developm

entandbehavioral

processes.

(↓PPI;trendon

ly)

McD

onaldet

al.20

01FGFR3-nu

llmutants,

M,F

FGFR

may

contribu

teto

neuron

algrow

th,

angiog

enesis,mitagenesisand

skeletal

developm

ent

↓PPI


Tab

le3

(con

tinued)

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

Miyakaw

aet

al.20

03CN-m

utants,M

CN

isinvo

lved

inneurite

extensionandneuron

alplasticity.C

N-m

utantsdisplay

behavioral

abno

rmalities

↓PPI

Parket

al.20

02CDFmutantsand

Catna2-TG

(of

CDFmutants)

CDF-m

utantsshow

morph

olog

ical

abno

rmalities

intheHPCandcerebellu

mas

wellas

behavioral

abno

rmalities.Catna2-TG

have

partially

restored

CDF

region

sandno

rmal

HPCand

cerebellu

mmorph

olog

y

↓PPIin

CDF-m

utants;

∅PPIin

Catna2-TG

Porras-Garciaet

al.20

05Heterozyg

ousLurcher

mutants,M

Lurcher

mutantsdisplaya

prog

ressiveloss

ofPurkinje

neuron

s

↓PPI

Yuk

awaet

al.20

05STA

T6-deficient,M

STA

T6isexpressedin

the

CTX,HPC,striatum

(develop

ingbrain),andbasal

forebrain(adu

lts).STA

Tare

sign

alingmolecules

that

mediate

cytokine-related

mechanism

s

↓PPI

L.Mod

elsforspecific

disorders

Fragile

X-syn

drome

Human

s+mice

Frank

land

etal.20

041;

Spencer

etal.20

062

Hum

anchild

renwith

FXS,Fmr1-K

O,

Fmr2,or

Fmr1+2

doub

leKO

mice,

M

Fmr-KO

micearepu

tativ

eanim

almod

elsof

FXS

↓PPIin

child

renwith

FXS1andin

Fmr1-K

O1,

but∅PPIin

Fmr1-K

O2

andFMR1+

2do

uble

KO2

Bon

teko

eet

al.20

02FXR2-KO,M

FXR2isaho

molog

ofthe

FMRPprotein,

which

islackingor

mutated

inFXS.

↓PPI

ChenandToth20

01FMR1-KO,M

FMR1-gene

encodestheFMRP

protein,

which

islackingor

mutated

inFXS.

↑PPI

Nasu-H

asu-H

ikaladisease

Kaifu

etal.20

03Mice,

DAP12

-deficient,

M,F

DAP12

deletio

nslead

tothe

Nasu-Hikaladisease

↓PA,↓P

PI

22q11

deletionsyndrome

Payloret

al.20

06Mice,with

chromosom

aldeletio

nsDf1,2,

3,4

or5,

ormutations

ofgenesTbx

1,Gnb

1l,

orCdcrel1,M,F

Chrom

osom

alDf1

deletio

nsare

apu

tativ

eanim

almod

elof

22q11deletio

nsynd

rome,

which

islin

kedto

high

schizoph

reniarates.Df1

↓PPIin

micewith

deletio

nsof

Df1,Df2,

Df3

andmutations

ofTbX

1,Gnb

1l.∅PPIin

micewith

deletio

nsof


Tab

le3

(con

tinued)

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

deletio

nswere“behaviorally

mapped”

tomutations

ofsing

legenesviaPPI

Df4

orDf5,and

mutations

ofCdcrel1

Huntington

’sdisease

Van

Raamsdon

ket

al.20

05Mice,

YAC12

8HD

patientshave

motor-,

cogn

itive-andpsychiatric

disturbances.YAC12

8mice

expressmutanth

untin

gtin

and

areapresum

edanim

almod

elforHD

↓PPIin

oldermice

Alzheimer’s

disease

Mice

Ewerset

al.20

06APP&PS1do

uble-K

O,

M,F

AD

invo

lves

neurop

atho

logical

changesin

theHIP

∅PPI,bu

tcorrelation

betweenPPIdeficits

andneurop

atho

logical

changes

McC

oolet

al.20

03CRND8-TG,M

CRND8-TG

show

over

expression

ofSwedish/

Indianafamilial

mutations

ofAPPandan

agedepend

ent

increase

ofam

yloid

prod

uctio

n

↓PPI(smalleffects)

Taniguchi

etal.20

05WILD

andN27

9Kmutants,M,F

TAU

mutations

may

play

acausal

role

inform

sof

dementia

andPD.N

279K

and

WILD

mutantscontaina

mutationof

thehu

man

TAU

gene

↓PPIin

N27

9Kmutants,

∅PPIin

WILD

mutants

IV.Develop

mentalmod

els

A.Isolation/depriva

tion

/stress-related

1.IsolationRearing

Rats

Barret

al.20

061;Ciliaet

al.

2005

2;Day-W

ilson

etal.

2006

3;Harte

etal.20

074;

Pow

ellet

al.20

025,20

036;

Rosaet

al.20

057

SD,FLH,M;

LE,M;WI,M

IR↓P

PIin

MandF,

andall

strains1,2,3,4,5,6,7

Water

deprivation(∅

PPI)5

Ilop

eridon

e(broad

spectrum

DA/5-H

T/NEantago

nist,

maternaldep3.

∅PPI)1;

compo

undA

(α7agon

ist,

↑PPI2);DA-depletio

nwith

6-OHDA

(↑PPI)6;hand

ling

(↑PPI)7

Nun

esMam

edeRosa

etal.20

05WI,M

Post-weaning

isolation

for10

days

↑PPI(not

reversed

byresocialization)


Tab

le3

(con

tinued)

References

Species,Strain,

Sex

Mod

eldescription/

backgrou

nd/rationale

Basal

PPI

Effectsof

drug

stypically

used

toindu

cePPIdeficits

Effectsof

(presumed)

antip

sychotics/other

treatm

ents

Mice

Dai

etal.20

041,20

052;

Sakaueet

al.20

033;

Varty

etal.20

064

C57

,dd

Y,12

9andH1-

KO,allM

IR↓P

PIin

WTmice1,2,3;

↓PPI

(C57and129micein

atleastoneofthetwotest

sessions)4∅PP

Iin

H1-

KO2

Sensitizationto

AMPenhanced

effectsof

IRon

PPI

inWT1,2

butnotin

H1-KO2,RIS

and

MKC-242

(a5H

T1a

agonist,

both

↑PPI)3

2.Maternal

depriva

tion

Rats

Cho

yandvandenBuu

se20

07Early

stress:MD.Later

stress:

implantatio

nof

CORTpellets

↓PPI(trend

only

inMD

rats)

APO

(↓PPIin

CTRandrats

treatedwith

either

MD

orCORT,

but∅PPIin

rats

expo

sedto

MD

andCORT);

AMP(↓PPIin

CTR,bu

t∅PPIin

ratse

realistic expectations of prepulse inhibition in translational ......review realistic expectations...

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