T h e n e w e ng l a n d j o u r na l o f m e dic i n eTable 1. Monoamine-Related Gene Knockouts That Affect Depression-Related Behavior in Mice.*

Gene or Protein

FunctionCorroborationof MonoamineDeficiency
Hypothesis

Depression-Related Changes

Other Behavior Elicited byKnockout of Gene

sert

Serotonin transporter

Increased depressive behavior, reduced serotonin level, desensitized postsynaptic
5-HT1AR, and reduced presynaptic
5-HT1AR function32

No

Excessive anxiety32

net

Norepinephrine transporter Reduced depressive behavior, prolonged
norepinephrine clearance, elevated extracellular norepinephrine levels33

Yes

Increased locomotion responseto amphetamines and cocaine33

5-ht1ar

Serotonergic 1A receptor(presynaptic autoreceptor and postsynaptic)

Reduced depressive behavior, normal serotonin level and release, impaired SSRIinduced neurogenesis32

No

Excessive anxiety,impaired hippocampal learning32

5-ht1br

Serotonergic 1B receptor(presynaptic autoreceptor and postsynaptic)

Reduced response to SSRI in forced swim
test, reduced serotonin level and increased serotonin release, increased
SSRI-induced serotonin release, decreased serotonin-transporter expression32

Yes

Increased aggressiveness, reduced anxiety, increased exploration, increased use ofcocaine32

p11 (protein)

Interacts with and enhances signaling efficiencyof 5-HT1BR

Increased depressive behavior, increased
serotonin turnover20

No

Not reported20

5-ht2ar

Serotonergic 2A receptor

No change34

No

Reduced inhibition in conflictanxiety paradigms34

5-ht7

Serotonergic 7 receptor(possibly presynaptic
autoreceptor and postsynaptic)

Reduced depressive behavior and REM
sleep duration35

No

Normal locomotion35

α2aar

α2A-Adrenergic receptors(presynaptic autoreceptor)

Reduced norepinephrine levels, presynaptic
inhibition of release,36 increased depressive behavior37

No

Altered sympathetic regulation,36 impaired motor coordination

α2car

α2c-Adrenergic receptors(presynaptic autoreceptor restricted to central
nervous system)

Reduced depressive behavior38

Yes

Increased aggressiveness,32­increased locomotion response to amphetamines36

mao-a

Monoamine oxidase A

Increased brain serotonin and epinephrine
levels39

No

Increased aggressiveness andresponse to stress,30 decreased exploration32

ac VII (hetero­zygotes)

Adenylyl cyclase type 7

Reduced depressive behavior40

No

Unchanged anxiety40

impa1

Inositol monophosphatase 1

Reduced depressive behavior, unalteredbrain inositol levels41

Yes

Increased hyperactivity and­sensitivity to pilocarpine­induced seizures41

smit1

Sodium-myo-inositol transporter 1

Reduced depressive behavior and brain inositol levels42

Yes

Increased sensitivity to pilocarpine-induced seizures42

creb

Cyclic AMP–response element–binding protein

Reduced depressive behavior, normal antidepressant-induced behavior43

NoNo increase in BDNF after longterm use of antidepressants43

Brain-derived neurotrophicfactor

No depressive behavior44

No

Increased aggressiveness, hyperphagia,45 hyperactivity44

Increased depressive behavior44

Yes

Increased aggressiveness, hyperphagia45

bdnf
Male miceFemale mice Brain-derived neurotrophicfactor* BDNF denotes brain-derived neurotrophic factor, 5-HT1AR 5-hydroxytryptamine 1A receptor, 5-HT1BR 5-hydroxytryptamine 1B receptor,
REM rapid eye movement, and SSRI selective serotonin-reuptake inhibitor.

60

n engl j med 358;1

www.nejm.org

january 3, 2008