Stanislav S. ZakharenkoDepartment of Developmental Neurobiology,

St. Jude Children’s Research Hospital

Towards understanding mechanisms

of positive symptoms in 22q11DS and schizophrenia

Mouse

16qA13

Human

22q11.2

Centromere

Telomere

Phenotype 1

Phenotype 2

Phenotype 3

Phenotype 1000

Phenotype 999

• Hallucinations are mostly auditory (85%);

(Abnormal activity in the auditory cortex and thalamus during

auditory hallucinations)

• Psychotic symptoms are alleviated by antipsychotics.

(Antipsychotics are much less effective treating cognitive or

negative symptoms)

• Psychosis is prevalent later in life (>18 years of age).

Positive symptoms

(i.e. hallucinations and delusions)

Goal:

1) Find a phenotype specific to the central auditory system;

2) The phenotype should be rescued by antipsychotics;

3) The phenotype should be age-dependent;

4) The phenotype should be robust in order to study its molecular mechanisms.

T10

ProdhHtf9c

Dgcr6Dgcr2

Tsk1

Gscl

Ctp

Comt

Trxr2

Gnb1l

Tbx1

GpIbβ

Pnutl1 Cld5

Ufd1l

Nlvcf

Hira

Zdhhc8

Dgcr8

Es2el

Cdc45ArvcfRanbp1Rtn4r

Df(16)1/+ mouse

Cen Tel

4-month-old mice

Visual and somatosensory TC synaptic transmission is also normal.

ACx

MGv

Normal

ACx

MGv

22q11DS

Df(16)1/+ TC deficits are rescued by antipsychotics

TC projections CC projections

DH

TC deficit is also rescued by:

• clozapine

• olanzapine

D2 receptor levels are selectively elevated in the thalamus

ACx

MGv

Normal 22q11DS

Drd2

1. Dopamine hyperfunction

2. Glutamate hypofunction

3. TC disconnectivity

Sensitivity to

antipsychotics

ACx

MGv

Dgcr8 is the causal gene

Dgcr8 deletion in the MGv

replicates the TC disruption

and haloperidol sensitivity

Late onset of TC sensitivity to antipsychotics

ACx

MGv

Normal

ACx

MGv

22q11DS

Drd2

Dgcr8

miRNAs ?

Sensitivity to

antipsychotics

Chun et al. Science, 2014

Late onset

miR-338-3p rescues abnormal sensitivity to antipsychotics

miR-338-3p knockdown mimics sensitivity to antipsychotics

miR-338-3p mediates sensitivity to antipsychotics

miR-338-3p knockout eliminates age-dependency

ACx

MGv

Normal

ACx

MGv

22q11DS

Drd2

Dgcr8

miR-338-3p

Sensitivity to

antipsychotics

Late onset switchAuditory thalamus

specificity

Acknowledgements: Drs. Sungkun Chun, Fei Du, JJ Westmoreland, Michael Wang, Donnie Eddins, Ildar Bayazitov,

Prakash Devaraju, Jing Yu, Seung-Baek Han, Marcia Mellado Lagarde and Kara Anderson