Maschinenführerschein Seminarleiter: Mirko Spanzel Stanislav Ritter Stanislav Ritter.
Stanislav Zakharenko: Studying Psychosis in 22q11 Deletion Syndrome
Transcript of Stanislav Zakharenko: Studying Psychosis in 22q11 Deletion Syndrome
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
Df(16)1/+ TC deficits are rescued by antipsychotics
TC projections CC projections
DH
TC deficit is also rescued by:
• clozapine
• olanzapine
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
ACx
MGv
Normal
ACx
MGv
22q11DS
Drd2
Dgcr8
miRNAs ?
Sensitivity to
antipsychotics
Chun et al. Science, 2014
Late onset
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