Understanding genetic predisposition

CircuitCellGene System

Mutation

Behavior

DiseasePhenotype

22q11 deletion model mice

• Models smaller oftwo deletions

• 1.5 Mb deletion, 24genes

• Syntenic region:Mouse chr. 16

• Df(16)A+/– mouse

Joseph Gogos & Maria KarayiorgouStark et al., Nat Genetics, 2008; Mukai et al., Nat Neurosci, 2008

Understanding genetic predisposition

CircuitCell SystemGene

22q11

Behavior

Cognition

Testing working memory in rodents

T-maze Delayed-non-match-to-sample Test

Choice phaseDelaySample phase

Understanding genetic predisposition

CircuitCell SystemGene

22q11

Behavior

CognitionHPC/PFC

mPFC spike

dHPC LFP

200 ms

Probing circuit dynamics during behavior

Df(16)A+/– Mice are Deficient inmPFC-dHPC Phase-Locking

**

Phase-lockin

g(M

RL)

0

0.02

0.04

0.06

0.08

0.1

WT Df(16)

Mean

resulta

nt

length

Sample Choice0.1

0.12

0.14

0.16

0.18

Sigurdsson et al., Nature, 2010

Understanding genetic predisposition

CircuitCell SystemGene

22q11

Behavior

CognitionHPC/PFC

vHPC-to-PFC

Mukai et al, Neuron, 2015

Deficits in axon outgrowth/branching

MutantWT

Understanding genetic predisposition

CircuitCell SystemGene

22q11

Behavior

CognitionHPC/PFC

vHPC-to-PFC

AxonalBranching

• Zdhhc8: palmitoylationenzyme

• Deficiency:

- Altered axonal proteome

- Altered phosphorylation ofAkt1 & GSK3b at axon tip

- Impaired neuriteoutgrowth in vitro & in vivo

- Reversed with Gsk3bantagonist

Mukai et al, Neuron, 2015

22q11 dysconnectivity:Molecular & cellular basis

Branching(% of WT)

WT Z Z+SB

Developmental inhibition of Gsk3b

Tamura et al., Neuron, 2016

P2 P27 P90

DailyTreatment with

SB216763 Implant T-maze

Developmental inhibition of Gsk3b rescuesworking memory deficits in Df(16)+/– mice

* *

Vehicle SB216763

Behavior

Tamura et al., Neuron, 2016

Understanding genetic predisposition

Circuit SystemGene

22q11(Zdhhc8)

Behavior

CognitionHPC/PFC

vHPC-to-PFC

Cell

AxonalBranching