Multi-site recordings in Tg4510 mice

Liam Scott

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

7 month male Tg4510 mice show decreased MWM performance and hippocampal cell loss

Are

a (

mm

2)

1

1.2

1.4

1.6

1.8

2

2.2

2.4

2.6

2.8

3 months 6 months 8 months 10 months

Wild Type

Bigenic 4510

40

50

60

70

80

90

100

110

% W

ild T

ype

3 M 6M 8 M 10 M

Wild Type

Bigenic 4510

Normalized Ca1 Thickness

Hippocampus: Area

1 2 3 40

500

1000

1500

M++M--

F++F--

Day of testing

Len

gth

of

Pat

h (

cm)

***

*

3m

1 2 3 40

500

1000

1500

** * ** *

**

Day of testing

7m

3 vs. 7 month old Tg4510 male mice show:

(Wildtype for comparison)

Data: Yabe, Moore, Roof Data: Kawabe, Klein, Milici

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

1174 1176 1178 1180 1182 1184 1186 1188 1190 1192 1194 1196 1198 1200 1202 1204 1206 1208 1210 1212s

Keyboard311000

0

-1000

uV

CA

1 E

EG

1

5274 5276 5278 5280 5282 5284 5286 5288 5290 5292 5294 5296 5298 5300 5302 5304 5306 5308 5310 5312s

Keyboard311000

0

-1000

uVC

A1

EEG

1

Stimulation of the nPO drives the hippocampal EEG in anesthetized rats and mice

NPO

Hippo

EEG Stimulus

6-seconds

0.06 0.08 0.10 0.12 0.14 0.16

5.5

6.0

6.5

7.0

7.5

8.0

Fre

quen

cy (

Hz)

Stim Current (mA)

Theta Frequency

0.06 0.08 0.10 0.12 0.14 0.1615.0k20.0k

25.0k30.0k

35.0k40.0k

45.0k50.0k

Theta Power

The

ta P

ower

(V

2 )

Stim Current (mA)

0 5 10 15HzFrequency

10000

5000

0

uV^2

CA

1 E

EG

1

0 5 10 15HzFrequency

2000

1000

0

uV^2

CA

1 E

EG

1

–5-HT

–Hippocampal Formation

–pcells

–Median Raphe

–Gl

u

–ga

ba

–ACh

–Medial Septum

–Nucleus Pontis Oralis

–(nPO)

–Gl

u

–Supramammilary Bodies

–(SUM)

–Gl

u

–ga

ba

–ga

ba –ga

ba

–ga

ba

–5-HT

–Adapted from: RP Vertes (2005) Hippocampus 15:923-35

–= +–= -

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

Determining electrode position using stimulation of nPO

4

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

7 month male Tg4510 mice show decreased nPO-evoked hippocampal theta power and total power

Peak Frequency Relative Theta Power

Theta Power Total Power

** *

*

*

* * * *

***

**

*

*

**

* *

* *

**

(*=P<0.05, **=P<0.01, ***=P<0.001 ; unpaired t-test)

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

Perforant path – dentate gyrus LTP

6

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

Determining electrode position using stimulation of perforant path

7

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

7 month male Tg4510 mice show reduced amplitude of perforant path-evoked dentate gyrus population spike

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

7 month male Tg4510 mice show reduced amplitude of perforant path-evoked dentate gyrus population spike

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

7 month male Tg4510 mice show no change in perforant path - dentate gyrus LTP

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

–control

CA-1

DG

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

CA-1

DG

DG population spike

CA1 population spike

–Tg

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements.

Summary

Stimulated theta• No change in theta frequency or relative theta• Reduction in theta power and total power

PP-DG LTP• Reduction in amplitude of evoked population spike• No change in LTP due to HFS

All observations can be explained by reduction in cell number in hippocampal formation???

14

Confidential and Internal to Pfizer - subject to works council and/or union consultations and other legal requirements. 15