Experimental studies on stroke-induced neural plasticity

Marcela Pekna, MD, PhD

Institute of Neuroscience and Physiology,

Sahlgrenska Academy at University of Gothenburg, Sweden

Strokeforskningsdag, Gothenburg,

September 2012

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Ischemic strokeLoss of function, dysfunction/diaschisis

Wieloch & Nikolich, Curr. Opinion Neurobiol. 2006

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• Experience-dependent plasticity of the cerebral cortex (dendritic and axonal arborization, spine density, synapse number and size, receptor density and in some brain regions also the number of neurons)

• Cortical map re-arrangements

• Contralateral hemisphere involvement

• Contralesional axonal remodeling of the CST

Pekna, Pekny, Nilsson. Stroke, 2012

Neural plasticity after stroke

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Complement

• > 35 proteins both in plasma and on cell membranes

• Essential role in the humoral immune response

• Part of the innate immune system

• Early response to invading microorganisms

• Functions: Initiation of inflammation

Neutralization of pathogens

Regulation of antibody responses

Clearance of immune complexes

Disruption of cell membranes

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Complement cascade

AlternativePathway

ClassicalPathway

LectinPathway

C3

Terminal ComplementComplex (TCC)

MBP, MASP C4, C2

C1, C4, C2C3, Factor D,Factor B

C5b, C6, C7, C8, C9

C3b

C5a

C3aR

C5aR

C5L2

C3a

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Complement plays a role in basal neurogenesis

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Reduced number of newly formed migrating neuroblasts in C3-/- and C3aR antagonist

treated miceBrdU

DCX

BrdU DCX

Rahpeymai et. al. EMBO J. 2006

p<0.

05

p<0.

0005

p<0.

0005

p<0.

0005

p<0.

0001

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Reduced number of newly formed neurons in C3-/- and C3aR antagonist treated mice

NeuN

BrdU

NeuN BrdU

Rahpeymai et. al. EMBO J. 2006

p<0.

005

p<0.

005

p<0.

005

p<0.

05

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Basal neurogenesis is reduced in C3aR-/- mice

Rahpeymai et. al. EMBO J. 2006

p<0.05

p<0.05

p<0.05

p<0.05

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C3a stimulates neuronal differentiation and maturation of NPCs

Shinjyo et al., Stem Cells, 2009

Neuronal differentiation of NPCs

Control C3a (100 nM)

200 µm200 µm

Map2ab / DAPI

0.06

0.08

0.1

0.12

0.14

0.16

*

Map

2+ DAP

I+ /D

API+

(rat

io)

--+

-+-

C5a (100 nM)C3a (100 nM)

Mea

n ou

tgro

wth

pe

r pro

cess

(µm

)

0

10

20

30

40

50

**

Control C3a (100nM)

Neurite outgrowth

0

0.2

0.4

0.6

0.8

Abso

rban

ce

(57

0 nm

)

++-

---

C5a (100 nM)C3a (100 nM)

Proliferation

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C3a modulates SDF-1α induced migration of NPCs

Shinjyo et al., Stem Cells, 2009

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The role of complement in experimental ischemic stroke

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Complement could be protective: larger infarct volume in C3-/- mice

Rahpeymai et. al. EMBO J. 2006

p<0.01

p<0.0005

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Reduced number of neuroblasts in the ipsilateral subventricular zone of C3-/- mice

Rahpeymai et. al. EMBO J. 2006

p<0.05

p<0.005

p<0.01p<0.05 p<0.05

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Reduced number of newly formed neurons in the peri-infarct region of C3-/- mice

NeuN

BrdU

NeuN

BrdU

Rahpeymai et. al. EMBO J. 2006

p<0.001

p<0.005

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Axonal rewiring after stroke: CST remodeling

Chen et al, PNAS, 2002

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Acknowledgments Gothenburg Noriko Shinjyo

Anna Stokowska

Alison Atkins

Nancy Beyer

Marta Perez Alcazar

Katarina Järlestedt

Yalda Rahpeymai Bogestål

Albert Hietala

Ann-Katrin Nilsson

Milos Pekny

Ulrika Wilhelmsson

Anders Ståhlberg

Pete Smith

Maryam Faiz

Stanford, USABen BarresAlexander Stephan

Manchester, UK Ioan Davies Andrew Fotheringham

Boston, USA Craig Gerard Alison Humbles

Houston, USA Rick Wetsel

Birmingham, USA Scott Barnum

Göttingen, Germany Jörg Zwirner

Auckland, New Zealand Mike Dragunow

Michael Nilsson

Michelle Porritt

Henrik Hagberg

Carina Mallard

Catherine Rousset

Christian Blomstrand

Christina Jern

Klas Blomgren

Marie Kalm

Yoshiaki Sato

Lars Rönnbäck

Elisabeth Hansson

Mikael Persson

Maurice Curtis

Eric Hanse

StockholmStaffan CullheimJohan ZelanoAlexander Berg

LundChristine Ekdahl

Clementson

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