Kei Cho (Professor of Neuroscience) Henry Wellcome LINE and MRC Centre for Synaptic Plasticity How...

Kei Cho (Professor of Neuroscience)

Henry Wellcome LINE and MRC Centre for Synaptic Plasticity

How does Aβ influence synaptic plasticity?

How does Aβ regulate postsynaptic proteins?

Synaptic Plasticity: Pathways towards and away from Amyloid- peptide-mediated synaptic dysfunction

MRCMedicalResearchCouncil

Centre for Synaptic Plasticity

Synaptic Plasticity and Alzheimer’s Disease

Cerebral elevation and accumulation of A1-42 peptide in many aspects of AD mediated pathogenesis.

Oligomeric forms of A1-42 in the extracellular space correlates with cognitive decline and synaptic alterations (impairment of LTP, inflammation, fibrillization)

Synaptic Transmission

The role of AThe role of A in synaptic in synaptic plasticityplasticity

AA

LTP

LTD

Intracellular

Extracellular

?

A oligomers PlasmaMembrane

Signal cascades

?Output

Neurotoxicity, Cell death, Atrophy,

Synaptic dysfunction

Target and Strategy

Using a combination of biochemistry, molecular biology and electrophysiology, the project will explore whether soluble A regulates enzymes and postsynaptic protein-protein interactions involved in LTP and LTD.

Molecules of interest include PSD-95, GRIP1, PICK1, AMPARs, caspase and neuronal calcium sensors.

Method & Application

Dominant-negative

shRNAi

Interfering-peptide

Overexpression

Antibody

Pharmacology

Target Assays

Synaptic Transmission

Synaptic Plasticity (LTP/LTD)

Morphological Plasticity (multi-photon imaging)

Protein-protein interaction (Co-IP/GST-Pull down/Western-blot)

Target ProteinTarget ProteinRNAiRNAi

FluorescenceFluorescenceMarkerMarker

Two-Photon image:

Electrophysiology:LTP/LTD,Basal synaptic transmission(AMPAR and NMDAR-mediatedSynaptic current)

Approach 1

Dendritic spine morphology, Spine / Presynaptic bouton calcium imaging, Time-lapse imaging

Approach 2

A oligomers

Protein AssayBrain slice culture with A

Recent Relevant Publications from the Cho and Collingridge Groups

LTP inhibits LTD in the hippocampus via regulation of GSK3beta (2007, Neuron 53, 703-717)

Synaptic accumulation of PSD-95 and synaptic function regulated by phosphorylation of serine-295 of PSD-95 (2007, Neuron 56, 488-502)

An essential role for PICK1 in NMDA receptor-dependent bidirectional synaptic plasticity (2008, Neuron, 57, 872-882)

Metabotropic glutamate receptor-mediated LTD involves two interacting Ca2+ sensors, NCS-1 and PICK1 (2008, Neuron, 60, 1095-1111)

Postsynapticneuron

Molecule to Cognition Unit Satellite Research Facility

Molecule to Cognition Unit Consortium:

Graham Collingridge, Bong-Kiun Kaang, Sang-Jeong Kim and Min Zhou, Kei Cho (Adjunct Faculty)

United Kingdom Canada

SPINE (Synaptic Plasticity & Integrative Neuroscience and Endocrinology), Bristol

Physiology, Univ. of Toronto

MRC Centre for Synaptic Plasticity, Univ. of Bristol

Henry Wellcome Laboratories for Integrative Neuroscience & Endocrinology, Univ. of Bristol

Molecule to Cognition Unit

Brain & Cognitive Sciences, SNU, Korea

Henry Wellcome LINE

Alzheimer’s Disease

Synaptic Plasticity & Repair

Molecular Biology & Stem Cell Biology

MRC Centre for Synaptic Plasticity (23PIs)

SPINE, Bristol

Stress & Endocrinology

Multi-Photon Imaging Technique

Multi-photon microscopy enables high resolution imaging in brain tissue (e.g. slices and in vivo).

Confocal microscopy is limited to thin tissue preparations (cell cultures or organotypic slices)

1 m

High resolution multi-photon image: dendrite with spines

Single-Photon Multi-Photon

Not Just Experiment but also……..

Molecule to Cognition Unit Satellite Research Facility

‘Best Regards’ to All of You from Kei’s Lab

Plus Me!