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!