From molecule to memory in the cerebellar neural circuit
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From molecule to memory in the cerebellar neural circuit. Sang Jeong Kim Department of Physiology Seoul National University College of Medicine, Korea. Linden DJ (2003) Science 301. Cerebellar cortical circuit. Purkinje cell (PC) - Main sole output of cerebellar cortex. Sensory-motor

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From molecule to memory in the cerebellar neural circuit

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From molecule to memory in the cerebellar neural circuit

From molecule to memory in the cerebellar neural circuit

Sang Jeong Kim

Department of Physiology

Seoul National University College of Medicine, Korea


Cerebellar cortical circuit

Linden DJ (2003) Science301.

Cerebellar cortical circuit

Purkinje cell (PC)

- Main sole output of cerebellar cortex

Sensory-motor

input

Error signals

Motor output

Two inputs to PC : parallel fiber (PF)

climbing fiber (CF)


Pairing of pf and cf induces long term depression ltd of pf pc synapse

Pairing of PF and CF induces long-term depression (LTD) of PF-PC synapse

Parallel

fiber

Pairing

Tone

180

160

140

LTD

120

Purkinje Cell response

100

80

60

Climbing

fiber

Shock

40

-10

-5

0

5

10

15

20

25

30

35

Time (min)

LTD = Memory trace


Eye blink conditioning a simple form of associative motor learning

Eye-Blink Conditioning:A simple form of associative motor learning

LTD = memory trace -> Tone means Shock

Linden DJ (2003) Science301.


Dendritic spines of cerebellar purkinje cell

Dendritic spines of cerebellar Purkinje cell


Pf pc synapse

PF-PC synapse

Presynaptic

Terminal of PF

  • Excitatory glutamatergic synapse

  • Single firing of PF evokes fast excitatory postsynaptic current (fast EPSC) via AMPA receptor (GluR2-containing, Ca2+-impermeable variety).

  • Mature PC has no NMDA receptor.

  • Pairing of PF and CF induces long-term depression (LTD) which is internalization of AMPA-R in dendritic spines of PC.

  • AMPA-R LTD is a memory trace

  • PF drives PC up to 100 Hz.

Glutamate

Spine

of PC

AMPA-R


Metabotropic glutamate receptor type1 mglur1

Metabotropic glutamate receptor type1 (mGluR1)

Presynaptic

Terminal of PF

  • Single firing of PF : fast EPSC only

  • Tetanic burst stimulation of PF

  • Spillover of glutamate to perisynaptic region

  • mGluR1 in the perisynaptic region of the spine

  • Activation of mGluR1 by burst only

Glutamate

Spine

of PC

AMPA-R

mGluR1

LTD is mGluR1-dependent: mGluR1 knock-out mice show defects in PF-PC LTD and motor learning


Mglur1 mediated signaling in pf pc synapse

mGluR1-mediated signaling in PF-PC synapse

Presynaptic

Terminal of PF

  • mGluR1 signal has two limbs

    • 1) PLC pathway

    • IP3-mediated Ca release

    • 2) Activation of membrane conductance

    • Slow excitatory postsynaptic current (slow EPSC)

Glutamate

Spine

of PC

AMPA-R

DAG

Gq

Ca2+

IP3

PLCb4

mGluR1

pump

Ca2+

TRPC1

IP3R1

Na+, Ca2+

Ca2+

RyR

Endoplasmic reticulum


Tetanic stimulus to pf induces mglur1 evoked slow epsc in purkinje cells

Tetanic stimulus to PF induces mGluR1-evoked slow EPSC in Purkinje cells

100 pA

0.5 s

2,5,10,15 pulses in 100 Hz, 14 mA tetanus at -70 mV

10 mM CNQX

04020318-22


The slow epsc evoked by parallel fiber bursts is mediated by an mglur1 trpc1 pathway

The slow EPSC evoked by parallel fiber bursts is mediated by an mGluR1-TRPC1 pathway

Slow EPSC is also blocked by a dominant-negative TRPC1 and a TRPC1 Ab

Kim et al, 2003 nature


Ltd of the parallel fiber evoked mglur1 mediated slow epsc by strong depolarization

LTD of the parallel fiber-evoked mGluR1-mediated slow EPSC by strong depolarization

Pre

PF burst

(10 pulses, 100 Hz)


Ltd of the parallel fiber evoked mglur1 mediated slow epsc by strong depolarization1

LTD of the parallel fiber-evoked mGluR1-mediated slow EPSC by strong depolarization

Pre

30 s after depol

PF burst

(10 pulses, 100 Hz)


Ltd of the parallel fiber evoked mglur1 mediated slow epsc by strong depolarization2

depolarization

LTD of the parallel fiber-evoked mGluR1-mediated slow EPSC by strong depolarization

A

Pre

30 s after depol

1200 s after depol

n=11

120

100

80

Current amplitude (%)

60

40

200 pA

0.5 s

**

20

PF burst

(10 pulses, 100 Hz)

0

Fast EPSC( )

Slow EPSC( )

B

120

1 s

n=14

n=11

100

2 s

100

*

5 s

80

80

60

Slow EPSC (%)

60

Slow EPSC (%)

40

40

n=11

20

20

**

0

0

Time (s)

1

2

5

-300

0

300

600

900

1200

1500

Duration of depolarization (s)


How mglur1 itself undergoes ltd

How mGluR1 itself undergoes LTD?


Ltd mglur1 is blocked by removing external ca

200 pA

1 s

LTD(mGluR1) is blocked by removing external Ca

depolarization (n=14)

A

Ca-free

120

90 s after depolarization

Pre

100

80

Current amplitude (%)

60

Fast current

Slow current

DHPG/Glu

40

20

Time (min)

-6

-4

-2

0

2

4

6

B

depolarization (n=11)

Ca-free

120

Pre

Ca-free ACSF

5 min after depolarization

100

80

Current amplitude (%)

60

40

Fast EPSC

Fast EPSC

200 pA

Slow EPSC

Slow EPSC

PF burst

20

0.5 s

0

Time (min)

-10

-5

0

5

10

15

20


A dynamin blocker dynasore inhibited ltd of mglur1

A dynamin blocker, dynasore inhibited LTD of mGluR1

Before depolarization

30 min after depolarization


What is the function of ltd of mglur1 in physiological and patho physiological conditions

What is the function of LTD of mGluR1 in physiological and patho-physiological conditions?


Physiological cf bursts produce ltd of mglur1 mediated dendritic ca transients

Physiological CF bursts produce LTD of mGluR1-mediated dendritic Ca transients

Pre-drug

+CPCCOEt

100 %

1 s

1 mm

PF burst

CF burst x 50

50 %

20 s

dF/F

1 nA

CF burst x 50

100 %

1st burst

2nd burst

50th burst

1 s

20 mV

20 ms

1.2 s


Ltd mglur1 blocks subsequent ltd of ampa rs

LTD(mGluR1) blocks subsequent LTD of AMPA-Rs

B

After LTD(mGluR1) (n=8)

Control (n=9)

A

100 pA

100 pA

0.1 s

0.1 s

pairing

pairing

180

180

160

160

140

140

120

120

Normalized EPSC (%)

Normalized EPSC (%)

100

100

80

80

60

60

40

40

Time (min)

Time (min)

-10

-5

0

5

10

15

20

25

30

35

-10

-5

0

5

10

15

20

25

30

35

C

PF

5 stim. @ 100 Hz

X 30, 2 sec interval

PC

0 mV for 75 ms


Ltd of mglur1 in a ischemia model oxygen glucose deprivation in organotypic slice culture

120

100

80

60

40

20

0

600

48hr

6hr

con

24hr

1hr

500

120

400

100

% of PI uptake

300

80

60

200

40

100

20

0

0

48hr

con

24hr

6hr

1hr

Control

OGD(100min)

LTD of mGluR1 in a Ischemia Model: Oxygen-Glucose Deprivation in Organotypic Slice Culture

48hr after OGD

24hr after OGD

6hr after OGD

1hr after OGD

Surface expression of mGluR1a

Con

OGD(100min)

Control

Surface mGluR1a

Total mGluR1a

DIC

Actin

Total expression of mGluR1a

PI staining


Internalization of mglur1 as expression mechanism of ltd of mglur1

Internalization of mGluR1 as expression mechanism of LTD of mGluR1

Spine

Internalization ??

mGluR1

Depolarization

CF

Hypoxia

mGluR1

LTD of mGluR1

AMPA 수용체 (AMPAR)


Taking advantages of multiphoton microscopy

Taking advantages of multiphoton-microscopy

  • Higher axial resolution

    • Monitoring of tagged mGluR1 distribution

  • Greater sample penetration

    • Dendritic and axonal mobility in the intact brain such as spinal cord

Multi-photon

Single-photon

OGB-1, Zeiss LSM 510


Implementation

Implementation

mGluR1/TRPC signaling

Identification

Coincidence detector for AMPA-R LTD

Function

Regulation

LTD of mGluR1/TRPC

Control

Mechanisms of mGluR1 internalization

Tool Development

Peptide delivery to Purkinje cell

Vestibulo-ocular reflex

Apply to Behavior


From molecule to memory in the cerebellar neural circuit

Acknowledgements

Lab of Neuronal information storage, Seoul National University College of Medicine

(http://brain.snu.ac.kr)

  • Sang Jeong Kim

  • Jun Kim

  • Hong Goo Chae

  • Yunju Jin

  • Yon Wha Hong

  • Hae Young Kim

  • Lyan Choi

  • Won Sok Chang

  • Sung Soo Chang

  • Ji Young Kim

  • Sung Won Hur

  • Chang Hee Kim

Johns Hopkins University: David Linden Lab, Paul Worley Lab


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