Plasticity How are synapse number & strength adjusted?

anatomical evidence

electrophysiological evidence

Elimination of synapses during development

Visual deprivation

The role of spontaneous activity

Sensory experience: activity influences synaptic connections

Activity-dependent synaptic depression

Calcium and NMDA receptors

Mechanisms of synaptic plasticity

Keller-Peck et al., 2001!

P7! P8! P9!

Elimination of motor neuron contact in vivo

motor axons (green) endplate (red)

Functional synapse elimination

Synapse elimination in visual cortex

LeVay et al., 1978; Crair et al., 2001!

P21

P14

P8

P92

P39

P22

Hubel and Wiesel, 1962!

The geniculocortical pathway

Control

Monocular deprivation

Wiesel and Hubel, 1963!

NR

NR

Wiesel and Hubel, 1965!

Binocular deprivation

Hubel and Wiesel, 1965!

Strabismus

Ocular Dominance

LeVay et al., 1980!

Critical periods Layer 4 Stripes

Age of Monocular Deprivation (mos)

Stryker and Harris, 1986!

Spontaneous activity & synapse elimination Dark rear Action potential blockade

Meister et al., 1991; Demas et al., 2003!

Spontaneous activity in the retina

Tritsch et al., 2007!

Spontaneous activity in the cochlea

isolated cochlea

Garaschuk et al., 2000!

Spontaneous activity in the cortex

Adelsberger et al., 2005!

Spontaneous activity in the cortex

Sretavan and Shatz, 1986: Stellwagen et al., 2002!

Increase spontaneous activity in one eye

contra projection ipsi projection More active projection expands

Spontaneous activity & synapse elimination

Forskolin!

larger

contra ipsi

Control!

cAMP!

Stryker et al., 1978; Pasternak et al., 1985!

Influence of environment on coding properties

Li et al., 2006, 2008!

Influence of environment on coding properties

Rapid induction of direction selectivity

Li et al., 2008!

Imaging the intrinsic signal of visual cortex in response to moving bars

Visually inexperienced ferrets

stimulus direction

exposure time (hours)

responds to rightward moving bar

Auditory system plasticity

24 hours stimulation !

T1-weighted brain images!Sound Stimulation!

16 kHz (4 Hz AM)! 40 kHz (4 Hz AM)!

0.4 mmol/kg!

MnCl2 injection!

Brain imaging with Mn-enhanced MRI

Yu et al., 2007

7-Tesla horizontal magnet! 100 µm resolution!

pre-IP injection 24 h post-injection

Rearing: 16 + 40 KHz (75 dB SPL; AM; 20-23 hr/day)

dB SPL

kHz

Two-tone rearing protocol

16 32 64 0 0

80

40

P19

16 kHz

or

40 kHz

Stim Mn

Quiet

P18

pre-injection 24h post-injection

P9 P20

Image

7-Tesla horizontal magnet! 100 µm resolution!

Influence of environment on tonotopic map

Rear with!16+40 kHz tones!Control!

Yu et al., 2007

Rear with 7.1 kHz tone

?

Han et al., 2007

7.1 kHz Control

28

14

7.0

3.5

1.8

Cha

ract

eris

tic fr

eqen

cy (k

Hz)

Rear with 7.1 kHz tone!

Influence of environment on tonotopic map!

Influence of environment on auditory behavior

Han et al., 2007!

Rear with 7.1 kHz tone!

100!

0!

Discrimination Performance at ∆0.1 octave!

(%)!

5.0! 5.9! 7.1! 8.4! 10! 11.9!14.1!16.8!20!Frequency (kHz)!

Control!

7.1k-reared!

*!

*!

*!80!

60!

40!

20!

Synaptic mechanisms of plasticity

Lo and Poo, 1992

Heterosynaptic depression in vitro

Synaptic depression & synapse elimination

Li et al., 2001

presynaptic terminal

Synaptic depression & elimination

postsynaptic ACh receptors

Yang et al., 2001

Synaptic depression & elimination

LTD correlated with elimination in hippocampus

Label pre and postsynaptic cells

pre

post

Stimulate presynaptic to induce LTD

pre

post yellow is area of colocalization

Bastrikova et al., 2008!

Bastrikova et al., 2008!

LTD (% of initial baseline)

Col

ocal

izat

ion

(% o

f bas

elin

e)

More LTD is correlated with less colocalization

LTD correlated with elimination in hippocampus

Synaptic depression depends on Ca+2

Cash et al., 1996!

Activator of postsynaptic CaMKII decreases retinal axon arbor

Zhou and Cline, 1996!

Control axons!

Active CaMKII!

NMDA receptors & excitatory synaptic plasticity

Three-eyed frogs have stripes in tectum

Constantine-Paton and Law, 1978!

Cline et al., 1987; Cline and Constantine-Paton, 1990!

Segregation of retinal axons & NMDA receptors

Review: Hensch, 2005!

Critical period for MD in mice

(a lot of) molecular mechanisms

Review: Tropea et al., 2009!

Review: Hensch, 2005!

Inhibitory control of critical period

Enhance GABA Function critical period ends early

Pla

stic

ity (r

espo

nse

to m

onoc

ular

dep

rivat

ion)

Age (days postnatal) 30 13

Reduce GABA Function critical period ends late

Only effective when cells are 33-35 days old

Inhibitory control of critical period

Use-dependent plasticity of inhibitory synapses

Kotak et al., 205, 2008!

P10!

Sensorineural Hearing Loss"

cochlea!removal!

Use-dependent plasticity of inhibitory synapses

Kotak et al., 205, 2008!

Use-dependent plasticity of inhibitory synapses