Bi/CNS 150 Lecture 21

Friday November 15, 2013

Learning & Memory 1. Synaptic plasticity

Henry Lester

Chapters 66, 67

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From The Organization of Behavior by Donald Hebb, 1949:

“When an axon of cell A is near enough to excite cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells

firing B, is increased.”

Hebb postulated that this behavior of synapses in neuronal networks would permit the networks to store memories.

A Hebbian synapse is a “coincidence detector”

NMDA receptors, back-propagating action potentials, and summation of epsp’s appear to be the components that confer “Hebbian” behavior on the

synapse.

The Hebbian Synapse

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The Hippocampus—a Key Region for Memory and Learning

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Many synapses occur on spines, which form on dendritic shafts.

Spines are dynamic, plastic, changeable.

Reconstruction of dendritic spines from serial EM pictures in hippocampus

Atlas of Ultrastructural Neurocytology, http://synapse-web.org/atlas/contents.stm4

Electron micrograph of hippocampalsynapse

“Map” of micrograph to the left

400 nm

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A postsynaptic density, with a cartoon of important proteins

NMDA receptor

AMPA receptor

CaMKII

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1. Binding of glutamate

2. Strong postsynaptic membrane

depolarization

(as by an action potential)

The depolarization relieves block by Mg2+

Modified from Zigmond et al. (Eds.) Fundamental Neuroscience, Sinauer (1999)

The coincidence readout:

NMDA receptors are very permeable to Ca2+

NMDA receptors are “coincidence detectors”.Their channel opens only when two events happen concurrently:

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Mary Kennedy

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Mechanism of Activation of CaMKII, and “Autophosphorylation”

Autophosphorylation of CaMKII can prolong its activation by calcium.

CaMKII is activated by the calcium-binding protein

calmodulin

“Ca2+/calmodulin-dependent protein kinase”

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Control of Synaptic Plasticity by NMDA Receptors

I. The central role of Ca2+ in initiation of long-term plastic changesA. The “Ca2+ hypothesis” for control of synaptic plasticityB. Measurement of cytosolic Ca2+ with fluorescent dyes.

C. Control of postsynaptic Ca2+ by “spike timing”

II. Structure and behavior of the NMDA receptorA. Subunit composition

B. Gating (“coincidence detection”)C. Ion selectivity (Na+, K+, Ca2+)

D. Kinetics, NMDA receptors are slower than AMPA receptorsE. Pharmacology

F. The NMDA receptor is also a “scaffold.”

III. The postsynaptic densityA. LTP and LTD are triggered by Ca2+-sensitive signaling machinery

located near the mouth of the NMDA receptor.B. Critical components of the postsynaptic density

C. Biochemical pathways mediating changes in synaptic strength

From previous lectures

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Synaptic Plasticity in the Hippocampus, Cortex, and Striatum

Synapses in the cortex and hippocampus are tightly regulated.1. Regulation helps to maintain homeostatic balance

Homeostasis, adaptation, plasticity, compensation:

These are summary processes, not mechanisms.

They are best used as adjectives.

We do not say, “a synapse changes because of homeostasis”;

We say, “a synapse changes because of a homeostatic process”

During the 21st century, scientists will continue to discover . . .

the molecular instantiations of homeostatic processes.

2. It also serves to process and store information in neural circuits.

The chemical synapse is a biophysical machine, specialized to function on a time scale of milliseconds and a distance scale < 1 μm.

But **also** to adapt to changing needs and activity levels.

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I. The size of synaptic potentials can be modulated: A. by regulating the number of number of vesicles (quanta) released.

B. by regulating the size of the current generated by a released quantum at the postsynaptic membrane.

II. Short term modulation (ms - min)A. The mechanisms of these forms of modulation are almost

always presynaptic.B. Paired-pulse facilitation (~10 to 100 ms)

C. Synaptic depression (50 ms to min)D. Post-tetanic potentiation (min)

III. Long-term plasticityA. The mechanisms of these forms of modulation are

usually both pre- and postsynapticB. LTP (30 min to yr)C. LTD (30 min to yr)

Presynaptic vs. Postsynaptic

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Paired Pulse Facilitation

Paired activations of a synapse onto a Layer 2/3 cortical neuron. “Residual Ca2+” in terminal for 10 to 100 ms after first stimulus

increases probability of release.

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Short-term Synaptic Depression

Successive stimuli at 50 Hz

Cook et al. Nature 421, 66-70 (2003)

Both the rate and the steady-state level of

depression depend on the stimulus frequency.

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Post-Tetanic Potentiation

PTP believed to be caused by a large accumulation of Ca2+ in the terminal caused by a high frequency tetanic stimulation.

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Recording of Long-Term Potentiation in a Hippocampal Slice

Stimulation frequencies that produce LTP usually range from ~50 to 200 Hz.

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I. Frequency-dependent Long-term Potentiation (LTP)

A. This term actually represents many mechanisms, all of which

result in strengthening of the synapse for varying periods of time

following tetanic stimulation.

B. The mechanisms for LTP lasting 30 min to a few hr do not require

new protein synthesis

C. The mechanisms for LTP lasting longer than a few hr do require

protein synthesis.

II. Frequency-dependent Long-term Depression (LTD)

A. This term also represents many mechanisms

B. LTD, like LTP is thought to be used for sculpting circuits to store

information.

III. Spike-timing dependent synaptic plasticity (STDP) is thought to arise

from the same set of mechanisms as LTP and LTD.

Long-term Synaptic Plasticity

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Postsynaptic Calcium Levels and Synaptic Plasticity

1. Level and timing of Ca2+ rise in spine determines LTD or LTP.

2. Low frequency synaptic firing (~5 Hz) produces LTD; high frequency synaptic firing (~50 to 100 Hz) produces LTP.

3. The same Ca2+ rules may underlie “spike-timing-dependent synaptic plasticity (STDP).

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Recording of LTD in the Hippocampus

Stimulation frequencies usually range from 1 to 10 Hz.

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Two cellular processes underlie the major changes during LTP and LTD

1. Insertion of AMPA receptors into the postsynaptic membrane (LTP); or

their removal from the postsynaptic membrane (LTD).

2. Growth or shrinkage of the spine via reshaping of the actin cytoskeleton.

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LTP is probably “input specific”

Figure 67-6

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Spike-timing Dependent Synaptic Plasticity

From Bi and Poo J. Neurosci. 18, 10464 (1998)

These recordings were made on cultured neurons

See next slide for experiments in slices.“anti-Hebbian” “Hebbian”

Pre- fires 5-30 ms before post → LTPPre- fires 5-30 ms after post → LTD

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Supralinear influx of Ca2+ during paired EPSP and AP

From Schiller, Schiller and Clapham, Nature Neuroscience 1, 114 (1998)

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Figure 67-8

Early LTP,< 2 h

Increased size of quantum usually arises from

additional receptors

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Figure 67-8

Late LTP, > 2 h

Increased number of quanta usually arises from additional release

Protein synthesis is involved

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Overall View of NMDA-dependent LTP in hippocampus (CA3-CA1 synapse)

Gene activation via CREB / CRE

Dendritic protein synthesis

Retrograde signal(nitric oxide?)

Cytoskeleton changes?

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Targets of calcium influx through the NMDA receptor

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1. Calcium ion flows through the activated NMDA receptor.

Role of CaMKII in LTP

2. One of its targets is calcium/calmodulin-regulated Protein Kinase II (CaMKII).

3. CaMKII can phosphorylate the subunits of the AMPA receptor.A. The phosphorylated AMPA receptor has a larger currentB. This is likely one mechanism of relatively short LTP (30 min or so).

5. Helps regulate processes that re-arrange and enlarge the cytoskeleton.

4. CaMKII initiates a process that results in addition of new AMPA receptors to the synapse

A. This process may be developmentally importantB. It likely also contributes to longer lasting LTP.

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2. One of its targets is calcineurin (or protein phosphatase 2B), a Ca2+/CaM-dependent protein phosphatase.

Role of Calcineurin in LTD

1. Calcium ion flows through the activated NMDA receptor.

3. Calcineurin regulates an inhibitor (Inhibitor 1) of a more general protein phosphatase called phosphatase 1.

A. Inhibition of calcineurin blocks induction of LTDB. LTD results from removal of AMPA receptors by endocytosis.

C. One popular hypothesis is that the direction of long-term changes in synaptic strength depends on the relative levels of activation of

CaMKII and calcineurin.

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Signals in long-term depression

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Dominant negative

Distinct Molecular Bases

of

Long-Term Potentiation

at

Three Synapses in Hippocampus

Figure 67-331

Figure 67-18

LTP changes DNA methyltransferases (DNMT)

Epigenetic Changes in Chromatin Structure may also Participate in Long-Term Memory

Phosphorylation of CREB-1

Recruits CREB Binding Protein (CBP-1)

CBP acetylates lysine(+) resides on histones

Histones release DNA(-)

Allow transcription during late LTP

Figure 67-18

This recruits methyl-CpG binding proteins (Me-CpG-BP)

This recruits histone deacetylases (HDAC), which remove actyl groups

This allows CREB-2 binding, which represses transciption

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End of lecture 21

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Henry Lester’s”office” hours 1:15 – 2 M, FRed Door

Spike-timing Dependent Plasticity in Cortical Neurons

Dual whole-cell patch recordings from neurons in cortical slices from 14-16 day old rats (Markram et al., Science 275, 213 (1997)

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NMDA-Dependent Long-Term Potentiation in the Hippocampus

Stim.

Record

The third synapse in the “tri-synaptic pathway”35