Neuroscience essay: Synaptic Plasticity

This is a scientific essay! Only for tutors with Neuroscience background or someone who can write a scientific essay.

Please refer to these scientific papers http://www.actabiomedica.it/data/2007/supp_1_2007/benfenati http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827315/

Instructions on how to write your essay.

The paper has to meet the following criteria:

The text should be a review of minimal 1500 and maximal 2500 words, covering the topic of synaptic plasticity.

The review should include the following sections: introduction, main part of text , conclusion, and references.

The first part is the introduction. Start with a heading:

Introduction

. The introduction outlines the overall background of the topic, provides relevant information and logically leads to the aim of the paper, which should be at the end of this section. No further text should follow the aim of the paper. The introduction is limited to max 300 words.

The second section of the paper, the main text, starts without a general heading like Results or Discussion. You should organize the main text by using headings and subheadings that help the reader to a structured reading and make it easy to grasp the logic of your review paper.

The main text is followed by a section for which you use the heading: Conclusion. In this section you describe the main conclusions of the paper. This section should not include further discussion of the data and should not include references.

At the end of your paper, you should provide a list of references (Note: The list is not included in the word count). Use the heading: References for this part. Use Vancouver style.

i. Citations in the reference list are listed in the order they appear in the text, starting with number 1 (see also ii) Use abbreviated journal names as provided in PubMed.

In case of journal publications use the following format:

1. Author A, Author B, Author, C (2010) Writing of a scientific essay. J Imaginat. 5:57-63.

In case of a book chapter or a book:

2. Author A (2010) Writing of a scientific essay. In: How to write and publish a paper. A. Author, B. Author, editors. Publisher, city, country, pp 5-11.

3. Author B (2010) How to write and publish a paper. Publisher, city, country.

ii. In your text, refer to a publication by using a number in super script, in the order they appear in the paper. For example:

Introduction

The development of the entorhinal-hippocampal region continues well into postnatal life. While entorhinal-hippocampal principal neurons and interconnections are present during the late embryonic stages of development in the rat1-5, over 80% of the granule cells in the dentate gyrus are born postnatally2 and interneurons generally reach their final position only at the end of the second postnatal week6. Hippocampal dendrites continue to arborize and form synapses for several weeks after birth3,7-9, GABAergic synapses remain excitatory for about two weeks10,11, and the rhythmic network activity typical of the adult hippocampus appears only at the end of the second week12.

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LEARNING AND MEMORY
– Cellular and molecular mechanisms

Øyvind Høydal

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What is learning and memory?

 Learning can be defined as acquisition of new
knowledge or skills and/or changes in behaviour as
a result of experience.

 Memory refers to the storage and retrieval of
learned knowledge, skills or behaviours.

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 Information and skills are stored within the networks
of neurons in the brain.

 When we learn, changes take place that alters the way
neurons communicate with eachother.

 Can you guess what changes take place?

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Cellular plasticity in learning
and memory

 The efficacy of signalling between neurons are altered.

 New synapses form

 New neurons?

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Aplysia californica as a model system for
cellular learning and memory

 Studying cellular mechanisms for learning and memory in the mammalian
brain is a formidable challenge due to the enormous number of neurons and
the complexity of synaptic connections.

 Aplysia californica is an advantagous model organism because:

– Neurons are quite few (20 000) and can be identified in the circuit.

– Neurons are rather big, making them readily accessable

for in vivo intracellular recordings

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The gill-siphon reflex in aplysia offers a great
opportunity to link changes in neurons and
synapses with a behavioral output.

 When a mechanical stimulus

is applied to the siphon, the

slug responds by withdrawing

its gill.

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Gill-siphon-withdrawal reflex

Tactile

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The synapse and some common forms of short-
term synaptic plasticity

 Synaptic facilitation: rapid increase in synaptic strength when two APs arrive at the axon terminal
within a short interval of time. Increased Ca+ -influx causes more transmitter substance to be
released.

 Synaptic depression: neurotransmitter release decline with sustained stimulation. A possible
mechanism might be depletion of neurotransmitter-containing vesicles in the presynaptic neuron.

 Augementation (acts over seconds) and potentation (post-tetanic, acts over minutes) are other forms
of short-term plasticity that enhance transmitter release due to prolonged and increased Ca+ levels.

NMDA

AMPA

Na+

Ca+ Ca+ Ca
+

Na+
Na+

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Habituation in Aplysia

 Habituation: reduced response to a stimulus that is neither harmful nor
beneficial.

 In Aplysia: if the siphon is touched repeatedly, the snail will eventually stop
withdrawing its gill.

 The response in the sensory neuron is mostly unchanged, so the habituating
effect on behaviour is likely to be mediated by a change in the efficacy of the

synapse between the sensory neuron and the motoneuron.

Motor neurons

Sensory neurons

Gill withdrawal

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Habituation in Aplysia

A possible mechanism for the short-term habituating effect is that presynaptic
Ca2+ channels become less sensitive with repeated stimulation.

Long-term habituation involves a decrease in the number of synaptic contacts
between the sensory neurons and the motoneurons.

Control sensory

neuron

Habituated

sensory neuron

S
S

Long-term habituation

m
m

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S
M
S

Current

Tactile

Sensitization: Increased response to harmful stimulus and stimuli concurrent to the harmful

stimulus.

In Aplysia: touching the siphon while applying electric shock to the tail, causes enhanced

response to subsequent siphon stimulation.

Sensitization in Aplysia

Gill reflex

Stimulus

One single tail shock gives short term

(minutes) while repeting shock gives a

lasting sensitization (weeks).

Before sensitization After sensitization

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AdC

ATP

cAMP

PKA

K+

PLC
DAG

PKC

Sensory

neuron

Motor neuron

Interneuron

Short and middle term sensitization

PKA

Glutamate

Seretonin

Voltage sensitive

calcium

channel

Potassium

channel

Ca 2+

Potassium
channel
Potassium
channel

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1. Tail shock: facilitating interneurons active.

2. Facilitating interneurons release 5-HT

onto the presynaptic terminal of the

sensory neuron

3. 5-HT binds to G-protein coupled

receptors to activate adenylate cyclase.

5. cAMP activates PKA which

phosphorylates K+ channels. This

causes K+ channels to close. Now:

a) cells stay depolarised longer

b) and release more neurotransmitter

6. The synapses are more efficient in

transmitting information

4. Adenylate cyclase makes cAMP from

ATP

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Long-term sensitization

 One tailshock leads to enhanced sensitivity for several
minutes.

 If the slug is exposed to many tailshocks, the synaptic
activity (and thus the behavioural response), can be
strengthened for several days.

 This long-term response requires protein synthesis.

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G
AdC

ATP
cAMP

PKA PKA

MAPK

PKA

CREB1

CREB2

CRE

K+
K+
Interneuron
Sensory
neuron

Motor

neuron

Protein

synthesis

Mechanisms for long-term sensitization

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Molecular mechanisms for long-term sensitization

Release of serotonin from interneuron which binds to G-protein coupled receptors on

sensory neuron.

G-protein activates adenylate cyclase

Adenylate cyclase transforms ATP to cAMP

cAMP activates PKA

PKA recruites MAPK

PKA activates CREB1

MAPK deactivates CREB2, wich when active inhibits CREB1.

CREB1 bindes to CRE wich induce transcription of genes involved in synaptic growth and

development.

S S

Normal neuron Sensitized neuron

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Structural changes in long-term habituation and
long-term sensitization

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 So the sensory-to-motor pathway in Aplysia serves as a
prime example of how changes in synapses can lead to
a changed (learned) behavior.

 But what of the more complex declarative memories of
humans? Can these also be explained by changes in
synaptic transmission?

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Molecular mechanisms for LTP

 3 main type of glutamate receptors

 AMPA/kainate are iontropic Na+

channels

 NMDA receptors also pass Ca2+

currents, but the pore is blocked by

Mg2+ unless the cell is depolarised.

 NMDA receptors thus have the

requirements to act as coincidence

detectors.

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LTP induction (early phase)

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LTP induction (late phase)

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Structural changes associated with LTP

 LTP induce formation of dendritic spines.

 LTP causes existing spines to split or enlarge.

 Ref lects an increase in synaptic contacts.

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 In essence LTP depends on influx of sufficient amounts of Ca2+ to
activate kinases (phosphorylating enzymes). These kinases cause
higher activity in AMPA receptors, more AMPA receptors to be
included in the membrane, and synthesis of proteins involved with
making new spines etc.

 The net result is that the presynaptic cells become more efficient at
activating the postsynaptic cell.

 However, if all synapses could only increase in strength, then at some
point LTP would reach its limits.

 The opposite phenomena, where synapses decrease in strength, is
termed long term depression (LTD).

 This phenomena also depend on the NMDA receptor.

 How?

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LTD
 Whether we have LTP or LTD depends on the amount

of Ca2+ that enters the cell.

 If the cell is depolarised when the stimulus

arrives, alot of Ca2+ will enter to activate kinases.

This results in LTP.

 If the cell is not depolarised, little Ca2+ will enter. This

activates phosphatases (enzymes that dephosphorylates

proteins). This causes reduction of AMPA receptor

activity and density and, in the long term, a decrease in

number of dendritic spines. The result is thus a long term

depression (LTD) of the synapse.

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Spike timing dependent plasticity (STDP)

 Just before the postsynaptic cell fires an action potential, it is highly
depolarised. This relieves the Mg2+ block from the NMDAR. Thus, if the signal
from the presynaptic cell arrives just before the postsynaptic cell fires, large
amounts of Ca2+ will enter the postsynaptic cells, and the result will be LTP.

 Conversely, if the postsynaptic cell has just fired an action potential, it is
hyperpolarised. If the signal from the presynaptic cell arrives at this point, little
Ca2+ will enter the postsynaptic cell, and the result will be LTD.

 Since the direction of plasticity relies on the timing of the presynaptic spiking
activity relative to the postsynaptic activity, this phenomena has been termed
spike timing dependent plasticity.

 In short, the connections between neurons that are active simultaneously will
be strengthened. The connections between asynchronized neurons will be
weakened.

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LTP has several features that makes it an
attractive candidate as a cellular mechanism for

learning and memory

 Induction is rapid and long-lasting

 Input specificity

 Cooperativity

 Associativity

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Questions to be answered if we want to know if
LTP really is a cellular mechanism for learning

 If we block or modify factors involved in LTP-
induction, will it also affect learning and memory?

 Does LTP accompany learning?

 If we saturate LTP, will it affect subsequent learning?

 Does learning occlude further LTP?

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Effects of manipulating LTP

 Spatial memory is commonly

studied using the Morris water-maze

task.

 NMDA-knockout mice show impaired

LTP and deficits in spatial learning

Tsien et al., 1996

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Effects of manipulating LTP

 PKMζ is neccesary for maintaining

LTP.

 Blocking the activity of PKMζ with

the drug ZIP erases both LTP and

memory.

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Does LTP accompany learning?
 Inhibitory avoidance (IA) training induce rapid learning.

 IA trained animals display LTP in the dorsal CA1 area of the hippocampus

ControlShock

GluR1

Actin

Trained vs. Walk Shock vs. Control

GluR1

Trained Walk

NR1

NR1
Actin

100

110

120

130

140

%
C

o
n

tr
o

l
c
o
n

d
it
o

n
s

Trained Walk
GluR1
GluR1
Actin

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Effects of saturating LTP prior to learning

 Saturating LTP impairs spatial learning.

 Infusing an NMDA antagonist rescues

memory.

Moser et al., 1998

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Does learning occlude subsequent LTP

 LTP induced by IA training occludes subsequent LTP

in vivo

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From LTP/LTD to memory

 So the mammalian brain clearly displays synaptic
plasticity, and seemingly it is very much involved with
learning and memory.

 But how can changes in synapses result in the
formation of complex memories?

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Hebbian learning theory

 «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 so that A’s efficiency as one of the cells firing
B is increased».

 In short: “Neurons that fire together wire together”

 And: “Neurons that fire out of sync lose their link”

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Hebbian learning theory

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= ”Cirkel”

External

stimulus
Cell

assembly

Activation in cell

assembly

Reverberating

Activity in

Cell assembly
Hebbian

modification

Hebbian learning Memory / Engram

Partly activating

of network gives

Activation in whole

Bear 2008

reciprocal connections

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2006 2007

Leutgeb & Moser, Neuron, 2007

David Marr:
Pattern
separation
(1969)

Different memories are stored as different
patterns

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Emotions and memories

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Good luck on your exam!!!!

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