12/1/17

Principles underlying information processing and storage

by the brain

Prof. Dr. Denise Manahan-Vaughan

Ruhr University Bochum
Medical Faculty
Department of Neurophysiology

Reading list

For the basics: Bear and Paradiso “Exploring the Brain”

In depth reading:

Kemp and Manahan-Vaughan, Trends Neurosci, 2007, 30:118

Kemp and Manahan-Vaughan, Cerebral Cortex, 2012 doi: 10.1093/cercor/bhr233

Hartley et al, Philos Trans R Soc Lond B Biol Sci., 2013 doi: 10.1098/rstb.2012.0510
Moser et al, Nat Rev Neurosci. 2014 doi: 10.1038/nrn3766
Muir & Taube, Behav Cogn Neurosci Rev. 2002 Dec;1(4):297-317
Pastalkova et al, Science, 2008 doi: 10.1126/science.1159775

Further reading and food for thought:

Cheng S. Front Neural Circuits. 2013 May 6;7:88. doi: 10.3389/fncir.2013.00088
Zhang et al, Front Behav Neurosci 2014 Jun 24;8:222. doi: 10.3389/fnbeh.2014.00222

ALSO: please refer to the papers cited throughout the slides/script if you wish to obtain further
information about the examples given.

N.B. The slides used in this course may not be used, reproduced or copied without the prior
permission of Prof. Dr. Manahan-Vaughan

Your Goals

By the end of this lecture course, you should be able to explain:

1. Why the statements in the three “mythology” slides shown at the start of the lecture course are wrong

2. Why neural integration potently influences the outcome of synaptic transmission

3. Why the basic principles of an attractor network, Hopfield network and Hebb assembly could underlie how networks first become
established in the hippocampus

4. Why David Marr was convinced that the CA3 region and the cerebellum fulfill key criteria as a structure that enable long-term memory

5. What grid cells, head direction cells and place cells are, where they can be found, and what they are believed to encode

6. How grid cells, head direction cells and place cells differ from one another with regard to their intrinsic properties

7. How grid cells, head direction cells and place cells are assumed to work together to generate a spatial representation

8. Why Hebb’s postulates are a key criteria for mechanisms that could underlie memory formation at the cellular level

9. What LTP and LTD are, and how they could work together to generate a long-term spatial memory

10. What the subforms of very short-lasting plasticity are, and how they arise

11. What physiological phenomena are believed lead to the “erasure” of long-term forms of plasticity, or support the rapid “switching off” of
these forms soon after their initiation.

12. The differences between pattern separation and pattern completion and how hippocampal structures may enable these processes

13. The key molecular steps in the triggering and maintenance of hippocampal LTD, hippocampal LTP and cerebellar LTD

14. How the cerebellum may interact with the hippocampus to enable optimisation of spatial representations

15. What the subcategories of memory are, in which structures they are processed, and how they are differentiated from one another in
terms of their classification with regard to persistency, durability and informational content (declarative Vs non-declarative, procedural vs
other forms of implicit memory etc…)

1
 12/1/17

Neuroscience Myths

“The average person uses 10% of their brain

capacity. “

Long-term memories are formed exclusively by

strengthening
synaptic connections
WRONG!
All long-term memories are reliable and robust.

In order for information to be processed and stored,

neurons must talk to one another.

Information is transferred from neuron to neuron by

means of synaptic transmission

• neurotransmitter is released "

into the synaptic cleft from a "
presynaptic neuron"

• it binds to a specific receptor on the

postsynaptic neuron"
and triggers a neural impulse"

2
 12/1/17

There are two types of synapses!

•excitatory: in which a pre-synaptic neuron tries to

cause the post-synaptic neuron to fire

•inhibitory: in which a pre-synaptic neuron tries to

prevent the post-synaptic neuron from firing"

•a neuron will normally have multiple excitatory

and inhibitory synapses"

•"neural integration”: the sum of the inhibitory and excitatory stimuli at a given time-
point determines whether the postsynaptic neuron will fire, be inhibited or remain
quiescent"

“ changes in synaptic structure mediate learning and memory“!

! ! ! ! ! !Tanzi, Ramon y Cajal, 1890’s"

" " " " " "!

Ramon y Cajal

“ When the axon of cell A is near enough to excite the axon of !

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. “!

A Neurophysiological Postulate"
D.O. Hebb, 1949"

3
 12/1/17

Hebbs’ concept from the perspective of computational modelling!

Attractor network: A network of nodes (i.e., neurons in a

biological network) that settle into a pattern of
coincident or mutual activation

Image source: Neuron. 2012;76(2):435-49

Hopfield network: recurrent connections between

neurons serve to stabilise the attractor network

Image source: Wikipedia

Example: creation of a SPATIAL REPRESENTATION (a map with which one "

" " "navigate one’s way through the environment"

To navigate efficiently and to build robust cognitive

representations of an environment an animal must processes
many different types of cues.!

These can be defined loosely as !

1. External landmarks and"

1. "
2. Idiothetic (self-motion) cues"

4
 12/1/17

Generation of a SPATIAL REPRESENTATION!

Acquisition of spatial information!

Location..........Grid Cells.........................entorhinal cortex "

Direction.........Head direction cells.......subiculum"
Context...........Place cells........................hippocampus"

Generation of a SPATIAL REPRESENTATION!

Role of Grid Cells!

Ithas already been established that the dorsal hippocampus processes

precise information about location"

Whereas the ventral hippocampus processes very general information about

location....... "

As the interface between hippocampus and neocortex,!

the entorhinal cortex is likely to play a pivotal role in the generation of!
spatial representaions, and memory formation!

5
 12/1/17

-examination of spatial modulation of neural "

activity in the medial entorhinal cortex (MEC) "

-The (MEC projects to the hippocampus"

-staining of dorsal and ventral MEC showed"

that the dorsal MEC projects to the CA1 region"
and that the ventral MEC projects to the ventral "
hippocampus"

Fyhn et al, 2004, Science, 305:1258."

Generation of a SPATIAL REPRESENTATION!

Role of Grid Cells!

-Grid Cells are precisely topographically "

Organised"

-rat location in a circular environment"

translates exactly to a topographical map"
in the dorsal MEC"

-firing rates of grid cells have a "

repetitive triangular structure"

Harting et al, 2005, Nature, 436:801."

Generation of a SPATIAL REPRESENTATION!

Role of Grid Cells!

Dorsal MEC" Ventral MEC"

-The dorsal MEC responds with cell firing when the animal finds itself in a specific location."
-the ventral MEC shows little consistency in cell firing"
-cell firing, cell spacing and field size increase from the dorsal to the ventral MEC"

6
 12/1/17

Generation of a SPATIAL REPRESENTATION!

Role of Grid Cells!

-the medial entorhinal cortex possesses grid cells that fire when the animal
find itself at specific coordinates in space."

-changing the orientation of the animal does not change the cell firing (no
trajectory firing)"

Grid cells !

-are topographically organised"

-are anchored to external cues"
-persist after cue removal"
-may serve to register location"

Generation of a SPATIAL REPRESENTATION!

Role of Grid Cells!

- Sensory input is transformed into allocentric spatial representations in the

dorsal MEC "

-enables a continuously updated metric representation of an animal‘s location"

Generation of a SPATIAL REPRESENTATION!

Role of Head Direction Cells!

-found in postsubiculum, posterior cortex, striatum

and the thalamus"

-assisted by vestibular information"

-head direction cells fire selectively when the rat's head is pointed in a specific direction
and which may serve as an internal compass to orient the cognitive map"

Knierim et al, 1998, J Neurophysiol 80: 425; Knierim et al, J Neurosci 1995, 15:1648."

7
 12/1/17

Generation of a SPATIAL REPRESENTATION!

Role of Head Direction Cells!

-The spatially and directionally selective properties of head direction cells arise from a
complex interaction between input from the vestibular system, external landmarks
and from idiothetic cues"

-may serve as a spatial compass

Generation of a SPATIAL REPRESENTATION!

Role of Place Cells!

Generation of a SPATIAL REPRESENTATION!

Role of Place Cells!

Regions of the environment where a single cell fires at a high rate define the
place field of that cell"

Neurons showing this pattern of activity = place cells"

Place fields are networks of place cells"

hippocampal place fields are controlled by the salient sensory cues in the
environment, in that rotation of the cues causes an equal rotation of the place
fields. "

8
 12/1/17

Generation of a SPATIAL REPRESENTATION!

Role of Place Cells!

Place cells do not passively encode sensory input“ sequential exposure to two almost
identical environments cause very different place representations (Skaggs & McNaughton
1998 J Neurosci 18: 8455)"

Place fields are maintained even if significant landmarks are removed (Quirk et al 1990 J
Neurosci 10: 2008)"

Generation of a SPATIAL REPRESENTATION!

Role of Place Cells!

……Hippocampus contributes to memory by encoding locations within a spatial

framework (O‘Keefe & Nadel, 1978, The Hippocampus as a Cognitive Map)"

However, the hippocampus also encodes information which is independent of location

and is needed for learning nonspatial information (Bunsey & Eichenbaum, 1996, Nature
379:255)"

PLACECELLS MAY GENERATE THE SPATIAL FRAMEWORK INTO WHICH

SYNAPTIC PLASTICITY ADDS THE CONTEXT DETAILS!

The hippocampus:
indispensible for the formation of a multitude of forms of
declarative memory

•Working and long-term declarative memory

•Spatial memory

•Episodic memory

•Semantic memory

•Associative memory

•Place, context, time

9
 12/1/17

HM:!
Bilateral hippocampectomy!

Normal working memory"

Old long-term memories retained"

No consolidation of new information (facts)"

Skill learning possible"

First evidence of dissociation between declarative"

(factual) and procedural (skill) learning"

Clive Wearing:!
Highly selective, sudden and complete loss of both hippocampi !
after a brief viral infection!

Normal working memory that endures for 7-10 min"

No consolidation of new declarative information (facts/episodes)"

Old (robust) declarative memories intact"

Skill learning possible"

Lesions of the rodent hippocampus disable spatial memory ability!

Eichenbaum et al, Morris et al, 1982."

10
 12/1/17

Synaptic transmission can become strengthened or weakened"

…... Synaptic Plasticity!

It is very likely that synaptic plasticity allows information storage in the form of
long-term memory !

David Marr (1945-1970):"

The hippocampus and the cerebellum possess distinct wiring properties that put them in
the unique position to rapidly and specifically store information

(1969) "A theory of cerebellar cortex." J. Physiol., 202:437–470.

(1970) "A theory for cerebral neocortex." Proceedings of the Royal Society of London B, 176:161–234.
(1971) "Simple memory: a theory for archicortex." Phil. Trans. Royal Soc. London, 262:23–81.

David Marr (1945-1970):"

The hippocampus and the cerebellum possess distinct wiring properties that put them in
the unique position to rapidly and specifically store information

11
 12/1/17

David Marr (1945-1970):"

For memories to persist, synaptic information storage must be robust"

Two forms of persistent synaptic plasticity:

long-term potentiation (LTP) and long-term depression (LTD)

Manahan-Vaughan, 1997, JNeurosci

Back to Hebb.......!

Three Hebbian conditions for a physiological property to correspond to a memory

storage mechanism:!

Cooperativity: the higher the stimulation"

intensity, the more axons recruited, the more
robust will be the plasticity response"

Input specificity:Plasticity resonse is

restricted to the inputs that receive patterned
afferent stimulation"

Associativity: necessity of temporal "

concidence of two events (essential"
property of memory)"

Both LTP and LTD fulfill these three conditions!

12
 12/1/17

Components of spatial memory

Space as a novel experience/ the scene

Components of spatial memory

Landmarks/
directional cues

Components of spatial memory

Discrete details/
positional cues

13
 12/1/17

Relationship between LTP and spatial memory

Dentate gyrus

Straube, Korz, Frey, Neuroscience Lett. 2003

LTP is facilitated by a general change in space/scene change?

Sensory information

From: Neves et al, Nat Rev Neuroscience, 2008

The property of “space/scene” encoding by LTP is common to all

hippocampal subfields
Perforant path-granule cell !

Kemp and Manahan-Vaughan. (2008) Cerebral Cortex 18"

Mossy fiber-Stratum Lucidum !

Schaffer collateral-Stratum Radiatum!

Hagena and Manahan-Vaughan. (2012) Cerebral Cortex! Kemp and Manahan-Vaughan. (2004) Proc Natl Acad Sci. 101. "

14
 12/1/17

If LTP is encoding space, what function does LTD have?

LTD is tightly associated with learning about spatial

content

But it does this in a subfield-specific way……..

In the dentate gyrus LTD is facilitated by novel landmark

configurations

preLFS!

24h
postLFS!

Kemp and Manahan-Vaughan. Cerebral Cortex (2008)18:968"

15
 12/1/17

The same is true for mossy fiber-

CA3 synapses

preLFS!

24h
postLFS!

Hagena and Manahan-Vaughan. Cerebral Cortex (2012)"

In the CA1 region LTD occurs as a consequence of learning about

discrete spatial constellations (positional content)

Manahan-Vaughan and Braunewell. Proc Acad Natl Sci (1999)"

Kemp and Manahan-Vaughan. Proc Acad Natl Sci (2004)"

Goh and Manahan-Vaughan. Cerebral Cortex (2013)"

Differentiation between spatial content ‘encoded’ by LTD in the

different hippocampal subfields

Landmark constellations do not facilitate CA1 LTD

Discrete spatial constellations do not facilitate DG LTD or

mf-CA3 LTD

Effects are tied to the novel spatial learning experience

16
 12/1/17

A Hierarchy for the encoding of spatial representations

CA1

Prior to novel
spatial experience
CA3
DG
CA1

Encoding of new t
tpu
space/general ou
CA3 change in space/
DG scene

CA1

Inclusion of
landmark/
CA3 directional content
DG LTP

CA1
No
change
Inclusion of
CA3 discrete/positional
LTD
DG content

A Hierarchy for the encoding of spatial representations

CA1

Prior to novel
spatial experience
CA3
DG
CA1

CREATION OF HEBB
Encoding of new
tpu
t
space/general ou
CA3
DG
ASSEMBLY
change in space/
scene

CA1

Inclusion of
landmark/
CA3 directional content
DG LTP

CA1
No
change
Inclusion of
CA3 discrete/positional
LTD
DG content

HOW?

LTP
Time

LTP is the “first responder”

•When we encounter “new space” or our environment changes

substantially, hippocampal excitability increases, and selected
synapses across the hippocampus become potentiated

•The network becomes identified………we store the “gist” of the

scene…..or the general schema

•N.B: LTP can be induced in as fast as seconds!

17
 12/1/17

HOW?

LTP LTD

Time

LTD is “kickstarted” based on the saliency of the experience

LTD in the dentate gyrus and mf-CA3 synapse develops if the experience is
salient enough for landmark/navigational/orientational cues to be stored

LTD in the AC-CA1 synapse follows if the environment is relevant enough

for finer more subtle content, or positional information should be stored

•N.B: LTD requires minutes

Spatial learning is cumulative……the more
time we have to observe the environment and
the more important it is, the better we are!

A hierarchy for the encoding of

spatial representations

Encoding of finer!
details?: LTD in CA1

Orientation in environment!
required?: LTD in dentate gyrus

New environment: input-specific LTP (DG,CA3,CA1)

Spatial and sensory information!

Pattern Separation Vs Pattern Completion

By this means, the hippocampus can “decide” whether incoming

information should be stored as a new experience, dismissed as irrelevant,
or used to retrieve an established memory

18
 12/1/17

Pattern Separation = the differentiation of very similar new

experiences from old experiences

Pattern Separation = HOW?

Entorhinal cortex

Current assumptions:
•The DENTATE GYRUS detects sensory information that is being relayed to the hippocampus by
the entorhinal cortex
• Arousal structures relieve some of the strong inhibitory control through which dentate gyrus (DG)
excitability normally is constrained
•This information either “enters“ the Hebb assembly within the DG and is recognised as a known
„engram“, or fails to find a Hebb Assembly and is processed as new data by the DG, and
subsequently, CA structures
•In this latter case, DG mossy fibers send the information to the CA3 (detonator synapses) that in
turn trigger information encoding

Pattern Completion = the retrieval of the entire memory

following exposure to just a fragment of that memory

19
 12/1/17

Pattern Completion

CA1

A Hebb Assembly
CA3
DG

Not only stores the information, but enables recall, if even one
very small part of the memory is reactivated…….

Pattern Completion = the retrieval of the entire memory

following exposure to just a fragment of that memory

Pattern Completion = HOW?

Entorhinal cortex

Current assumption:

•The entorhinal cortex passes on sensory information to the CA3 region.

• The recurrent fibers relay the information to the pyramidal cells.
•If this sensory experience was previously a component of a stored memory, the CA3
network reactivates the entire network assembly and enables retrieval of the memory.

Diagram from: Neves et al, Nat Rev Neuroscience, 2008

20
 12/1/17

Types of Synaptic Plasticity in the Hippocampus!

NOT ALL FORMS LAST FOR VERY LONG TIMES! !

Synaptic potentiation!

Short-term Facilitation.........................Lasts milliseconds"

Paired-pulse Facilitation......................Lasts milliseconds"
PTP........post-tetanic potentiation.... Lasts seconds"
STP.......short-term potentiation........ Lasts minutes"
LTP........long-term potentiaion...........lasts hours"
L-LTP....late-LTP.................................. Lasts days, months, years "

Synaptic depression!

Paired pulse Depression......................Lasts milliseconds"

STD.......short-term depression.......... Lasts minutes"
LTD........long-term depression...........lasts hours"
L-LTD....late-LTD.................................. Lasts days, months, years "

Morphological correlates of short-term memory!

Dendritic Spines: Site of Plasticity!

•Each dendritic spine usually forms

one synapse with one presynaptic
axon terminal"

•Large heads and long thin necks

restrict spines from exchanging
content freely with dendritic shafts
and neighbouring dendritic spines"

•Thus each dendritic spine can be

considered an individual unit for
synaptic connections, and can be
modulated individually"

Morphological correlates of LTP!

Dendritic Spines: Site of Plasticity!

•Typically 0.5 - 2µm in length (but up

to 6µm in CA3 region)"

•Linear density of 1-10 spines per

µm of dendritic length in mature
neurons"

•0.01 - 0.8 µm3 volume"

•4 main types: thin, stubby,

mushroom- and cup-shaped but
form is very dynamic!"

•Filopodia may comprise spine

precursors or precursors of dendritic
branches"
Hering & Sheng, 2001, Nat Rev Neurosci 2: 880"

21
 12/1/17

Dendritic Spines!

•dendritic spine are highly enriched in F-actin"

•F-actin is the only cytoskeletal element present in spines"

•Spines move rapidly"

•Spine movement is inhibited by drugs which prevent actin polymerisation"

•Spine motility may enable a searching function during synaptogenesis,

thus permitting more efficient neuronal connectivity"

Switching off Synaptic Plasticity in the Hippocampus !

Depotentiation.........................terminates LTP if triggered in the STP phase"

Dedepression.........................terminates LTD if triggered in the STD phase"

Synaptic run-down................loss of proteins required to sustain plasticity"

Active decay…………………processes are activated that abolish established

plasticity"

Classification of memory in terms of type

Declarative/ Explicit Non-declarative/ Implicit

•Is subdivided in to semantic and episodic •Is subdivided into subtypes that are
subtypes differentiated on the basis of their complexity

•Must be verbalised/ articulated/ consciously •Must NOT be verbalised/articulated/

retrieved in order to be used consciously retrieved in order to be used

•Typically requires multiple rehearsals in order to •Simple forms can be acquired very rapidly
be retained over long periods (cumulative. N.B. one- and/or unconsciously
trial or low trial-repeat emotional learning)
•Complex forms (i.e complex procedural memory)
•Must be regularly retrieved in order to maintained must first be processed at the declarative level
the content detail of the memory before being processed and persistently
stored
•Can be relatively easily edited, but is vulnerable to
accumulating errors (N.B. episodic memory) •Must NOT be regularly retrieved in order to
persist

•Are very robust once acquired

22
 12/1/17

Classification of memory in terms of subtype and originating brain structure(s)

Declarative (explicit) Non-declarative (implicit)

Skills & Habits Priming Basic Non-associative

Facts Events (procedural) associative learning
learning

Emotional Skeletal
responses Musculature
Reflex
Pathways
Neocortex
Striatum,
Hippocampus, Motor cortex,
Medial temporal lobe, Cerebellum
Amygdala Cerebellum
Diencephalon

Classification of memory in terms of persistency

Working memory, Short-term memory, Long-term memory

•Lasts for milliseconds, seconds or minutes •Lasts for hours, days, weeks, months

•Typically has a very restricted content •Its content capacity depends on the nature of
capacity the informations stored and the time taken to
(working memory = max. 7 items “online” store it (one trial-learning vs. cumulative learning,
level and incidents of consolidation, episodic Vs
•Is highly vulnerable (attention, distraction, semantic vs implicit)
interference)
•Its vulnerabilty depends on the type of long-
•Does not require protein translation or term memory (explicit Vs implicit)
transcription
•Forms that last over ca. 8h require protein
translation, longer lasting forms typically
require transcription

Classification of memory in terms of subtype and originating brain structure(s)

Declarative (explicit)

LTP and LTD

MECHANISMS
Facts Events

Hippocampus,
Medial temporal lobe,
Diencephalon

23
 12/1/17

Phases of LTP!
EPSP Amplitude (% pre-HFS)!

200!
STP! E-LTP! L-LTP! LL-LTP!
(NMDA-R)! (mGlu-R,! (signal! (protein synthesis)!
Kinases)! transduction)!
100!

0.5! 2! 8!
Time (hours)!

Molecular basis of LTP!

Critical cellular and molecular events underlying LTP!

•NMDA receptors!

•Calcium!

•mGlu receptors!

•Protein kinases/ !
signal transduction!

•Gene expression/!
synaptic modelling!

Mg 2+! Post!
Pre!
Ca 2+!

Ca 2+!
NMDA!
GLU!
Ca 2+! LTP !
(30 min)!
Ca 2+!
AMPA!

ER!

VDCC! mGlu1/ 5!
Ca 2+!
Ca 2+!

24
 12/1/17

Pre! Post!
Ca 2+!

Mg 2+!

NMDA!
GLU! Ca 2+!
LTP !
(<120 min)!
AMPA!

ER!
PLC
VDCC!
Ca 2+! mGlu1/ 5! IP3!
Ca 2+!

Intermediate postsynaptic effects (LTP < 120 min)!

Role of Kinases!

•Elevation of intracellular calcium levels leads to activation of kinases"

•Key kinases for LTP = "

Calcium-calmodulin kinase II (CAMKII)"

Protein Kinase C"

Protein Kinase A"

Extracellular signal-related kinase/ Mitogen activated

protein kinase (erk MAPK)"

Intermediate postsynaptic effects (LTP)!

CAMKII: a key postsynaptic !

component of LTP!

•Ca 2+ -activated enzyme"

•Highly abundant in the brain (1-2% of total protein)"

•Enriched at synapses"

•Main protein of the postsynaptic density"

•Central to the regulation of glutamatergic synapses"

•Essential for expression of LTP"

•Functions as a transducer (senses Calcium)"
•Functions in persistence of LTP (autophosphorylation)"

25
 12/1/17

CAMKII!
•28 similar isoforms, derived from 4 genes
(α,β,γ,δ) (α and β subunits are the predominant
isoforms in the brain)"

•Each isoform consists of a catalytic domain,

an autoinhibitory domain, a variable segment
and a self-association domain"

•catalytic domain = ATP- and substrate-binding

sites & sites for interaction with anchoring
proteins"

•autoinhibitory domain (AD) = normally inhibits

enzyme activity. Disinihibition occurs when
calmodulin binds to AD."

•Binding of calmodulin also exposes Thr286.

Thr286 can then be phosphorylated and
enables persistent activity of CAMKII."

•Presence of calmodulin also enables

interaction of NMDA GluN2B subunit with AD
also enabling persistent activity of CAMKII in
the absence of calmodulin."

1! Different forms of CAMKII

Activation!

1. Activation without phosphorylation. CAMKII

is active while Ca 2+ /calmodulin is present
(calmodulin dissociates ca. 1 sec after Ca 2+ -
2!
levels fall). "

2. Short-term persistent activation by

autophosphorylation of Thr 286. Two
molecules of Ca 2+ /calmodulin are required.
Activity persists after after Ca 2+ -levels fall but
declines if Thr286 becomes dephosphorylated
(endures for minutes)"
3!
3. Long-term persistent activation when the
rate of autophosphorylation exceeds
dephosphorylation. PP1 dephosphorylates
CAMKII but the kinase phosphorylation is
faster ."

Lisman et al 2002 Nat Rev 3: 175"

Multiple Mechanisms through which CAMKII may Enhance Transmission!

1. Phosphorylation of AMPA Receptors (AMPAR)"

2. Binding to NMDAR and enabling new AMPAR to anchor"

3. Stimulating delivery of new AMPAR to membrane"

Lisman et al 2002 Nat Rev 3: 175"

26
 12/1/17

Intermediate postsynaptic effects (LTP)!

Role of Phosphatases!

•e.g. Inhibitor 1 (I-1)"

•Serves to amplify kinase activation with LTP-inducing stimulation"

•I-1 prevents protein phosphatase activity (esp. PP1) and amplifies

autophosphorylation of CAMKII at Thr 286 (inhibition of dephosphorylation)"

Intermediate postsynaptic effects (LTP)!

Role of KInases!

PKA and PKC!

•Ca 2+ - activated enzymes"

•Augmentation of calmodulin-dependent processes (e.g. CAMKII) in LTP"

•Amplification of membrane depolarisation during LTP"

Intermediate postsynaptic effects (LTP)!

Role of KInases!

Erk MAPK!

•Serves as an integrator of signals from a wide range of cell surface

receptors"

•Erk MAPK activity is regulated by MEK (Map/Erk kinase)"

•MEK activation occurs as a consequence of PKC and PKA activation"

•MEK phosphorylates Erk MAPK on both a Tyr and Thr residue"

•The dual phosphorylation leads to activation of Erk MAPK "

•Erk MAPK regulates gene expression via regulation of Ca 2+ - cAMP

response element binding (CREB) protein phosphorylation"

27
 12/1/17

long-term postsynaptic effects (L-LTP)!

CREB (cAMP response element binding protein): !

a key transcription factor for LTP!

•CREB is activated by 2 key signalling pathways in

LTP"

•Both phosphorylate CREB on Ser133"

•Ca2+ entry through NMDAR is the trigger"

•Pathway 1 = Ca2+ dependent CaM kinase pathway

(probably CaMK IV)"

•Pathway 2 = Ca2+ independent Ras-erk MAPK

pathway (recruited by PKA activation)"

•Pathway 1 = fast-activating and short-lasting"

•Pathway 2 = slow-activating and long-lasting"

Hardingham, Bading 2003 Trends Neurosci 26:81"

long-term postsynaptic effects (L-LTP)!

CREB (cAMP response element binding protein): !

a key transcription factor for LTP!

•Both pathways lead to phosphorylation of CREB on

Ser133 "

•This leads to recruitment of transcriptional activator,

CREB-binding protein (CBP) to the promoter"

•This step is not enough to fully activate transcription"

•Nuclear CAMK IV (additional Ca2+ elevation) must

additionally phosphorylate Ser 301"

•Ras-erk MAPK pathway sustains the phosphorylation

state"

Hardingham, Bading 2003 Trends Neurosci 26:81"

long-term postsynaptic effects (L-LTP)!

CREB (cAMP response element binding protein): !

a key transcription factor for LTP!

•phosphorylation of CREB leads to activation of

transcriptional activator, CREB-binding protein (CBP) "

•CBP binds to cAMP response elements (CRE) and

stimulates transcription"

Hardingham, Bading 2003 Trends Neurosci 26:81"

28
 12/1/17

Synopsis of the mechanisms underlying hipocampal LTP!

Short-term Potentiation is mediated by phosphorylation of NMDA and AMPA

receptors and enhanced synaptic currents"

Intermediate potentiation (LTP > 2h) is mediated by mGlu receptors (calcium

release from intracellular stores)"

Calcium and CAMKII are the key to persistent LTP"

CAMKII phosphorylates AMPAR and enhances depolarisation currents"

Autophosphorylation of CAMKII leads to persistently enhanced AMPAR

depolarisation currents (L-LTP > 4h) "

PKA and PKC lead to phosphorylation of VDCC and NMDAR respectively"

PKA and PKC lead to activation of erk MAPK"

Erk MAPK activates CREB and triggers gene transcription (LL-LTP > 8h) "

Mechanisms underlying LTD!

•LTD requires activation of NMDA receptors!

Dudek and Bear, 1992 Proc Natl Acad Sci 89: 4363-4367; Heynen et al, 1996 Nature 381:
163-166; Manahan-Vaughan, 1997 J Neurosci 17: 3303-3311."

Plasticity conditions!
Mg 2+! Post!
Pre!
Ca 2+!

Ca 2+!
NMDA!
GLU!
Ca 2+! LTD !
(30 min)!
Ca 2+!
AMPA!

ER!

VDCC! mGlu1/ 5!
Ca 2+!
Ca 2+!

29
 12/1/17

•LTD requires activation of mGlu receptors and prolonged

elevations in intracellular calcium!
Mukherjee and Manahan-Vaughan, 2012, Neuropharmacology; Cummings et al (1996) Neuron.
"16:825-833"

Plasticity conditions!

Pre! AC Post!
mGlu2/ 3!

Mg 2+! Ca 2+!
-! NMDA!
GLU!
Ca 2+! LTD !
(120 min)!
Ca 2+!
AMPA!

ER!
PLC
VDCC! mGlu1/ 5!
Ca 2+! IP3!
Ca 2+!

•LTD requires activation of phosphatases!

Plasticity conditions!

Pre! AC Post!
mGlu2/ 3! Calcineurin (PP2b)!

Mg 2+! Ca 2+!
-! NMDA!
P
Inhibitor 1!
GLU!
Ca 2+!

Ca 2+!
AMPA! PP1!

ER!
PLC
VDCC! mGlu1/ 5!
Ca 2+! IP3! LTD !
Ca 2+! (<120 min)!

•LTD requires protein synthesis!

Plasticity conditions!

Pre! AC Post!
mGlu2/ 3!

Mg 2+! Ca 2+!
-! NMDA!
GLU! IEG! Protein!
Ca 2+!
synthesis!
Ca 2+!
AMPA!

ER!
PLC LTD !
VDCC! (< days)!
Ca 2+! mGlu1/ 5! IP3!
Ca 2+!

30
 12/1/17

Synopsis of the mechanisms underlying hippocampal LTD!

Short-term depression is mediated by dephosphorylation of NMDA and AMPA

receptors and reduced synaptic currents"

Intermediate depression (LTD > 2h) is mediated by pre- and postsynaptic mGlu
receptors (calcium release from intracellular stores)"

Calcium and Calcineurin are the key to persistent LTD"

LTD-phosphatases dephosphorylate excitatory receptors, mediate, removal of

AMPA receptors and synaptic reconfigurations"

LTD is protein synthesis dependent (LL-LTD > 8h) "

LTP versus LTD!

LTP! LTD!

NMDA receptor dependent?!

mGlu receptor dependent?!

Requires elevation in intracellular Ca2+?!

LTP versus LTD!

LTP! LTD!

Input specific?!

Protein synthesis dependent?!

Experimental evidence re: learning?!

31
 12/1/17

LTP versus LTD!

LTP! LTD!

Immediate early gene dependent?!

+! +!
Kinase dependent?!
+!+!+! +!
Phosphatase dependent?!
+! +!+!+!

Induction of LTP or LTD!

The intensity and duration of the intracellular calcium signal is of paramount importance!

♦HFS-high frequency stimulation- large (10µM), brief (3 sec), calcium influx-activates CAMKII-
LTP synaptic protein becomes phosphorylated"

♦LFS-low frequency stimulation- small (0.7µm), sustained (60 sec), calcium influx-
dephosphorylates the synaptic protein leading to LTD"

Multiple Memory Systems and Different!

Types of Learning!
MEMORY!

Non-declarative (implicit)!

Non-associative!
learning!

Reflex !
Pathways!

32
 12/1/17

Non-associative Learning:!
Reflex pathways!

Short-lasting plasticity at the Neuromuscular Junction!

Facilitation! Depression! Stim ceases!

PTP!

PRE!

•Facilitation: Repeated activation elevates presynaptic calcium and Ach release"

•Depression: Prolonged stimulation overwhelms the vesicular release mechanisms"

•PTP (post-tetanic potentiation): Minutes later, vesicles replenished, presynaptic

calcium still elevated enhanced Ach release"

Multiple Memory Systems and Different!

Types of Learning!
MEMORY!

Non-declarative (implicit)!

Basic!
associative!
learning!

Emotional! Skeletal !
responses! Musculature!

Amygdala! Cerebellum!

33
 12/1/17

Associative learning and classical!

Conditioning: Aplysia californica!

Simple nervous system containing ca. 20,000 neurons!

Model for studying implicit forms of memory!

•Short-term storage of implicit memory for simple forms of

learning results from changes in the effectiveness of
synaptic transmission"

•HABITUATION involves an activity-dependent

depression of synaptic transmission"
•SENSITISATION involves presynaptic facilitation of
synaptic transmission"

•CLASSICAL CONDITIONING involves presynaptic

facilitation of synaptic transmission which is dependent
upon activity in both the presynaptic and postsynaptic
neurons"

Associative learning and classical (Pavlovian)!

conditioning!

US UR!
CS US (pairing)!

CS CR!

Multiple Memory Systems and Different!

Types of Learning!
MEMORY!

Non-declarative (implicit)!

Priming!

Neocortex!

34
 12/1/17

Priming!

Unconscious Recall!

Multiple Memory Systems and Different!

Types of Learning!
MEMORY!

Non-declarative (implicit)!

Skills & Habits!

(procedural)!

Striatum, !
Motor cortex,!
Cerebellum!

Procedural Memory!

Learning and Plasticity in the Cerebellum!

The cerebellum fulfills coordinating tasks with regard to movement"

It is a monitor and not and initiator of movement"

It undergoes synaptic plasticity"

35
 12/1/17

parallel fibers!
Purkinje cell!
Molecular layer!

Purkinje cell layer!

Cerebellum-Mediated !
Granule cell layer!
Learning!

parallel fibers!

Stellate cell"

Basket cell"
Mossy Climbing!
fibers! fibers!

Purkinje cell"

Golgi cell"

Granule cell"

Cerebellar nucleus"

Mossy fibers"

Excitatory"

Inhibitory"

David Marr : The Cerebellum can encode simple associative forms of

Learning (conditioning), as well as procedural memories (skill learning)!

Parallel fibers

Compare with
recurrent
fibers of the
Purkinje Purkinje Purkinje CA3 region!

cell cell cell

Granule
cell

Granule
cell

Relaying information from the vestibular

system, pons, spinal cord

David Marr : The Cerebellum can encode simple associative forms of

Learning (conditioning), as well as procedural memories (skill learning)!

Climbing
Purkinje Purkinje Purkinje
fibers
cell cell cell
Relaying
information from
the deep
cerebellar
nuclei

Compare with
mossy
fibers of the
CA3 region!

36
 12/1/17

David Marr : The Cerebellum can encode simple associative forms of

Learning (conditioning), as well as procedural memories (skill learning)!

Climbing
Purkinje Purkinje Purkinje
fibers
cell cell cell

David Marr : The Cerebellum can encode simple associative forms of

Learning (conditioning), as well as procedural memories (skill learning)!

Parallel fibers ACTIVATED

Climbing
Purkinje Purkinje Purkinje
Fibers
cell cell cell
ACTIVATED

Granule
cell

Granule
cell

LTD is triggered at the Purkinje cell-parallel fiber synapses!

LTD is the plasticity mechanism underlying motor learning in the

cerebellum!

•Paired low frequency

stimulation (1-4 Hz, 2-6 min)
of the CF and PF input to the
Purkinje cell gives rise to LTD"

37
 12/1/17

Role of Climbing Fiber Activation in

LTD!

•Climbing Fiber Input = 1400 synapses per climbing fiber per Purkinje cell!

•Thus, activation of 1 climbing fiber, provides sufficient postsynaptic

depolarisation through AMPAR to allow calcium influx through VDCCs"

•Although there are many granule cells, each gives rise to 1 long
bifurcated axon that travels in essentially a straight path, synapsing
infrequently (1 -3 times per Purkinje cell).!

•Thus, the parallel fiber when active on its own will not produce much
depolarisation"

Role of Glutamate receptors in cerebellar LTD!

•NMDAR- only during early development- not invoved in mature cerebellar LTD"

•AMPAR - are predominantly composed of GluA2 i.e. Ca2+ -impermeable"

•mGlu receptors- occur in high density on spines of Purkinje cells"

•Source of Ca2+ for induction of LTD comes from mGlu receptor-mediated

release from intracellular stores"

Induction of Cerebellar LTD: postsynaptic mechanisms!

Ca 2+! GLU!

Post!
VDCC!
CF!
Ca 2+!
VDCC!

Ca 2+! Purkinje Cell!

Ca 2+! P!
Na +!
Na +!
Ca 2+! GLU! ER!
AMPA! IP3!

Na/Ca !
PF! Ex! DAG!
Ca 2+!
PLC!
VDCC! mGlu1/ 5! PIP2!
Ca 2+!

•PF triggers glutamate release and activation of mGlu1 receptor"

•mGlu1 triggers diacylglycerol that stimulates PKC & IP3 production that stimulates release of calcium from intracellular stores"

•Under normal (non-plasticity) circumstances, this supports the coordinated release of GABA from Purkinje cells"

38
 12/1/17

Induction of Cerebellar LTD: postsynaptic mechanisms!

Ca 2+! GLU!

Post!
VDCC!
CF!
Ca 2+! Ca 2+!
VDCC!

Ca2+! Purkinje Cell!

Ca 2+! P!
Na +!
Na +!
Ca 2+! GLU! ER!
AMPA! IP3!

Na/Ca !
PF! Ex! DAG!
Ca 2+!
PLC!
VDCC! mGlu1/ 5! PIP2!
Ca 2+!

•PF triggers glutamate release and activation of mGlu1 receptor"

•mGlu1 triggers diacylglycerol that stimulates PKC & IP3 production that stimulates release of calcium from intracellular stores"
•Under normal (non-plasticity) circumstances, this supports the coordinated release of GABA from Purkinje cells"

•If CF are activated CF depolarisation leads to a strongintracellular Ca2+ signal via voltage dependent calcium channels"

•Simultaneous activation of the same synapse by CF and PF, results in the triggering of intracellular cascades and protein "
Synthesis, that lead to long-lasting LTD of GABAergic transmission at the affected PF synapse."

Synopsis of the mechanisms underlying cerebellar LTD!

Information relay accross the cerebellar Purkinje cells is enable by parallel fiber
synapses"

When the parallel fibers release glutamate onto the postsynaptic density of the
Purkinje cells, synaptic transmission occurs via activation of metabotropic
glutamate receptors"
This activates the PCs and if sufficiently strong, will trigger GABA release from
the PCs"

Climbing fibers do not make synapses with muliple PCs, rather, they synapse
intensely on just one PC"

They only fire if information is beging relayed from deep ceberellar nuclei."
Transmission is mediated by AMPA receptors, and is very potent."
If the PF and CF synapses onto the same PC are active simultaneously, LTD
of PC transmission will result."

Thus, the subsequent transmission of an impulse to the PC via the PF is less

likely to cause the PC to fire."

Spatial (explicit) Vs Procedural (implicit) Memory:!

Radial Maze"

Maze 1: spatial cues only" Maze 2: Lights indicated food location"

39
 12/1/17

Maze 1: spatial cues only: animals learnt the location of the "
" food based on their orientation in space =!
declarative memory!

Maze 2: Lights indicated food location: animals learnt an "

association of light with food = procedural memory!

Maze 1: spatial cues only: animals learnt the location of the "
" food based on their orientation in space =!
declarative memory!

Maze 2: Lights indicated food location: animals learnt an "

association of light with food = procedural memory!

Hippocampal lesions: impaired performance in Maze 1 but "

had no effect on performance in Maze 2.!

Striatal lesions: impaired performance in Maze 2 but "

had no effect on performance in Maze 1.!

Relationship between cerebellar and !

hippocampal information processing!

Hippocampus
Place cells

Use of the acquired spatial

representation

Building of the spatial

representation

Cerebellum
PF-Purkinje cell LTD
Self-motion information Organisation of the
processing trajectory

Sensorimotor Goal-directed
information navigation

40
12/1/17

41