NBL Module 13

LTP Expression

• requires the activation of calmodulin and calmodulin-dependent kinase II (CaM KII), which are essential for enhancing synaptic strength.

• This activation leads to phosphorylation of key substrates involved in synaptic plasticity.

Early phase of LTP

• requires activation of kinases like CaM KII, PKC, and PKA, triggered by calcium entry through NMDA receptors, leading to the modulation of AMPA receptors.

• These kinases facilitate synaptic changes that enhance signal transmission.

Calmodulin

• a small adaptor protein that binds four calcium ions, undergoing conformational changes to activate targets such as CaM KII.

• plays a critical role in intracellular calcium signaling pathways.

CaM KII (CaM Kinase II)

• becomes active when calcium-bound calmodulin binds to its regulatory domain, releasing the catalytic domain for phosphorylation of substrates like AMPA receptors.

• This activation is crucial for synaptic plasticity and memory formation.

AMPA receptor regulation

• Kinases such as CaM KII, PKC, and ERK regulate AMPA receptors by direct phosphorylation or by modulating trafficking and tethering, increasing their number and activity.

• This enhances the postsynaptic response to neurotransmitters.

PKC (Protein Kinase C)

• a kinase activated by calcium and other cofactors, playing a role in the phosphorylation of AMPA receptors and their associated proteins.

• contributes to various cellular processes including synaptic plasticity.

PKA (Protein Kinase A)

• is indirectly activated by calcium through increased cAMP levels, contributing to the phosphorylation and regulation of synaptic proteins.

• plays a role in learning and memory.

ERK Kinase

• activated downstream of calcium entry, participates in the long-term maintenance of synaptic changes by modulating gene transcription and protein synthesis.

• is involved in various cellular functions including growth and differentiation.

Early phase LTP Targets

• increases AMPA receptor numbers and activity at the synaptic membrane through phosphorylation of receptor subunits and trafficking proteins.

• This enhances synaptic strength and efficiency.

TARPs and Stargazin

• are phosphorylated by CaM KII, tethering AMPA receptors at the postsynaptic membrane and preventing endocytosis.

• maintains a high level of receptor activity.

Silent synapses

• initially containing only NMDA receptors, can be unsilenced by activity-dependent recruitment of AMPA receptors, enhancing synaptic response.

• Crucial for synaptic plasticity and memory.

High vs low-frequency stimulation

• LTP is induced by high-frequency stimulation leading to increased AMPA receptor activity,

• LTD is triggered by low-frequency stimulation and involves AMPA receptor removal.

• Both processes modulate synaptic strength.

cooperative and associative

• LTP requires ____________________ properties, with simultaneous presynaptic glutamate release and postsynaptic depolarization to strengthen synaptic connections.

• These properties ensure precise synaptic modifications.

Late phase of LTP (L-LTP)

• lasting hours to days, depends on new mRNA synthesis and translation, leading to long-term increases in AMPA receptor levels and synaptic strength.

• ensures the persistence of synaptic changes.

CREB and ERK in Late LTP

• In the late phase of LTP, these enhance the transcription of genes necessary for sustained synaptic changes.

• This results in long-term potentiation and memory consolidation.

Role of ERK in LTP

• activated by kinases like CaMKII, PKC, and PKA, phosphorylates transcription factors such as CREB and ELK, leading to gene transcription necessary for late LTP.

• plays a pivotal role in synaptic plasticity and memory formation.

CREB Activation

• a transcription factor phosphorylated by kinases downstream of ERK, such as RSK2 and MSK1, and by PKA and CaMKII.

• This phosphorylation recruits CBP, leading to histone acetylation and gene transcription.

Immediate Early Genes (IEGs)

• such as cFOS and BDNF, are quickly transcribed in response to LTP and are involved in synaptic plasticity and memory.

• often contain CRE or SRE in their promoters.

Role of BDNF in LTP

• synthesized in response to LTP, binds to TrkB receptors, enhancing synaptic strength and AMPA receptor trafficking.

• functions both presynaptically and postsynaptically.

AMPA Receptor Trafficking

Early LTP involves the phosphorylation of AMPA receptors and their regulatory proteins by kinases like CaMKII, leading to increased receptor numbers at the postsynaptic membrane and enhanced synaptic response.

Role of CaM KII in LTP

• phosphorylates AMPA receptors and CREB, playing a crucial role in both the early and late phases of LTP.

• activation is essential for synaptic plasticity and memory formation.

Protein Phosphatase 1 (PP1)

• a memory suppressor gene whose activity is reduced during LTP, leading to a net increase in protein phosphorylation.

• This decrease in phosphatase activity supports sustained synaptic changes.

Calcineurin (PP2B)

• another memory suppressor gene, dephosphorylates proteins during LTP.

• reduced activity during LTP contributes to the maintenance of increased protein phosphorylation necessary for synaptic plasticity.

Histone Acetylation in LTP

• CBP, a histone acetyltransferase, is recruited by phosphorylated CREB, leading to histone acetylation.

• This process relaxes chromatin structure, facilitating transcription of plasticity-related genes.

Activation of CREB by CaM KII

• CaMKII can phosphorylate CREB at Serine 133, a modification necessary for CREB's transcriptional activity.

• This phosphorylation supports the transcription of genes involved in synaptic plasticity.

Back-Propagating Action Potentials

• generated by strong postsynaptic depolarization, open voltage-gated calcium channels near the cell body and nucleus.

• This calcium influx activates kinases like ERK, leading to gene transcription necessary for LTP.

Role of RSK and MSK in LTP

• phosphorylated by ERK and translocate to the nucleus to phosphorylate CREB, promoting gene transcription.

• These kinases are essential for the late phase of LTP and the maintenance of synaptic changes.

Synaptic Plasticity

• The ability of synapses to strengthen or weaken over time in response to increases or decreases in their activity.

• fundamental mechanism underlying learning and memory.

Dendritic Spine Enlargement

• A process during LTP where the volume of dendritic spines increases to accommodate newly synthesized proteins.

• This enlargement supports the enhanced synaptic strength by providing more surface area for receptor incorporation.

Hebbian plasticity

• A principle stating that synapses are strengthened when the presynaptic and postsynaptic neurons are activated simultaneously.

• This mechanism underlies the specificity and associativity of synaptic changes during LTP.

Synaptic capture

• A process where newly synthesized proteins and mRNAs are captured by tagged synapses.

• ensures that only the activated synapses are strengthened, maintaining the specificity of synaptic plasticity.

Protein Kinase M Zeta (PKM Zeta)

• A protein kinase synthesized rapidly in response to LTP.

• Essential for maintaining long-term changes in synaptic strength and spine volume by regulating protein trafficking and synthesis.

Activity-Regulated Cytoskeletal Protein (ARC)

• A protein crucial for changes in the actin cytoskeleton during LTP.

• necessary for the transition from early to late LTP and plays a role in synaptic plasticity and cognitive functions.

Ribosomal S6 Kinase (RSK)

• A kinase involved in protein synthesis by phosphorylating translation-related proteins.

• upregulates protein synthesis in both the cell soma and dendritic spines, supporting long-term synaptic changes.

Neuroligins and Neurexins

• Cell adhesion molecules that form trans-synaptic complexes, stabilizing synaptic connections.

• play a role in the synaptic maturation and plasticity essential for effective neural communication

Cadherins

• Cell adhesion proteins that bind to each other across the synaptic cleft.

• expression increases during LTP, contributing to the structural stability and strengthening of synapses.

ERK Pathway

• A signaling pathway involving extracellular signal-regulated kinases that regulate transcription and translation.

• Activation of this pathway is critical for the protein synthesis necessary for late LTP.

Filopodia

• Thin, actin-rich protrusions from dendrites that can develop into mature spines.

• During synaptic activity, they form early contacts with presynaptic terminals, potentially leading to new synapse formation.

Systems consolidation

• The process by which memories initially dependent on the hippocampus are transferred to the cortex for long-term storage.

• involves synaptic and molecular changes similar to those occurring within the hippocampus during LTP.

Synaptic/Cellular consolidations

• The biochemical and morphological changes that stabilize memory traces shortly after learning.

• This process occurs within hours in the hippocampus and involves strengthening synaptic connections.

Sleep and Memory Consolidation

• Sleep, particularly the sequential phases of slow-wave sleep (SWS) and rapid eye movement (REM) sleep, plays a crucial role in consolidating different types of memories.

• SWS supports systems consolidation, while REM sleep strengthens neocortical memory representations.

Sleep spindles

• Bursts of oscillatory brain activity visible on an EEG that occur during NREM sleep.

• These are thought to facilitate the transfer of information from the hippocampus to the neocortex, contributing to long-term memory consolidation.

Memory Reconsolidation

• A process that occurs after memory retrieval, where the memory trace becomes temporarily labile and susceptible to modification.

• This allows for the memory to be updated or altered before it is re-stabilized.

Multiple Trace Model

• A theory suggesting that episodic memories require the hippocampus for retrieval over extended periods, while semantic memories become independent of the hippocampus over time.

• This model highlights the differential dependence on the hippocampus for various types of memories

Synaptic Renormalization

• The process where synaptic strength is reduced back to a baseline level following memory encoding.

• This involves mechanisms like long-term depression (LTD) and is essential for preventing saturation of synaptic efficacy.

SWS (Slow-Wave Sleep)

• A phase of deep sleep characterized by slow brain waves, which is important for systems consolidation of memories.

• helps to integrate and stabilize new information within the neocortex.

REM (Rapid Eye Movement) sleep

• A stage of sleep marked by rapid eye movements, vivid dreams, and heightened brain activity.

• contributes to the strengthening of neocortical memory representations and emotional regulation.

Neocortical Circuit Modification

• The process where synaptic connections within the neocortex are altered to store new information.

• This involves changes in synaptic efficacy and the incorporation of new proteins and receptors.

Declarative Memory Storage

• The long-term storage of factual information and events within the cortical networks.

• Once stabilized, these memories can be recalled independently of the hippocampus.

Episodic Memory Encoding

• The process by which personal experiences and specific events are initially encoded in the hippocampus.

• These memories often require the hippocampus for long-term retrieval and detailed recollection

Semantic Memory Consolidation

• The stabilization and storage of general knowledge and facts within the cortical networks.

• Over time, these memories become independent of the hippocampus, allowing for easier retrieval.

Memory Reactivation During Sleep

• The phenomenon where previously encoded memories are replayed and strengthened during sleep.

• Crucial for the consolidation and integration of new information.

Hippocampal-Neocortical Dialogue

• The ongoing communication between the hippocampus and neocortex that facilitates the transfer and consolidation of memories.

• Essential for the stabilization and integration of new information into existing cortical networks.

Ca2+ activated protein kinases

E-LTP involves the activation of _____.

Ca2+ activated protein kinases

Ca2+ activated protein phosphatases

Ca2+ activated transcription factors

All of these answers

Ca2+ activated proteases

Requires transcription and translation, and involves regulation of gene expression

The feature(s) that distinguish(es) late LTP (L-LTP) from early LTP (E-LTP) is that L-LTP ____.

Requires transcription and translation, and involves regulation of gene expression

Requires protein kinases

Leads to an increase in AMPA receptors and activity at the postsynaptic membrane

Occurs following tetanic stimulation in the hippocampus Schaffer collateral (CA3-CA1)

All of these answers

Elk

Which of the following IS NOT a protein kinase involved in E-LTP or L-LTP?

Elk

Erk

Msk

Rsk

CamKII

All of these answers

LTP "expression" during both early and late LTP involves ______.

An increase in AMPA receptor activity

All of these answers

An increase in presynaptic glutamate levels

An increase in the postsynaptic EPSP responses

An increase in AMPA receptor number at the postsynaptic membrane

Ca2+ activated protein phosphatases

The early phase of LTD involves ________.

All of these answers

Ca2+ activated transcription

Ca2+ activated protein kinases

Ca2+ activated proteases

Ca2+ activated protein phosphatases

All of these answers

A reasonable potential function for LTD may be to ____.

Reverse LTP at hippocampal synapses so the hippocampus can be used for future encoding

Prevent hippocampal neurons from becoming too excitable

Reset synapses in the hippocampus following encoding

Decrease synaptic transmission at synapses that receive low input activity

All of these answers

They both lead to long term regulation of AMPA receptor number and activity

Which of the following features is shared by LTP and LTD?

They both lead to long term regulation of NMDA receptors

They both require a long term increase in postsynaptic Ca2+ levels

They both lead to long term regulation of AMPA receptor number and activity

They both involve a long term increase in presynaptic glutamate release

All of these answers

Under physiological conditions

The associative and cooperative properties of LTP are most likely to be important for strengthening of synapses ____.

That do not have any presynaptic glutamate input

Following a low frequency (1 hz) stimulation

When the Schaffer collateral (axons) are stimulated with a tetanus

All of these answers

Under physiological conditions

They have NMDA receptors but no AMPA receptors

Which of the following BEST DESCRIBES silent synapses?

They can be activated/unsilenced during LTD

They have no presynaptic glutamate release

They have NMDA receptors but no AMPA receptors

They can be detected by depolarizing the presynaptic neuron and measuring the AMPA response

All of these answers

Are upregulated in neurons during L-LTP

Memory genes are genes that ___.

Are upregulated in neurons during L-LTP

All of these answers

Regulate CREB transcription

Activate transcription factors

Are increased by LTP or LTD

Synapse specificity (Hebbian)

The synaptic tag and capture hypothesis attempts to explain the ____ feature of LTP.

Reversibility and saturability

Latency and time course

Associativity and cooperativity

All of these answers

Synapse specificity (Hebbian)

CAMKII and PKMz

Candidate synaptic tags are ___.

CAMKII and PKMz

IEGs and ARGs

NMDA and AMPA receptors

CREB and Elk-1

All of these answers

IEG/ARG proteins and/or mRNAs

Synaptic tags are thought to capture ___.

IEG/ARG proteins and/or mRNAs

All of these answers

Ca2+/calmodulin and PKC

Transcription factors

Synaptic vesicles for glutamate release

All of these answers

Synapses get stronger during L-LTP which involves_____.

An increase in adhesion between the presynaptic and postsynaptic neuron

An increase in the dendritic PSD and spine volume

An increase in the postsynaptic responses: EPSPs

The unsilencing of previously silent synapses

All of these answers

Show decreased expression

One common feature of memory suppressor genes is that they are anticipated to ___ during LTP.

Inactivate protein kinases

Inhibit NMDA receptors

Show decreased expression

All of these answers

Only be expressed in inhibitory neurons

Transcription

Epigenetic modifications are thought to mainly control ___.

Transcription

Translation

Tethering

All of these answers

Trafficking

All of these answers

________is/are involved in controlling transcription during L-LTP.

Transcription factors

Covalent modifications of DNA and histones

Transcription factors and epigenetic modifications

All of these answers

Epigenetic modifications

Protein phosphatases calcineurin and PP2B

Which of the following genes are NOT memory genes?

Effector IEGs/ARGs

Transcription factors cFos and Zif-268

Cytoskeletal protein Arc and protease tPA

Protein phosphatases calcineurin and PP2B

AMPA receptors and neurotrophic factor BDNF

AMPA receptor and neurotrophic factor BDNF

The memory genes that have the most direct/obvious impact on L-LTP expression are the ____.

AMPA receptor and neurotrophic factor BDNF

Transcription factors cFos and Zif-268

Protein phosphatases calcineurin and PP2B

Cytoskeletal protein Arc and protease tPA

L-LTP

Synaptic consolidation is thought to be synonymous with ____.

All of these answers

LTD

L-LTP

E-LTP

LTP induction

Across all animal species for long-term memory tasks

Synaptic consolidation is observed ________.

In only humans for declarative memory tasks

In only mammals for both short term working and long term memory tasks

Across all animal species for all memory tasks

Across all animal species for long-term memory tasks

The hippocampus to cortical circuits

For declarative/explicit memory, systems consolidation is though to involve transmission/transfer of information from ______.

Sensory association areas to the entorhinal cortex

All of these answers

The hippocampus to cortical circuits

Short term working memory to the hippocampus

The dentate gyrus to CA3 to CA1

Epigenetics

The long-term nature of _______, and its role in transcriptional regulation make it an ideal candidate mechanism to be involved in long term memory storage.

Protein kinases

Synaptogenesis

Neurogenesis

LTP and LTD

Epigenetics

IEGs/ARGs

Which of the following is not a proposed molecular mechanism for the "long term" nature of memory?

Epigenetic modifications

Self perpetuating activity, such as a kinase

Prion-like protein

IEGs/ARGs

Hippocampus

In the standard model of memory consolidation for declarative memory, the ______ is believed to rapidly integrate and bind together information transmitted from distributed cortical networks that support the various features of a whole experience in order to form a coherent memory trace.

Hippocampus

Entorhinal cortex

All of these answers

Subiculum

Prefrontal cortex

Whether long term episodic memory becomes independent of the hippocampus

One important DIFFERENCE between the standard two state model and the multiple trace model is _____.

The role of the hippocampus in synaptic consolidation during sleep

What mechanisms are involved in systems consolidation in the cerebral cortex

Whether long term episodic memory becomes independent of the hippocampus

How semantic and episodic memories are integrated into the memory trace

Where short term working memories are temporarily stored in the prefrontal cortex

Stored jointly in hippocampal and extrahippocampal circuits

In the multiple trace theory, some memories are _______.

Stored jointly in hippocampal and extrahippocampal circuits

Retrieved from multiple circuits in the neocortex

Transmitted through multiple synapses before consolidation

Encoded by multiple regions of the hippocampus

Little incoming sensory or cognitive activity, hence no interference with

Sleep is an ideal period for system consolidation of declarative memory because during sleep there is _____ the transmission/transfer of information from hippocampus to neocortex.

An increase in gamma and theta waves that enhance

Regeneration of ATP by many brain regions, so more ATP will be available for

An increase in traveling waves that can facilitate

Release of free radicals and toxic proteins that improves

Little incoming sensory or cognitive activity, hence no interference with

Both REM sleep and SWS are involved

It is proposed that _____ in memory consolidation.

REM= rapid eye movement

SWS= slow wave sleep

Sleep is not involved

Only non REM sleep is involved

Only REM sleep is involved

Only SWS is involved

Both REM sleep and SWS are involved

Reconstructed

When cortical memory traces are re-activated, the entire memory is proposed to be ______.

Reindexed

Reconstructed

Rewritten

Resolved

Rewired

Short term working memory

Activated neurons in the cortical memory traces send information to the ______ system .

Short term working memory

Sensory association

Hippocampal

Perceptual

All of these answers

Synapses, neurons

It has been proposed that memory is a pattern of strengthened ______ distributed across allocated _____.

Neurons, networks

Transmission, circuits

Synapses, neurons

Activities, brain regions

The hippocampus is susceptible to excitotoxicity, which would disrupt memory storage

All of the following are reasons why the brain uses system consolidation EXCEPT ___.

There is limited storage space of the hippocampus

The hippocampus is susceptible to excitotoxicity, which would disrupt memory storage

Hippocampal synapses are reset during sleep

It maximizes the benefit of neurogenesis in the hippocampus without the problem of interference

Reconsolidation

During memory ______, previously stored memories can be stabilized or become altered or degraded.

Retrieval

Reconsolidation

Consolidation

Reactivation

Hippocampal specific and selective

Which of the following is NOT a characteristic/feature of both LTP and LTD?

Reversible and saturable

Associative and cooperative

Hippocampal specific and selective

Synapse/input specific and Hebbian

Long term and persistent

L-LTP

You add a fast acting inhibitor of transcription one minute before LTP is induced in the hippocampal slice. Which phase(s) of LTP will be blocked?

E-LTP

All phases of LTP

L-LTP

LTP induction

No phases of LTP

They both can be induced by theta burst stimulation

LTP and LTD share the following features EXCEPT ___.

They both lead to the regulation of AMPA receptor number and activity

They both depend on presynaptic glutamate release

They both are required for encoding of long term memory

They both can be induced by theta burst stimulation

They both depend on NMDA receptors and postsynaptic Ca2+ increases for induction

Weaken neighboring synapses that experience coincident activation

Which of the following is NOT a proposed function for LTD?

Reverse LTP at hippocampal synapses so the hippocampus can be used for future encoding

Reset synapses in the hippocampus following encoding

Weaken neighboring synapses that experience coincident activation

Prevent hippocampal neurons from becoming too excitable

Decrease synaptic transmission at synapses that receive low input activity

Have AMPA receptors but no NMDA receptors

Which of the following is NOT TRUE about silent synapses? Silent synapses ____.

Have AMPA receptors but no NMDA receptors

Can be detected by depolarizing the postsynaptic neuron and measuring the NMDA response

Represent a type of Hebbian plasticity

Can be activated/unsilenced during LTP

Have presynaptic glutamate release

Glutamate release

The presynaptic mechanism that contributes to LTP involves increased ____.

NMDA receptor activation

AMPA receptor phosphorylation

Action potential firing

Glutamate release

All of these answers

Ca2+

It has been demonstrated that, in the absence of any presynaptic stimulation, the injection high levels of ___ directly into a postsynaptic neuron is sufficient to induce LTP.

Glutamate

Current

All of these answers

Phosphate

Ca2+

Sustained high postsynaptic Ca2+ levels

Postsynaptic LTP "expression" during early LTP involves all of the following EXCEPT ___.

Sustained high postsynaptic Ca2+ levels

An increase in AMPA receptor activity and number

An increase in AMPA receptor-dependent responses

Phosphorylation of AMPA receptors, AMPA receptor trafficking proteins and AMPA receptor tethering proteins

An increase in postsynaptic EPSPs

Covalent modifications of AMPA receptors

Which of the following is NOT DIRECTLY INVOLVED in controlling transcription during L-LTP?

Epigenetic modifications

Covalent modification of transcription factors

Covalent modification of DNA

Covalent modifications of AMPA receptors

Covalent modification of histones

Encoded by genes that bind CREB or Elk-1 in their promoters

What do all IEG/memory genes have in common? They are all ___.

Cytoskeletal regulators that modulate spine morphology

Only expressed in neurons during LTP

Transcriptional activators that stimulate transcription

Encoded by genes that bind CREB or Elk-1 in their promoters

Down regulated in LTD

Transcription factors CREB and Elk-1

Which of the following genes ARE NOT considered IEG/memory genes?

Cytoskeletal protein Arc and protease tPA

Transcription factors cFos and Zif-268

Glutamate receptors and neurotrophic factors

Effector IEGs/memory genes

Transcription factors CREB and Elk-1

Transcription factors

The local protein synthesis that occurs in dendrites and dendritic spines in L-LTP requires all of the following in the dendrite EXCEPT _____.

Transcription factors

Ribosomes

Translation factors

RER for transmembrane proteins

mRNA transported from the nucleus

Synapse specificity (Hebbian)

The synaptic tag and capture hypothesis attempts to explain the ____ feature of LTP.

Latency and time course

All of these answers

Associativity and cooperativity

Synapse specificity (Hebbian)

Reversibility and saturability