Molecular Mechanisms of Long-Term Potentiation

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Questions and Answers

What is the function of the liquid-liquid phase separation of CaMKII, as mentioned in the content?

  • It is a mechanism used to trigger the expression phase of LTP.
  • It is a novel mechanism involved in Long-Term Potentiation (LTP). (correct)
  • It is involved in the induction phase of LTP.
  • It controls the maintenance phase of LTP.

Which of the following is a step involved in LTP as discussed in the text?

  • Maintenance (correct)
  • Inversion
  • Suppression
  • Repression

What does the term "induction" refer to in the context of LTP?

  • The long-term strengthening of synaptic connections.
  • The process by which a signal activates cellular signaling pathways. (correct)
  • The maintenance of the strengthened synaptic connections.
  • The immediate changes that occur at the synapse.

What is the primary focus of the book referenced by the author in 1949?

<p>How learning and memory processes are stored in the brain. (C)</p> Signup and view all the answers

What is the proposed mechanism by which Hebb's model explains learning and memory?

<p>Repeated stimulation of a neuron increases its efficiency in transmitting signals. (B)</p> Signup and view all the answers

What is the significance of the term "efficiency" as used in the context of Hebb's model?

<p>The strength of a connection between two neurons. (A)</p> Signup and view all the answers

What is the relationship between CaMKII and other effector proteins?

<p>CaMKII and effector proteins activate each other in a reciprocal manner. (B)</p> Signup and view all the answers

What is the role of CaMKII in maintaining the strength of synaptic connections as discussed in the text?

<p>CaMKII is involved in processes that strengthen synaptic connections. (A)</p> Signup and view all the answers

Which study examined the impact of reduced NMDA receptor expression on mouse behavior?

<p>Mohn et al., 1999 (B)</p> Signup and view all the answers

What is the primary focus of the study by N.E. et al., 2014?

<p>Examining the balance and stability of synaptic structures during plasticity (A)</p> Signup and view all the answers

Which study explored the role of GluR1 phosphorylation in synaptic plasticity?

<p>Lee et al., 2003 (C)</p> Signup and view all the answers

What technique was used to create a probe for fluorescence lifetime imaging of CaMKII activity in the study by Kwok et al., 2008?

<p>Genetically encoded probes (B)</p> Signup and view all the answers

In the context of synaptic plasticity, what does the study by Larkman et al., 1992, suggest about presynaptic release probability?

<p>It influences where long-term potentiation occurs (C)</p> Signup and view all the answers

According to the study by Miller et al., 1988, which receptors play a role in the induction and expression of long-term potentiation?

<p>Both AMPA and NMDA receptors (D)</p> Signup and view all the answers

The study by Miyawaki, 2005, focused on which aspect of brain function?

<p>Imaging brain function using fluorescent proteins (C)</p> Signup and view all the answers

Which study investigated the molecular basis of intellectual disability?

<p>Yang et al., 2017 (A)</p> Signup and view all the answers

Which of these is NOT a characteristic of Hebbian synaptic plasticity?

<p>A process that is solely dependent on the diffusion and turnover of component molecules. (B)</p> Signup and view all the answers

What is the primary role of NMDA receptors in synaptic transmission?

<p>They are primarily involved in the induction of long-term potentiation (LTP). (C)</p> Signup and view all the answers

Which of the following researchers conducted experiments that provided the first experimental demonstration of Hebbian plasticity in an animal?

<p>Bliss and Lømo (A)</p> Signup and view all the answers

Why is in vitro hippocampal slice preparation considered advantageous for studying LTP?

<p>It allows for easier manipulation and control of synaptic activity. (A)</p> Signup and view all the answers

What is the specific phenomenon that Hebbian plasticity refers to?

<p>The strengthening of synapses due to coincidental pre- and post-synaptic activity. (D)</p> Signup and view all the answers

What is the primary role of AMPA receptors in basal synaptic transmission?

<p>They mediate the majority of synaptic transmission signals. (B)</p> Signup and view all the answers

Which of the following is NOT a mechanism that contributes to the maintenance of LTP?

<p>The diffusion and turnover of synaptic molecules. (A)</p> Signup and view all the answers

What is the core concept behind the term “expression” in the context of Hebbian synaptic plasticity?

<p>The biochemical changes triggered by signaling that lead to enhanced synaptic transmission. (B)</p> Signup and view all the answers

What role does calcium/calmodulin-dependent protein kinase II play in neuron function?

<p>Facilitates synaptic Ca2+ signaling (A)</p> Signup and view all the answers

What is the effect of repeated stress on cognitive function as suggested in the content?

<p>Suppresses glutamate receptor expression (A)</p> Signup and view all the answers

What is a key finding related to nitric oxide and carbon monoxide regarding synaptic enhancement?

<p>They induce activity-dependent long-term synaptic enhancement (D)</p> Signup and view all the answers

Which of the following techniques is used to visualize synaptic calcium signaling in neurons?

<p>Fluorescence resonance energy transfer microscopy (B)</p> Signup and view all the answers

What phenomenon occurs due to the alignment of trans-synaptic nanocolumns?

<p>Enhanced receptor activation by neurotransmitters (B)</p> Signup and view all the answers

What role does calcium/calmodulin-dependent kinase II play in synaptic plasticity?

<p>It phosphorylates the GluR1 subunit of AMPA receptors. (D)</p> Signup and view all the answers

Which factor is critical for AMPA receptor expression in hippocampal pyramidal neurons?

<p>Dendritic spine geometry (B)</p> Signup and view all the answers

What hypothesis suggests that specific synaptic events can 'tag' synapses for later potentiation?

<p>The capture hypothesis (B)</p> Signup and view all the answers

What is the function of the Ras-like GTPase Rem2 in relation to calcium/calmodulin-dependent kinase II?

<p>It inhibits the kinase's activity. (B)</p> Signup and view all the answers

Which process is directly revealed by analyzing miniature synaptic currents?

<p>Post-synaptic contributions to long-term potentiation (B)</p> Signup and view all the answers

What does the phosphorylation and regulation of glutamate receptors depend on?

<p>Calcium/calmodulin-dependent protein kinase II (B)</p> Signup and view all the answers

Which of the following studies focused on the structural basis of long-term potentiation?

<p>Matsuzaki, M., et al., 2004 (C)</p> Signup and view all the answers

What is one of the key findings from the study on postsynaptic contributions to long-term potentiation?

<p>Long-term potentiation involves changes in postsynaptic current dynamics. (C)</p> Signup and view all the answers

What is one role of Ca2+/calmodulin-dependent protein kinase II in relation to synaptic activity?

<p>Facilitates structural long-term potentiation (A)</p> Signup and view all the answers

What mechanism is suggested to underlie post-tetanic potentiation?

<p>Swelling of dendritic spines (B)</p> Signup and view all the answers

Which process is examined in the context of cGMP's role in long-term potentiation?

<p>Its modulation of ion channel activity (A)</p> Signup and view all the answers

What was identified adjacent to the inhibitory and calmodulin-binding domains of CaMKII?

<p>A phosphorylation site (D)</p> Signup and view all the answers

Which neurotransmitter's transporter is affected by the blockade that potentiates postsynaptic excitation?

<p>Glutamate (C)</p> Signup and view all the answers

What is the primary focus of the study by Shen et al. regarding CaMKII?

<p>Dynamic control of translocation and localization (C)</p> Signup and view all the answers

What type of dependency does CaMKII exhibit in its functionality?

<p>Calcium-dependent (B)</p> Signup and view all the answers

What role does the study suggest for NMDA receptor stimulation in neurons?

<p>Regulating CaMKII activity (D)</p> Signup and view all the answers

Flashcards

Hebbian synaptic plasticity

A property of synapses that undergo changes during strengthened connections due to activation.

Tetanic stimulation

A brief, strong stimulation of synaptic input that can trigger changes in synaptic transmission.

Long-term potentiation (LTP)

A persistent increase in synaptic strength following high-frequency stimulation.

AMPA receptors

Glutamate receptors that mediate fast synaptic transmission in the brain.

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NMDA receptors

Receptors that play a critical role in synaptic plasticity and memory function, activating in response to glutamate.

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Expression of synaptic transmission

The observable increase in synaptic strength following potentiation.

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Maintenance mechanisms

Processes that sustain heightened synaptic strength over time against natural decay.

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Glutamate

The primary excitatory neurotransmitter in the brain that plays a key role in LTP.

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Synaptic Plasticity

The ability of synapses to strengthen or weaken over time, affecting communication between neurons.

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Calcium/Calmodulin-dependent Protein Kinase II (CaMKII)

A key enzyme involved in memory and synaptic plasticity that becomes activated by calcium ions.

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Autophosphorylation

A process where a kinase enzyme attaches a phosphate to itself, crucial for its activity.

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Synaptic Stability

The maintenance of synaptic structure and function despite changes in activity and plasticity.

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CaMKII Role

CaMKII is a key enzyme involved in synaptic plasticity and learning.

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Hebb's Model

A theory that explains how neurons store information through repeated firing.

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LTP Steps

Long-Term Potentiation is divided into induction, expression, and maintenance stages.

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Induction in LTP

The initial signaling process that triggers Long-Term Potentiation.

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Reciprocal Activation

Interplay where CaMKII activates and is activated by effector proteins.

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Liquid-liquid Phase Separation

A process where CaMKII forms droplets to enhance synaptic functions in LTP.

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Human Diseases and Synaptic Plasticity

Altered synaptic plasticity mechanisms can contribute to various human diseases.

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Calcium/Calmodulin-Dependent Protein Kinase II

A protein kinase that is activated by calcium-bound calmodulin, playing a key role in calcium signaling pathways.

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Fluorescence Resonance Energy Transfer (FRET)

A technique used to measure the interaction between proteins in live cells by detecting energy transfer between fluorescent dyes.

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Dendritic Spines

Small protrusions from a neuron's dendrite that function as synaptic sites for signaling between neurons.

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Nitric Oxide in Synaptic Enhancement

A signaling molecule that modulates neuronal communication, associated with long-term synaptic enhancement in the hippocampus.

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Cognitive Impairment from Stress

A decrease in cognitive functions resulting from repeated stress, which affects receptor expression in the brain.

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Phosphorylation

Addition of a phosphate group to a molecule, often proteins, influencing their function.

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Calcium/calmodulin-dependent kinase II

An enzyme that phosphorylates proteins in response to calcium ions, playing a key role in synaptic plasticity.

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Structural Basis of LTP

Physical changes in synapses, such as dendritic spine formation, contributing to long-term potentiation.

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Structural LTP

Long-term potentiation characterized by changes in synapse structure enhancing communication between neurons.

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Glutamate Receptors

Ion channels that mediate excitatory synaptic transmission in the brain.

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cGMP in LTP

Cyclic guanosine monophosphate, a signaling molecule that plays a role in mediating some forms of long-term potentiation.

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Post-tetanic Potentiation

An increase in synaptic strength that follows a high-frequency stimulation of a synapse.

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Study Notes

Molecular Mechanism of Hippocampal Long-Term Potentiation

  • Long-term potentiation (LTP) is a cellular process thought to underlie learning and memory
  • Postsynaptic NMDA receptor activation triggers AMPA receptor and protein trafficking to synapses
  • Spine enlargement occurs alongside actin modulation (structural LTP or sLTP) during LTP
  • Maintaining LTP despite protein turnover is a key research focus
  • Ca²⁺ influx through NMDA receptors activates kinases like Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)
  • CaMKII can sustain long-term signaling via a reciprocally-activating complex with its substrate proteins, including Tiam1
  • This regulation helps maintain downstream signalling
  • CaMKII can condense at the synapse through liquid-liquid phase separation (LLPS)
  • LLPS increases binding capacity at the synapse, supporting expanded protein complexes
  • LLPS may function as a synapse tag to capture newly synthesized proteins

First Step of LTP: Induction

  • LTP occurs in three phases: induction, expression, and maintenance
  • Induction is triggered by tetanic stimulation, altering synapse function
  • This leads to increased synaptic transmission (expression)
  • Maintenance mechanisms sustain this enhanced transmission despite component turnover and reverse reactions

Debate on Pre- or Postsynaptic Expression and Maintenance of LTP

  • Whether LTP is presynaptic (increased transmitter release) or postsynaptic (increased sensitivity to glutamate) was debated early
  • Studies used radiolabeled glutamate, which suggested presynaptic enhancement
  • Quantal analysis also supported presynaptic involvement
  • Independent measures now show postsynaptic LTP expression, notably AMPA receptor changes
  • Postsynaptic changes necessitate retrograde communication, possibly involving diffusible messengers (e.g., NO, CO, arachidonic acid)

AMPA Receptor Trafficking

  • Advancements in technologies like neural gene introduction and fluorescence microscopy have aided LTP studies
  • AMPA receptor translocation to the synapse is key to LTP expression and maintenance
  • Lateral diffusion and exocytosis of AMPA receptors play roles in this translocation

Structural LTP

  • LTP is linked to changes in dendritic spine structure (structural LTP, or sLTP)
  • Tetanic stimulation triggers early spine enlargement, a process that can last several hours
  • sLTP is linked to NMDA receptor activation
  • Observations from in vivo studies, in addition to electrical recordings, demonstrated that spines undergo morphological changes

Trafficking of Various Proteins

  • Many molecules, including receptors and signaling proteins, experience regulated trafficking during LTP
  • This trafficking is crucial for maintaining synaptic function

Cellular Signaling Leading to LTP

  • CaMKII is a key signaling molecule in LTP induction and maintenance
  • Postsynaptic Ca²⁺ influx activates CaMKII
  • Genetic ablation or inhibition of CaMKII impairs LTP and memory
  • CaMKII can phosphorylate other proteins like AMPA receptors, enhancing synapse function
  • The constitutive activity of CaMKII, even under basal conditions, is important for maintenance of LTP

Possible Substrates of CaMKII

  • AMPA receptors, NMDA receptor subunits, Neuroligin, Shank, and other proteins are possible targets of CaMKII
  • Phosphorylation of specific sites on certain proteins (e.g., AMPA receptor S831) may be vital for LTP expression

Liquid-Liquid Phase Separation of CaMKII

  • CaMKII aggregation through liquid-liquid phase separation (LLPS) occurs within a synapse
  • This LLPS process can result in the formation of synaptic nanodomains
  • The temporary Ca²⁺ signal can be persistently remembered through LLPS condensates
  • The formation of different protein phases within a synapse is important for LTP maintenance

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