Lecture 11 - Synaptic Basis of Memory - Part III

1. Introduction: Fundamental Concepts and Historical Foundations

  • Overview of the importance of understanding memory and its mechanisms in the brain.

2. Memory and the Brain: Central Concepts

  • Introduction to studies focusing on how memories are formed, stored, and recalled.

3. Generating Long-Term Potentiation (LTP)

  • LTP defined as a persistent strengthening of synapses based on recent patterns of activity.

4. Stabilizing LTP

  • Discussion on mechanisms of stabilizing LTP once it has been generated.

5. Consolidating LTP: Transcription and Translation

  • Overview of the processes involved in the consolidation of LTP, highlighting transcription and translation roles.

  • Significance of new protein synthesis in long-term memory formation.

6. Consolidating LTP: Specific Mechanisms

  • Various processes contributing to the consolidation of LTP, including the role of specific proteins.

7. Maintaining LTP

  • Investigation into how LTP is maintained over time.

8. Bringing it all together

  • Synthesizing information from various topics on memory and LTP to provide a cohesive understanding.

CONSOLIDATING LONG-TERM POTENTIATION: TRANSCRIPTION AND TRANSLATION

3. Learning Objectives

  • Understand consolidation and what processes or components get consolidated.

  • Explain the de novo protein synthesis hypothesis.

  • Describe aspects of local protein synthesis and its implications for memory.

  • Discuss synaptic events' signals to the nucleus regarding memory gene transcription.

  • Identify sources of calcium contributing to LTP.

4. Müller and Pilzecker’s Consolidation Hypothesis

Key Points

  • Initial hypothesis suggested new memories take time to stabilize.

  • Influential findings showed protein synthesis inhibitors disrupted long-term but not short-term memory.

  • Proposed de novo protein synthesis (DNPS) hypothesis, positing that new proteins are vital for memory endurance.

5. What Gets Consolidation? An Enlarged Stable Spine

Evidence Findings

  • The fundamental consolidating event involves constructing an enlarged, stable actin cytoskeleton.

  • This process does not require new protein synthesis to occur initially.

  • Synaptic events can initiate transcription and translation processes for new proteins crucial for enduring synaptic changes.

7. The De Novo Protein Synthesis Hypothesis: Inhibiting Protein Synthesis

Points of Interest

  • Describes two forms of LTP: S-LTP (short-lasting) and L-LTP (long-lasting).

  • Investigates the impact of anisomycin, indicating that strong stimuli drive L-LTP through new protein synthesis, while S-LTP relies on existing proteins and modifications.

  • Introduces the idea that inhibiting new protein synthesis reverts LTP changes, demonstrating the importance in consolidation processes.

8. Long-Lasting LTP Depends on Translation and Transcriptional Processes

Mechanism of Action

  • LTP-inducing stimuli initiate local translation and genomic signaling pathways leading to new mRNA synthesis.

  • Two routes of new protein synthesis: local dendritic mRNA activity and synaptic signaling to the genome.

9. Local Protein Synthesis

Key Findings

  • Presence of mRNA and translational machinery in the dendritic spine.

  • Synaptic activity activates translation, emphasizing the localized nature of protein synthesis.

10. Evidence of Local Translation

Experimental Design

  • Dendritic fields separated from soma show stimulation can still produce long-lasting LTP.

  • Indicates local translation of proteins is sufficient for LTP in stimulated spines.

11. Two Ways to Signal the Nucleus

Synapse-to-Nucleus Model

  • Initiation of signaling cascades from synapses leads to transcription activation in the nucleus involving second messengers and protein kinases.

Soma-to-Nucleus Model

  • Ca2+ influx through voltage-dependent calcium channels (vdCCs) in the soma can also open transcription pathways, suggesting a dual signaling method.

12. Evidence for Soma-to-Nucleus Hypothesis

Key Investigations

  • Weak stimulation followed by antidromic stimulation reveals how action potentials convert short-lasting LTP into enduring forms.

  • Demonstrates that action potentials are critical for the transcription processes associated with LTP.

13. Two Waves of Protein Synthesis

  • Local translation occurs first, followed by genomic signaling producing new mRNA for subsequent translation.

  • Emphasizes that increased calcium levels are required for successful translation waves.

14. The Neuron as a Set of Compartments

Compartmentalization

  • Calcium sources within the neuron structured into specific compartments: spine, dendritic, and soma.

15. Different Sources of Ca2+ Contributes to Different Forms of LTP

Sources Identified

  • Exogenous and endogenous sources of Ca2+ including vdCCs, NMDA receptors, and intracellular stores in ER.

16. Local Protein Synthesis Solves Many Problems

The Challenge of Localized Translation

  • Introduces the concept that localized mRNA synthesis addresses the need for rapid response in times of stimulation, mitigating issues related to the central dogma.

17. Local Dendritic mRNA and Ribosome Dynamics

Functional Observations

  • Localized synthesis alters structural and functional dynamics, allowing efficient capture and translation.

18. BDNF Initiates Local Protein Synthesis: The BDNF→TrkB→mTOR→TOP Signaling Pathway

Mechanistic Insights

  • BDNF binding activates major signaling pathways essential for mRNA translations, showcasing BDNF's role as a facilitator of local protein synthesis.

19. Consolidation Also Requires Protein Degradation

Balancing Synthesis and Degradation

  • Discusses the importance of protein degradation alongside synthesis, highlighting the roles played by the ubiquitin-proteasome system (UPS).

20. What New Proteins Are Translated: Arc

Arc Protein Functions

  • Emphasizes Arc protein's role in stabilizing synaptic changes post-translational modifications.

21. The Clustered Plasticity Model

Overview of Model

  • Suggests the role of dendritic clusters in enhancing function and action potential propagation through collective synaptic strengthening.

22. Evidence Supports the Synaptic Tag and Capture

Experimental Analysis

  • Looks at studies showing how stimulation creates synaptic tags that enable subsequent interaction with newly synthesized proteins.

23. Conclusion

  • Synthesizes insights from various sections, reiterating the complexity and interdependence of protein synthesis, degradation, and synaptic activity in memory consolidation.