Ch 11

Predicting the Impact of mTOR Inhibition/

  • Blocking mTOR activation prior to training would likely impair memory consolidation.

    • Rationale: mTOR plays a crucial role in the initiation of local protein synthesis, which is essential for the consolidation of LTM. Inhibiting mTOR would prevent the translation of mRNAs needed to produce proteins that contribute to synaptic plasticity.

    • This prediction is based on the understanding that mTOR is a key player in the signaling cascade that leads to local protein synthesis. By blocking mTOR, you would essentially be cutting off the supply of new proteins needed for the structural and functional changes in synapses that underlie memory consolidation.

  • Rapamycin is a compound that can be administered to block the activation of mTOR. It specifically inhibits mTORC1, one of the two functionally distinct protein complexes formed by mTOR.

Comparing Effects of Pre- vs. Post-Training Administration of mTOR Inhibitor

  • Administering an mTOR inhibitor prior to training is expected to prevent memory consolidation and thus impair LTM.

  • Administering the inhibitor a few minutes after training is predicted to have no effect on LTM, as local translation is initiated rapidly and new proteins would already be in place.

  • Neither pre- nor post-training administration of the mTOR inhibitor is expected to have a significant impact on STM. This is because STM relies on post-translational modifications and rearrangements of existing proteins, rather than new protein synthesis.

Distinct Functions of mTORC1 and mTORC2 in LTM

  • mTORC1 regulates the signaling cascade that increases local protein synthesis. It is sensitive to rapamycin.

    • By removing the inhibitory influence of the TOP protein 4E-BP, mTORC1 allows for the formation of functional polyribosomal complexes that translate mRNA into protein. This process provides the necessary proteins for the structural and functional changes underlying LTM consolidation.

  • mTORC2 regulates processes that contribute to the regulation of actin. It is insensitive to rapamycin.

    • Actin dynamics are essential for the formation and maintenance of dendritic spines, the sites of synaptic plasticity. By regulating actin polymerization, mTORC2 contributes to the structural stability of synapses, which is important for the persistence of LTM.

Guzowski's Experimental Approach

Mini-Concept Map

Guzowski's Experiment

└──> Target: CREB Protein

└──> Method: Antisense Oligodeoxynucleotides (ODNs)

└──> Effect: Disrupted CREB Translation

└──> Outcome: Impaired LTM, Intact STM

└──> Conclusion: CREB is critical for LTM consolidation.

Explanation

  • Guzowski used antisense oligodeoxynucleotides (ODNs) to disrupt CREB protein levels.

  • Antisense ODNs are short, synthetic DNA sequences that bind to specific mRNA molecules, preventing their translation into protein.

  • By infusing CREB antisense ODNs into the dorsal hippocampus, Guzowski was able to reduce the amount of CREB protein available.

  • He found that this manipulation impaired LTM but not STM.

    • Rats infused with CREB antisense ODNs were normal when tested 30 minutes after training on a spatial memory task, indicating intact STM.

    • However, they were markedly impaired when tested 3 days after training, demonstrating impaired LTM consolidation.

  • This experimental approach provided strong evidence that CREB is critical for the consolidation of LTM.

Interaction Between CREB and BDNF

  • BDNF is a potent upstream activator of CREB.

  • Several signaling pathways can phosphorylate CREB, but BDNF signaling is considered a critical player in this process.

  • Interfering with the BDNF signaling pathway can dramatically reduce levels of phosphorylated CREB, which in turn impairs LTM consolidation.

Autoregulatory Feedback Loop Involving BDNF

  • The initial activation of CREB by BDNF leads to the transcription of new BDNF mRNA.

  • This newly synthesized BDNF mRNA is then translated into protein, leading to a further increase in BDNF levels.

  • This positive feedback loop helps to sustain BDNF signaling and contribute to the long-term maintenance of synaptic changes that support LTM.

Explanation

The BDNF-CREB interaction exemplifies an autoregulatory feedback loop. This process ensures a sustained supply of BDNF, which is critical for:

  • Wave 1 of protein synthesis: BDNF triggers the mTOR pathway, leading to local protein synthesis in dendrites.

  • Wave 2 of protein synthesis: CREB activation, driven by BDNF, leads to the transcription of genes involved in long-lasting synaptic changes, including BDNF itself. This newly produced BDNF further fuels the cycle, promoting long-term potentiation and memory consolidation.

This feedback loop emphasizes the interconnected nature of molecular mechanisms underlying memory. The initial trigger (synaptic activity and BDNF release) sets off a chain reaction, amplifying and perpetuating the signal, leading to enduring synaptic modifications and stable memories.