Signalling L5

Signaling Cascades in Practice

  • Presented by: Miriam Moriarty

  • Email: miriam.moriarty@universityofgalway.ie

Long-Term Potentiation (LTP)

  • Concept: "Cells that fire together wire together"

  • Key Components:

    • NMDA receptor

    • AMPA receptor

    • Calcium ions (Ca2+) involved in signaling

    • Tetanus stimulation at various intervals

  • Observations:

    • Changes in synaptic strength are measured over time

    • Parameters:

      • Resting potential: -70 mV

      • LTP response: +40 mV

Memory and the Hippocampus

  • Damage to the hippocampus leads to anterograde amnesia.

  • Pharmacological blockade of LTP also results in anterograde amnesia.

NMDA Receptor Structure

  • Recognition and functional sites within the NMDA receptor:

    • Polyamine site

    • Zn2+ site

    • Glutamate recognition site

    • Glycine site

    • Extra-/Intracellular components for ion interactions (Na+, Ca2+, Mg2+)

Mechanism of Short-term and Long-term LTP

  • Short-term LTP

    • Involves transient changes in synaptic strength

    • Location: Presynaptic and postsynaptic terminals

  • Long-term LTP

    • Activation of NMDA and AMPA receptors

    • Calcium entry and activation of synaptic growth proteins

    • Dendritic spines and kinase involvement

    • Key pathway: cAMP and PKA activation leading to CREB transcription

Calcium Signaling

  • Ca2+ enters through NMDA receptors

  • Ca2+ binds to calmodulin, activating CaMKII which subsequently activates adenylate cyclase

  • Results in conversion of ATP to cAMP, activating PKA, leading to CREB phosphorylation and new protein synthesis

Phases of Long-term Potentiation

  • Early Phase LTP:

    • Involves post-translational modifications, such as phosphorylation of existing AMPA receptors.

  • Late Phase LTP:

    • Requires transcriptional changes and synthesis of new proteins to facilitate synaptic growth and receptor substitution.

Retrograde Messengers

  • Function: Send signals back to the presynaptic cell

  • Characteristics: Small/lipophilic molecules (e.g., Nitric Oxide, Arachidonic Acid)

BDNF (Brain-Derived Neurotrophic Factor)

  • Role:

    • Involved in neuronal maturation, synapse formation, and synaptic plasticity

  • Implications: Associated with disorders like Schizophrenia and mood disorders.

  • Evidence: BDNF levels lower in depression; increase with antidepressant treatment.

BDNF on Depression

  • Signaling Pathways:

    • TrkB receptor activation

    • Involved pathways: Akt activation leading to inhibition of GSK3-beta and interaction with Wnt signaling

  • Neurotrophic hypothesis:

    • 5-HT pathways stimulate BDNF transcription through CREB activation.

Mechanism of BDNF Signaling

  • BDNF signals through TrkB (tyrosine receptor kinase B)

  • Distinct pathways leading to survival and growth signaling.

Antidepressant Action

  • SSRIs and SNRIs increase BDNF expression

  • Indirect activation of pathways through stabilizing neurogenesis and modulating neurotransmitter systems.

Complexity of Interactions

  • Interplay between BDNF, serotonin, and various intracellular signaling processes necessitates a comprehensive understanding of psychiatric conditions and antidepressant mechanisms.

Conclusion

  • Signaling pathways and their outcomes illustrate the intricate relationship between neurobiology and mental health treatments.

  • Dotted line arrows in models indicate indirect effects (e.g., BDNF as a CREB target gene).

  • Emphasis on neurogenesis, synaptic plasticity, and their relevance in mood stabilization.