The Glutamatergic Synapse Lecture 2_KFChen_2023

Introduction to Postsynaptic Signalling

  • Understanding protein-protein interactions that organize postsynaptic signalling.

  • Importance of neurotransmitter receptors localization and linkage to signalling pathways.

Aim

  • Focus on receptor/channel localization during synaptic processes.

Contributions of Scaffolding Proteins

Evidence of Involvement

  • Scaffolding proteins facilitate signalling and support synaptic plasticity.

    • Formation of complexes between receptors and signalling molecules.

Second Order Interactions

  • Examining secondary interactions that influence signalling pathways.

Examples of Scaffolding Proteins in Action

Part 1: Specific Couplings

  1. NMDA Receptors and nNOS Coupling via PSD-95

    • PSD-95 couples NMDA receptors to neurotransmitter nitric oxide synthase (nNOS).

  2. AMPAR Interaction

    • Interaction between AMPAR, stargazin, and PSD-95 supporting synaptic transmission.

  3. mGluR Complexes

    • Homer coupling mGluRs to IP3 receptors.

Part 2: Receptor Complex Interactions

  • Investigation of higher-order complexes formed between receptors and signalling proteins.

    • NMDAR and mGluRs example: interaction with scaffolding proteins like PSD-95.

Synaptic Plasticity and PSD-95 Mutants

Long-term Potentiation (LTP) and Long-term Depression (LTD)

  • Research by Migaud et al. shows effects of PSD-95 mutants on synaptic plasticity.

    • Higher LTP observed in mutants under 100Hz stimulation.

    • Smaller EPSPs while potentiation observed with 1Hz stimulation.

Mutant Analysis Results

  • PSD-95 knockouts yield smaller AMPAR-mediated currents, yet show increased LTP.

  • Over-expression of PSD-95 impacts AMPA responses, which occludes LTP.

Functional Relevance of Scaffolding Proteins

Specific Interactions

  1. Detection of nNOS Interaction

    • Evidence from Brenman et al. showing nNOS binds to PSD-95 via its PDZ domain.

  2. Nitric Oxide Production

    • nNOS produces NO, leading to cGMP synthesis which is vital for calcium signalling.

  3. Impact of PSD-95 Deficiency

    • Reduced NO production observed in neurons lacking PSD-95.

Receptor Functionality in PSD-95 Deficient Neurons

  • NMDAR functionality is preserved despite PSD-95 disruption but impacts the coupling to nNOS.

The AMPAR-Stargazin-PSD-95 Complex

Mechanisms of Recruitment

  • Stargazin functions to recruit and anchor AMPARs to synapses.

  • Lateral movement of AMPARs mediated by interplay between NMDAR and PSD-95.

  • Overexpression leads to enhanced AMPA activity, influencing LTP dynamics.

Homer-mGluR-IP3R Complex

Structure and Function

  • Homer interacts with mGluRs, facilitating IP3 receptor coupling.

  • Upregulation during synaptic activity impacts receptor recruitment and signalling.

Role in Signal Transduction

  • Enhanced expression of Homer during synaptic activity; Homer 1a lacks multimerization.

  • Key in synaptic downscaling during sleep.

Summary of Scaffolding Protein Functions

  • Postsynaptic scaffolding proteins play a critical role in linking neurotransmitter receptors to signalling molecules, driving synaptic plasticity and signalling dynamics.

  • Major complexes involve:

    • NMDA-PSD-95-nNOS for NO signalling.

    • AMPAR-stargazin-PSD-95 for receptor traffic regulation.

    • Homer-mGluR-IP3R for intracellular calcium signalling.

Future Directions

  • Continued exploration of scaffolding proteins' roles can shed light on neuronal behaviour and disease mechanisms,

  • Associated study of SHANK proteins with autism adds to understanding of neural circuit functions.