Molecular Basis of Synaptic Plasticity I

Molecular Basis of Synaptic Plasticity I

• Synaptic plasticity is a biological process where specific patterns of synaptic activity cause changes in synaptic strength.
• This is thought to contribute to learning and memory.
• Both pre-synaptic and post-synaptic mechanisms contribute.
• LTP (long-term potentiation) is a family of processes strengthening synaptic transmission.
• These mechanisms differ based on receptor, ion channel, and second-messenger signaling pathway importance.
• Mechanisms are found both in pre-synaptic (altering release) and post-synaptic (sensitivity to the neurotransmitter) cells.

Lecture Outline

• Synaptic Plasticity
• LTP (Long-Term Potentiation)
  • Types of LTP
  • AMPAR Trafficking
  • Stages of LTP
    • Early LTP
    • Late LTP
  • Molecular Basis of LTD (Long-term Depression)
• LTP/LTD and Memory?
• Experience-Dependent Plasticity
  • Calcium Permeable AMPARS

What is Synaptic Plasticity?

• Synaptic plasticity is the biological process by which specific patterns of synaptic activity change synaptic strength. It's thought to be a key process in learning and memory.

Long-Term Potentiation (LTP)

• LTP can last for days to weeks.
• A graph shows the amplitude of population EPSPs (excitatory postsynaptic potentials) changes over time.
• Different pathways show varying magnitudes of the response.

LTP

• LTP is a family of processes that strengthen synaptic transmission.
• These processes differ based on the relative importance of various receptors, channels, and signaling pathways, either in the pre-synaptic cell (altering release) or the post-synaptic (sensitivity to the neurotransmitter) cell.

Presynaptic LTP: Mossy Fiber

• Large Ca2+ influx into the presynaptic terminal.
• Activation of a calcium/calmodulin-dependent adenyl cyclase complex.
• Activation of PKA (protein kinase A).
• Increase in glutamate release.

LTP in the Mossy Fiber: Non-associative

• Large Ca2+ influx into the presynaptic terminal.
• Activation of a calcium/calmodulin-dependent adenyl cyclase complex.
• Activation of PKA.
• Increase in glutamate release.

Classical Conditioning

• Siphon touch triggers action potentials in sensory neurons, causing Ca2+ influx in the pre-synaptic terminal.
• Activation of Ca2+-sensitive adenyl cyclase (AC), which generates cAMP, leading to increased cAMP production.
• Tail shock triggers further potentiation through 5-HT release.

Vesicle Life Cycle: Docking

• RIM binds to Munc13, and Rab3/27 to dock the vesicle, along with N, P, and Q-type Ca2+ channels.

Postsynaptic LTP: Schaeffer Collateral

• Normal synaptic transmission involves glutamate release from the presynaptic terminal, binding to NMDA and AMPA receptors, and subsequent membrane depolarization.
• The induction of LTP involves increased glutamate release and postsynaptic membrane depolarization, and this process involves NMDA receptor activation and Ca2+ influx.
• Retrograde messengers such as NO help enhance glutamate release.

AMPAR Insertion and Silent Synapses

• Alteration in AMPAR number is a crucial mechanism for LTP (Long-Term Potentiation) and LTD (Long-Term Depression).
• Silent synapses are synapses where AMPA receptors are not located on the post-synaptic membrane.
• Pairing stimuli initiates AMPA receptor insertion into post-synaptic membranes.

AMPAR Trafficking

• AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) are mobile in the plasma membrane and in spines.
• Local rises in intracellular calcium decrease GluA2 mobility and accumulate GluA2 in synapses.
• LTD (Long-term depression) involves internalization of AMPARs.

AMPAR trafficking: Lateralization

• AMPARs are mobile in the plasma membrane.
• Local rises in intracellular calcium decrease GluA2 mobility and accumulate GluA2 in synapses.
• LTD (long-term depression) involves internalization.

AMPAR Trafficking: Mechanisms

• Key protein mechanisms regulating AMPAR trafficking include PSD95 and TARPS, NSF and AP2, PICK1 and ABP/GRIP, and SAP97 and Myosin VI.

LTP vs AP2

• The AP2 adapter complex binds to an overlapping region of GluA2.
• NSF probably occupies this area to stabilize the receptors at synapses.

PICK1 vs ABP/GRIP

• PICK1 is involved in recycling AMPARs back to the plasma membrane.
• ABP/GRIP also plays a role in the lateral movement of AMPARs within synapses.

SAP97 and Myosin VI

• Synapse-associated protein 97 (SAP97) binds the GluA1 PDZ domain.
• Myosin VI is a motor protein, and the phosphorylation of SAP97 by CaMKII prompts the movement of GluA1 to synapses.

Early vs Late LTP

• Early-phase LTP (1-3 hours) does not need protein synthesis, while Late-phase LTP (24 hours) does require protein synthesis (including cAMP and PKA activation).

LTP Maintenance: PKMζ

• PKMζ (an isoform of protein kinase C) is constitutively active, maintaining LTP.
• PKMζ enhances the actions of NSF, preventing postsynaptic removal of GluA2.

Molecular basis of LTD

• NMDA-LTD and mGluR5-LTD mechanisms describe different pathways leading to LTD (long-term depression).
• There are protein phosphatase cascades and intracellular calcium changes involved in LTD (long-term depression).

Experience-Dependent Plasticity: Fear

• Pavlovian classical conditioning modifies synaptic transmission.
• Fear conditioning influences thalamic afferent potentiation.

Reconsolidation Update Successfully Erases Fear Memories in Mice, Rats, and Humans

• Extinction-reconsolidation boundaries are key to persistent attenuation of fear memories.
• Preventing fear return through reconsolidation update mechanisms is possible.
• A protocol for updating involves procedures to decrease CR (conditioned response).

Experience-Dependent Plasticity

• Structural and functional changes in neuronal circuits based on experience (response to experience) is the topic.
• A diagram shows the potential differences of neural response in response to environmental stimuli - suggesting modification.
• Some animals demonstrate changes in ocular dominance based on experience.

(cp-AMPARs and Plasticity)

• Increased cp-AMPARs in the lateral amygdala (LA) after fear conditioning.
• Removal of cp-AMPARs contributes to reconsolidation and memory extinction.
• Regulation of cp-AMPAR trafficking, including mechanisms like phosphorylation, recycling and movement.

AMPAR Subunit Composition

• AMPAR subunit composition (GluA1-lacking and AMPAR subunits) matters in postsynaptic plasticity. -Rectification in relation to AMPAR subunit composition.