Long term Potentiation (LTP)

Explain what LTP is and how it can be induced

Long-Term Potentiation (LTP) is a sustained enhancement of synaptic strength following high-frequency stimulation of a synapse. It is widely considered a cellular model for learning and memory.

Induction of LTP involves:

• High-frequency stimulation (HFS) or theta-burst stimulation of presynaptic neurons.

• This leads to postsynaptic depolarization and glutamate release, which activates AMPA receptors.

• The resulting depolarization relieves the Mg²⁺ block on NMDA receptors, allowing Ca²⁺ influx into the postsynaptic neuron.

• The increase in intracellular Ca²⁺ triggers signaling pathways (e.g. CaMKII) that strengthen the synapse.

Describe the properties of NMDAR-dependent LTP at CA3–CA1 synapses

• Site: CA3 presynaptic neurons to CA1 postsynaptic neurons in the hippocampus.

• Dependence on NMDA receptors (NMDARs):

• Require both ligand binding (glutamate) and voltage-dependent depolarization to open.

• Allow Ca²⁺ entry, which is essential for triggering downstream molecular cascades that result in LTP.

• Two phases:

• Early-phase LTP (E-LTP): Independent of protein synthesis.

• Late-phase LTP (L-LTP): Requires new protein synthesis (translation), possibly from localized dendritic mRNAs.

• LTP can last hours to days, making it a strong candidate mechanism for memory storage.

Describe the properties of NMDARs that allow them to act as coincidence detectors

NMDARs are uniquely suited as coincidence detectors because they only open when two conditions are met:

1. Glutamate binding: Released from the presynaptic terminal during synaptic activity.

2. Postsynaptic depolarization: Typically via AMPA receptor activation, which removes the Mg²⁺ block from the NMDAR pore.

This ensures that only active synapses with simultaneous pre- and postsynaptic activity undergo LTP — a key principle of Hebbian plasticity: “Neurons that fire together wire together.”

Describe mechanisms that could allow for long-term changes in synaptic efficacy and the evidence for such changes

Postsynaptic changes:

• Phosphorylation of AMPARs: Increases conductance or opening probability.

• Insertion of new AMPARs: Into the postsynaptic membrane to strengthen the synapse.

• Shown by increased miniature EPSC (mEPSC) amplitude after LTP.

• Silent synapses become active through AMPAR insertion.

• CaMKII activation is essential for these changes (Silva et al., 1992).

Presynaptic changes (less certain):

• Retrograde signaling (e.g., nitric oxide) may increase neurotransmitter release probability.

Molecular support:

• Late-phase LTP requires protein synthesis.

• Local dendritic translation is sufficient (Vickers et al., 2005).

• Translation inhibitor cycloheximide blocks LTP, while transcription inhibitor actinomycin D does not.

How does Hippocampus,learning and memory and LTP all relate to each other (6)

• hippocampus damage gives rise to deficits in certain aspects of learning and memory

• In experimental animal models, lesions of the hippocampus give rise to deficits in spatial learning

• Spatial learning, such as that tested in the Water Maze, is prevented by administration of D-AP5 (NMDA receptor antagonist

• Long-term potentiation (LTP) in some areas of the hippocampus requires NMDA receptor activation

• Learning induces some of the same molecular changes as LTP

• NMDA receptor-dependent LTP is the most widely studied cellular model of learning and memory

What is LTP and how does it relate to learning

• LTP: A long-lasting increase in synaptic strength following high-frequency stimulation.

• Key region: Hippocampus – essential for learning and memory.

• Human and animal studies show that damage or inhibition (e.g. with NMDA receptor antagonist D-AP5) impairs spatial learning.

• NMDA receptor (NMDAR)-dependent LTP is a model for synaptic plasticity and memory.

What’s the historical background on LTP

• Hebb’s Postulate (1949): “Neurons that fire together wire together.”

• First demonstration: Bliss & Lømo (1973) at perforant path–granule cell synapse.

• Common LTP study site: CA3–CA1 synapses in hippocampus.

What is the Tri-synaptic pathway

• Involves 3 glutamatergic synapses using:

• AMPA receptors

• NMDA receptors

• Kainate receptors

How are NMDA receptors coincidence detectors

• Require both:

1. Glutamate binding

2. Postsynaptic depolarization (to relieve Mg²⁺ block)

• Leads to Ca²⁺ influx, initiating intracellular signaling for LTP.

What are the 2 phases of LTP

• Early LTP (E-LTP): Lasts ~1 hour, independent of protein synthesis.

• Late LTP (L-LTP): Lasts >3-4 hours, requires protein synthesis.

Where does the LTP protein synthesis happen?

• Evidence supports local dendritic translation (Kelleher et al., 2004; Steward, 1982, 2001).

• Vickers et al. (2005):

• Cycloheximide (translation inhibitor) blocks LTP in isolated dendrites.

• Actinomycin D (transcription inhibitor) does not block LTP

What are the post synaptic and pre synaptic mechanisms of LTP

Postsynaptic

• Increased AMPA receptor function via:

• Phosphorylation (↑ conductance or open probability).

• Insertion of new AMPA receptors into the membrane.

• Activation of CaMKII is critical (Silva et al., 1992).

• Silent synapses: Can become active with AMPAR insertion (Isaac et al., 1995).

Presynaptic (Less certain)

• Requires retrograde messengers like:

• Nitric oxide, carbon monoxide, or arachidonic acid.

What evidence is there of functional changes

• Miniature EPSCs (mEPSCs) increase in amplitude after LTP.

• Membrane fusion inhibitors block these changes (Lledo et al., 1998; Baxter & Wyllie, 2006).

What is retrograde signalling

• Since NMDAR-dependent LTP is triggered postsynaptically, the postsynaptic cell must signal back to the presynaptic terminal.

• Retrograde messengers are small, diffusible molecules that travel back to the presynaptic terminal to modify function.

Examples of retrograde messengers:

• Nitric oxide (NO) – synthesized by nitric oxide synthase (NOS) in the postsynaptic neuron.

• Carbon monoxide (CO)

• Arachidonic acid derivatives

These messengers can increase presynaptic release probability or affect vesicle dynamics.

Presynaptic expression mechanisms of LTP

Increase the amount and probability of neurotransmitter release

Postsynaptic expression mechanisms of LTP

• Increase the efficacy of existing post-synaptic receptors:

  • Phosphorylation of AMPA receptors can lead to larger synaptic currents or greater probability that the channel opens.

• Increase the number of post-synaptic receptors:

  • Phosphorylation plays a role in AMPA receptor insertion into the post-synaptic membrane.  Potentially synthesis of new AMPA receptors