Long-Term Potentiation: Mechanisms, Receptors, and Changes

Posted on Jan 16, 2025 in Biology

Long-Term Potentiation (LTP) in CA1

For LTP to occur in area CA1: glutamate binds to NMDA receptors (ligand-gated).

The cell must be sufficiently depolarized to expel the Mg2+ block from the NMDAR (voltage-gated).

NMDAR passes Ca2+ ions ONLY when the Mg2+ block is removed.

To remove Mg2+: strong depolarization of the cell by a strong input is needed.

Other Glutamate Receptors

Other than NMDA receptors, what other receptors does glutamate bind to?

Two types of glutamate receptors: NMDA and AMPA.

Strengthening of individual synapses is accomplished by the insertion of additional AMPA receptors into the postsynaptic membrane.

AMPA receptors control sodium channels.

So, the next release of glutamate causes a larger EPSP.

Role of CaMKII

The entry of Ca2+ through the NMDA receptor activates protein kinases, which regulate different cellular functions.

CaM-KII (type II calcium-calmodulin kinase) is inactive until calcium ions bind with and activate it.

It is unique in that it can be activated by an increase in Ca2+ and remain active for many hours.

It can be persistently active in the absence of additional Ca2+ entry into the spine.

Summary: NMDAR, CaMKII, AMPARs & LTP Induction

Given sufficient depolarization of the postsynaptic cell during LTP induction:

  • The Mg2+ block can be removed from the NMDAR, allowing Ca2+ to pass into the spine.
  • Ca2+ can activate CaMKII, which can be persistently active.
  • Activated CaMKII can then target the subunit of the AMPA receptor, which drives it into synapses.

Other LTP-Associated Changes

LTP can cause new dendritic spines to grow (new synapses).

LTP causes changes in the size/shape of dendritic spines.

Thin spines can turn into fatter, mushroom-shaped spines.

Changes on the Presynaptic Side

LTP induction depends on postsynaptic depolarization and protein kinase signaling.

There are also clear changes on the presynaptic side of the synapse:

  • Increased transmitter release.

Retrograde Messenger Hypothesis

Retrograde Messenger Hypothesis: Since this presynaptic change requires the postsynaptic changes to occur first, it suggests that there must be some signal that is sent from the postsynaptic cell to the presynaptic cell.

Nitric Oxide (NO)

Nitric Oxide (NO): a soluble gas produced from the amino acid arginine by the enzyme nitric oxide synthase (NOS).

NO lasts only a short time before it is destroyed.

Once generated, NO is thought to diffuse back to the presynaptic side of the synapse and activate protein kinases, including protein kinase G (PKG).

Activation of PKG can enhance vesicle mobilization and release, and initiate presynaptic structural changes.

Brain Structures and Learning

3rd Interstitial Nucleus of Anterior Hypothalamus

  • L het. m
  • S het. f/m

Anterior Commissure

  • L homo m/ het. f
  • S het. m

Suprachiasmatic Nucleus of Hypothalamus

  • L homo m
  • S het. m/het. f

REJECT hypothesis: homo men have female hypothalamus

Classical Conditioning

CS (Tone) neural stim + aversive stim.

UnCS (Shock) stim. natural. Aversive

CR (change in heart rate/blood pressure/freezing) learned resp. to stim.

Amygdala Circuitry

  • Lateral Nucleus: most input to amygdala
  • Basal Nucleus: input from lateral nucleus
  • Central Nucleus: main output of amygdala

Types of Learning

  • Perceptual Learning: Categorize objects (stimuli)
  • Stimulus-Response Learning: perform behavior when stimulus present
  • CS/Instrumental Conditioning (lever)
  • Relational Learning: declarative/explicit memory of events
  • LTP (long-term potentiation)

Anterior Commissure

  • L homo m/ het. f
  • S het. m

Suprachiasmatic Nucleus of Hypothalamus

  • L homo m
  • S het. m/het. f

REJECT hypothesis: homo men have female hypothalamus

CS (Tone) neural stim + aversive stim.

UnCS (Shock) stim. natural. Aversive

CR (change in heart rate/blood pressure/freezing) learned resp. to stim.

  • Lateral Nucleus: most input to amygdala
  • Basal Nucleus: input from lateral nucleus
  • Central Nucleus: main output of amygdala

Perceptual Learning: Categorize objects (stimuli)

Stimulus-Response Learning: perform behavior when stimulus present

CS/Instrumental Conditioning (lever)

Relational Learning: declarative/explicit memory of events

LTP (long-term potentiation)