Long Term Potentiation: How your brain learns - signalling pathway in synapse

LTP is a key process underlying learning and memory.

It involves the strengthening of synaptic connections through repeated stimulation, allowing neurons to communicate more effectively. This phenomenon is primarily mediated by NMDA (N-methyl-D-aspartate) glutamate receptors and other molecular mechanisms.

Role of NMDA and AMPA Receptors

  • Glutamate, the major excitatory neurotransmitter in the CNS, plays a critical role in synaptic transmission.
  • It binds to two key receptors:
    • AMPA Receptors: Ionotropic receptors that allow Na+ and K+ ions to pass when activated, leading to fast excitatory synaptic transmission.
    • NMDA Receptors: Normally blocked by Mg2+ ions, preventing ion flow.
Definition: In this context, sensitivity refers to for the same amount of stimulation (AP to CA3), the response (AP of CA1) is greater.

Phases of LTP

A. Normal Synaptic Transmission (Before LTP)

  • When an action potential reaches the CA3 neuron terminal, glutamate is released into the synaptic cleft.
  • Glutamate binds to AMPA receptors, allowing Na+ influx and causing a slight depolarization.
  • NMDA receptors remain blocked by Mg2+, preventing Ca2+ entry.

B. Induction of LTP (Triggering Synaptic Strengthening)

  • During high-frequency stimulation, repeated AMPA receptor activation causes sufficient depolarization of the postsynaptic membrane.
  • This depolarization removes the Mg2+ block from NMDA receptors, allowing Ca2+ to enter.
  • Increased Ca2+ concentration inside the spine activates key signaling pathways:
    • Ca2+/calmodulin-dependent protein kinase II (CaMKII): Phosphorylates AMPA receptors, increasing their sensitivity. Also activates some previously silent receptor channels.
    • Protein Kinase C (PKC) and Tyrosine kinase (Fyn): Further modulate receptor function.
    • Metabotropic glutamate receptors (mGluRs): Trigger additional calcium release from the endoplasmic reticulum (ER).

C. Expression of LTP (Long-Term Strengthening)

  • Enhanced AMPA receptor function leads to:
    • More Na+ entry, causing a stronger postsynaptic response.
    • Insertion of new AMPA receptors into the membrane, increasing synaptic efficiency.
  • A retrograde messenger, likely nitric oxide (NO), signals the presynaptic neuron to release more glutamate, strengthening communication.


In summary: Structural and Functional Effects of LTP:
  • Postsynaptic changes:
    • Increased sensitivity of AMPA receptors.
    • Recruitment of silent synapses (previously inactive receptors become functional).
  • Presynaptic changes:
    • NO retrograde signaling increases neurotransmitter release.
  • Anatomical modifications:
    • Formation of new synaptic spines and presynaptic terminals, enhancing connectivity.

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