How does LTP work at the hippocampal synapse?

Contributing Author: Khayla Black

Answer: LTP, or long term potentiation, is the process by which synapses strengthen in response to stimulation.

LTP at hippocampal synapse

LTP is most often studied in the hippocampus, a seahorse-shaped structure of the limbic system. The hippocampus contains two segments which are intertwined: the dentate gyrus and the hippocampus proper. The hippocampus proper is divided into four segments: CA1, CA2, CA3, and CA4; however, most LTP studies focus solely on CA1 and CA3. Information passes from CA3 to CA1 via Schaffer collaterals, which are axons branching off of pyramidal cells. For this model of LTP, CA3 will act as our presynaptic portion, while CA1 will serve as the postsynaptic.

The entire process begins with action potentials, which travel down the Schaffer collaterals and trigger glutamate release into the synaptic cleft. This glutamate release stimulates two important receptors, AMPA and NMDA. Both are glutamate receptors; NMDA receptors are sodium and calcium permeable, while AMPA receptors are permeable only to sodium. Upon stimulation, the AMPA receptors open, and sodium is allowed to travel through the channel and into the postsynaptic membrane. This sodium influx results in a depolarization, which may not be strong enough to do anything. However, if the action potential that travels down the collateral has a high enough frequency, a large amount of glutamate will be released, which will allow the AMPA receptors to remain open for extended periods of time, longer than a low frequency stimulation would allow. This will result in a large amount of sodium entry and will create a large depolarization, which is key for activation of the NMDA receptors. Though the NMDA receptors are both sodium and calcium permeable, they cannot be activated upon low frequency stimulation because at the resting membrane potential, they experience a magnesium block. However, this large depolarization triggered by the activation of the AMPA receptor can displace the magnesium, which will allow sodium and calcium to enter into the postsynaptic cell.

This influx of calcium activates protein kinases and triggers cascades that contribute to two types of changes: short term and long term. In the short term changes, which last only a few hours, calcium binds to proteins which result in insertion of AMPA receptors onto the postsynaptic cell. In the long term changes, prolonged calcium influx influences transcription factors, which impact protein synthesis. These changes also result in insertion of AMPA receptors in the postsynaptic neuron, but, more importantly, they lead to protein modification and synthesis which allows for pruning of synapses. This is the basis of plasticity.