Notes

The Hippocampus as Model System to Study Plasticity Hippocampus is a model system of learning and memory. The role of Hippocampus in learning and memory has been shown with rat experiments with the Morris Water Maze (MWM). MWM is a large pool of opaque water where the rates are placed. The rats were trained to find and escape onto a platform which was hidden. Authors show that chronic infusion of an NMDA antagonist leads to impairment in place learning.

Neural Plasticity in the Hippocampus Recent work has shown that the hippocampus contains a class of receptors for the excitatory amino acid glutamate that are activated by N-methyl-D-aspartate (NMDA) and that exhibit a peculiar dependency on membrane voltage in becoming active only on depolarization. Blockade of these sites with the drug aminophos-phonovaleric acid (AP5) does not affect synaptic transmission in the hippocampus, but prevents the LTP following brief high-frequency stimulation.

Non-Hebbian Plasticity - Towards the Behavior Timescale Hippocampus neurons learn spatial representations.

Paper: "Behavioral time scale synaptic plasticity underlies CA1 place fields".

LTP and LTD Induction in the Hippocampus

Most Studied Synapse in Hippocampus: CA3 CA1

The main pyramidal cell layers in Hippocampus are the CA1-4 regions (principally CA1 and CA3) and the dentate gyrus. The Schaffer Collateral / Associational Commissural Pathway is derived from axons that project from the CA3 region of the hippocampus to the CA1 region. The axons either come from neurons in the same hippocampus (ipsilateral) or from the other hippocampus (contralateral). These latter fibers are termed commissural fibers, as they cross from one hemisphere of the brain to the other. This pathway is utilized very extensively to study NMDA receptor-dependent LTP and LTD.

To test plasticity in the hippocampus the CA3 to CA1 pathway was modulated and the EPSP in the CA1 was measured, this tells you the activity of the pathway. If the spiked generated overlap it leads to increased spiking strength as there is Residual Ca2+ in the cell. Short-term depression at about 40ms time frame can be observed if the CA3 to CA1 pathway is stimulated at 50hz it leads to a reduction in the EPSP which is dependent on the frequency of activation. LTP is measured in the hippocampus. The CA3 pathway is given a fast stimulus of (range 50 -- 200 hz) 100 hz known as tetanus. This leads to a stronger post tetanic potentiation caused by the accumulation of Ca in the terminals as well as LTP in the long-term. If the cells are stimulated at a lower time frequency 1-10 hz LTD will occur. (Estimated through in-vitro recordings).

Molecular Basis of Synaptic Plasticity

Short-Term Synaptic Facilitation/Depression

Once again, there are two types of short-term plasticity (STD): Short-Term Depression (STD) and Short-Term Facilitation (STF).

• STD is caused by depletion of neurotransmitters consumed during the synaptic signaling process at the axon terminal of a pre-synaptic neuron.
• STF is caused by influx of calcium into the axon terminal after spike generation, which increases the release probability of neurotransmitters.
• STP has been found in various cortical regions and exhibits great diversity in properties.
• Synapses in different cortical areas can have varied forms of plasticity, being either STD-dominated, STF-dominated, or showing a mixture of both forms.

Synaptic Plasticity Strongly Depends on Calcium Levels

1. Level and timing of Ca2+ rise in spine determines LTD or LTP.
2. Low frequency synaptic firing (approx. 5 Hz) produces LTD, high-frequency synaptic firing (approx. 50 to 100 Hz) produces LTP.
3. The same Ca2+ rules may underlie "spike-timing-dependent synaptic plasticity" (STDP).

Intracellular Plasticity Signaling Pathways LTP and LTD are dependent on CREB which controls the level of AMPA receptors in the cell. The level of AMPA receptors will determine how depolarized or hyperpolarized the cell becomes.

• What controls LTP and LTD:
  • CREB is controlled by many pathways that are dependent on Ca ions or directly by dopamine.
  • Ca ion levels can increase as it enters into the cell from the external environment or released from internal stores.
• How Ca levels change:
  • AMPA channel, when glutamate binds it causes depolarization opening voltage gated Ca channels as well as NMDA channels that further depolarize the cells. Dopamine D2 when binds in leads to Ca2+ increase from the ER, which leads to increased Ca.
• How Ca leads to CREB:
  • Positive: High levels of Ca activated Camkinse 1 and 2 that leads to increased CREB and thus AMPA receptors. Dopamine activated internal cell machinery that leads to increased phosphorylation (activation) of CREB these both pathways are known as the LTP pathways.
  • Negative: Low levels of Ca lead to Camkinse 2 and Calmodulin that reduces the phosphorylation (activation) of CREB thus AMPA receptors.