AMPA Receptor

Glutamate is endogenous agonist. AMPA ($\alpha$-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) is a synthetic compound used for selective activation of the corresponding receptor, how it got the name name. no endogenous role.

• primary mediators of fast excitatory synaptic transmission in the Central Nervous System
• Glutamate binding opens channel, allows for Na⁺ in and K⁺ out, produces fast EPSP

AMPA

No point in making a whole note for AMPA individually, receptor is important but synthetic compounds entire life is that it is a selective agonist for this kind of receptor - also what defines the receptor itself.

Synaptic Plasticity

AMPA receptors are the primary readout of LTP expression:

1. High-frequency stimulation activates NMDA Receptors ($M{g}^{2+}$ block removed by depolarization)
2. $C{a}^{2+}$ influx activates CaMKII
3. CaMKII phosphorylates GluA1 (Ser831) and drives AMPAR insertion into the postsynaptic density
4. More synaptic AMPARs = larger EPSP = potentiated synapse

Silent synapses contain only NMDARs and no AMPARs. They’re functionally silent at rest because the $M{g}^{2+}$ block prevents NMDAR activation. LTP converts them by inserting AMPARs, making the synapse active.

• LTD reverses this: dephosphorylation drives AMPAR internalization and synapse weakening.
• Receptor traffickinig gated by TARPs (transmembrane AMPAR regulatory proteins), particularly stargazin, which handles synaptic targeting and anchoring to PSD-95.

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AMPA Positive Allosteric Modulators (sirsadalot)

An AMPA PAM works by increasing the likelihood of information processing neurons, or spiking neurons, to fire electrical signals. This is a cascade set off by glutamate binding, which is a pivotal transaction in times of learning. This enhanced calcium signaling will cause long term potentiation (LTP) which strengthens memory and improves learning.¹

However, AMPA PAMs have an interesting characteristic: in non-human primates, the increased connectivity from spiking neurons in cortical association regions then activated the precuneus when it would normally be dormant. This is a significant finding, as it indicates entirely new abilities would be possible when otherwise limited by connectivity.² Interestingly, the precuneus is crucial for episodic memory and human consciousness, and is normally active in a rested state. ³

AMPA PAMs are split into two groups: low impact and high impact. Low impact AMPA PAMs preferentially block extracellular domains that deactivate the receptor,⁴ while high impact AMPA PAMs may also enhance agonist binding to AMPA, as a traditional PAM would.

Classic AMPA PAMs include TAK-653, Psilocybin, and Ketamine, however TAK-653 is much more acute in its focus.

Footnotes

1. https://sci-hub.hkvisa.net/https://www.sciencedirect.com/science/article/abs/pii/S0091305710004077?via%3Dihub ↩

2. https://sci-hub.hkvisa.net/https://www.sciencedirect.com/science/article/abs/pii/S0091305710004077?via%3Dihub ↩

3. https://academic.oup.com/brain/article/129/3/564/390904 ↩

4. https://sci-hub.hkvisa.net/https://www.sciencedirect.com/science/article/abs/pii/S0091305710004077?via%3Dihub ↩