Synaptic Plasticity 101: The Story of the AMPA Receptor for the Brain Stimulation Practitioner

The fields of Neurobiology and Neuromodulation have never been closer. Consequently, the phrase "synaptic plasticity" has become very familiar to non-basic scientists, without actually being very familiar. We present the "Story of the AMPA receptor," an easy-to-understand "10,000 ft" narrative overview of synaptic plasticity, oriented toward the brain stimulation clinician or scientist without basic science training. Neuromodulation is unparalleled in its capacity to both modulate and probe plasticity, yet many are not comfortable with their grasp of the topic. Here, we describe the seminal discoveries that defined the canonical mechanisms of long-term potentiation (LTP), long-term depression (LTD), and homeostatic plasticity. We then provide a conceptual framework for how plasticity at the synapse is accomplished, describing the functional roles of N-methyl-d-aspartate (NMDA) receptors and calcium, their effect on calmodulin, phosphatases (ie, calcineurin), kinases (ie, calcium/calmodulin-dependent protein kinase [CaMKII]), and structural "scaffolding" proteins (ie, post-synaptic density protein [PSD-95]). Ultimately, we describe how these affect the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor. More specifically, AMPA receptor delivery to (LTP induction), removal from (LTD), or recycling within (LTP maintenance) the synapse is determined by the status of phosphorylation and protein binding at specific sites on the tails of AMPA receptor subunits: GluA1 and GluA2. Finally, we relate these to transcranial magnetic stimulation (TMS) treatment, highlighting evidences for LTP as the basis of high-frequency TMS therapy, and briefly touch on the role of plasticity for other brain stimulation modalities. In summary, we present Synaptic Plasticity 101 as a singular introductory reference for those less familiar with the mechanisms of synaptic plasticity.