Silent synapses

Silent synapses come in two main forms: those that are presynaptically silent, which do not exhibit neurotransmitter release, and those that are postsynaptically silent, which do not possess the appropriate neurotransmitter receptors. To date, most described silent synapses are glutamatergic. Glutamate acts through two types of ionotropic receptors to mediate excitatory neurotransmission in the mammalian central nervous system: α‑amino‑3‑hydroxy‑5‑methyl‑4‑isoxazolepropionic acid (AMPA) and N‑methyl‑d‑aspartate (NMDA) receptors (AMPARs and NMDARs). AMPARs operate as conventional (i.e., voltage‑independent) ionotropic receptors, while NMDARs exhibit a strong voltage dependence, only passing current when glutamate is bound during depolarization, due to relief of a Mg²⁺ blockade. Silent glutamatergic synapses lack AMPARs and are thus functionally silent at resting membrane potentials (where many synapse physiology experiments are conducted); however, they can be unveiled upon depolarization due to the activation of NMDARs. The resulting functional accessibility of silent glutamatergic synapses for experimental inquiry has led to their predominance in terms of interest and progress in the field, to the extent that the term silent synapse has become almost synonymous with AMPA‑silent synapses.