Do group I metabotropic glutamate receptors mediate LTD?

Abstract

Synapses undergo significant structural and functional reorganization in response to varying patterns of stimulation. These forms of plasticity are considered fundamental to cognition and neuronal homeostasis. An increasing number of reports highlight the importance of activity-dependent synaptic strengthening (long term potentiation: LTP) for learning. However, the functional significance of activity-dependent weakening of synapses (long term depression: LTD) remains relatively poorly understood. One form of synaptic weakening, induced by group I metabotropic glutamate receptors (mGluRs), has received significant attention from a mechanistic point of view and because of its augmentation in a murine model of Fragile X Syndrome. Yet, studies of this form of plasticity often yield confusing, contradictory results. These conflicting findings are likely attributable to the bulk stimulation and recording techniques often used to study synaptic plasticity (typically involving evoked extracellular recordings, which represent the summed activity of many synapses). Such studies inherently blur the identity of the synapses undergoing change, thus giving the illusion that synapses per se are being modified when in fact this may only be true of a specific subset of synapses. Indeed, studies employing minimal synaptic activation paint a fundamentally different picture of what is commonly called “mGluR-LTD”. Here, I review the evidence in favour of group I mGluRs as mediators of various forms of synaptic downregulation and attempt to explain discrepancies in the literature. I argue that, while multiple forms of synaptic weakening may be triggered by these receptors, the canonical form of group I mGluR-mediated depression, mGluR-LTD, is in fact not a depression of basal synaptic responses. Rather, it is a reversal of established LTP and thus a form of depotentiation. Far from being arbitrary, this distinction has significant implications for the role of group I mGluRs in cognition, both in the healthy brain and in pathological conditions. Further, the differential actions of group I mGluRs at naïve and potentiated synapses suggest these receptors signal in a state-dependent manner to regulate various stages of the learning process.