Synapse-specific and size-dependent mechanisms of spine structural plasticity accompanying synaptic weakening

Abstract

Refinement of neural circuits in the mammalian cerebral cortex shapes brain function during development and in the adult. However, the signaling mechanisms underlying the synapse-specific shrinkage and loss of spiny synapses when neural circuits are remodeled remain poorly defined. Here, we show that low-frequency glutamatergic activity at individual dendritic spines leads to synapse-specific synaptic weakening and spine shrinkage on CA1 neurons in the hippocampus. We found that shrinkage of individual spines in response to lowfrequency glutamate uncaging is saturable, reversible, and requires NMDA receptor activation. Notably, shrinkage of large spines additionally requires signaling through metabotropic glutamate receptors (mGluRs) and inositol 1,4,5-trisphosphate receptors (IP 3 Rs), supported by higher levels of mGluR signaling activity in large spines. Our results support a model in which signaling through both NMDA receptors and mGluRs is required to drive activity-dependent synaptic weakening and spine shrinkage at large, mature dendritic spines when neural circuits undergo experience-dependent modification.two-photon microscopy | long-term depression | synaptic plasticity | spine dynamics S tructural plasticity of neurons, such as the growth and retraction of dendritic spines, is thought to contribute to the experience-dependent changes in brain circuitry that mediate learning and memory (1, 2). In particular, the destabilization and loss of spiny synapses plays a critical role in the refinement of neural circuits during development and during learning. Indeed, spine elimination occurs more frequently than does spine formation in young rodents between the first and the third month of age (3-5), a period when experience-dependent refinement of neural circuitry is in its peak. Furthermore, several in vivo studies demonstrate that manipulations leading to experience-dependent circuit plasticity also increase the rate of spine shrinkage and loss (6-9). However, it remains unclear how neural activity drives the selective shrinkage and loss of individual dendritic spines in response to sensory experience.Dendritic spines occur in a wide variety of shapes and sizes (10, 11), and their stability is strongly correlated with spine size (3, 12, 13). Small spines are in general more motile and thought to serve as substrates for plasticity, or "learning" spines; large spines are more stable and thought to serve as components of functioning neural circuits, or "memory" spines (12,14). It is the selective shrinkage and loss of individual circuit-incorporated, persistent spines that underlies experience-dependent circuit refinement (6, 9, 15). Thus, experience-dependent circuit remodeling requires an activity-dependent mechanism that selectively induces shrinkage and retraction of those specific individual dendritic spines that are no longer useful for circuit function.Previous studies have established that low-frequency glutamatergic stimulation (LFS), which causes long-term depression (LTD) of synaptic transmission in...

Long-term depression triggers the selective elimination of weakly integrated synapses

“…Thus, consistent with previous reports (23,44), delayed spine removal is not the endpoint of a slow and gradual shrinkage process that starts immediately after LFS. Some studies (24,27) reported immediate spine shrinkage after LFS, which we and others (23) did not observe. Glutamate photolysis at 0.1 Hz in Mg 2+ -free solution (27) induces rapid shrinkage of a subset of spines.…”

“…Some studies (24,27) reported immediate spine shrinkage after LFS, which we and others (23) did not observe. Glutamate photolysis at 0.1 Hz in Mg 2+ -free solution (27) induces rapid shrinkage of a subset of spines. It is difficult to compare this protocol to the 1-Hz optogenetic stimulation we use here, as the activation profiles of ionotropic and metabotropic glutamate receptors and their downstream pathways were almost certainly different.…”

“…It seems that functional depression and spine shrinkage are mediated by separate molecular pathways that can be pharmacologically dissociated (25). Thus, spine shrinkage accompanies LTD in certain populations of spines (27) under specific stimulation conditions. Our oLFS protocol evoked transmission at a sparse and distributed set of synapses.…”

“…Potentiation of individual spine synapses selectively increases their stability, pointing to a connection between synaptic plasticity and spine survival (22). Conversely, whether LTD is connected to spine shrinkage or a reduction in spine lifetime is less clear (23)(24)(25)(26)(27), as it was not possible to identify individual depressed synapses and to observe them over sufficiently long time periods. Because of these methodological limitations, we know little about LTD at the synaptic level: Are all synapses equally sensitive to depression-inducing activity patterns?…”

Spine neck plasticity regulates compartmentalization of synapses

“…3 Dendritic spines form the postsynaptic component of most excitatory synapses, whose plasticity is essential for brain development and higher brain functions 1,2 . In addition to the molecular composition of the synapse, the morphology of spines is thought to be critical for synaptic function, as spine head size correlates with synaptic strength 3,4 and undergoes changes during synaptic plasticity [5][6][7][8] . Even so, our understanding of how spine structure shapes synapse function remains fragmented.…”