Spine Expansion and Stabilization Associated with Long-Term Potentiation

Abstract

Stable expression of long-term synaptic plasticity is critical for the developmental refinement of neural circuits and for some forms of learning and memory. Although structural remodeling of dendritic spines is associated with the stable expression of long-term potentiation (LTP), the relationship between structural and physiological plasticity remains unclear. To define whether these two processes are related or distinct, we simultaneously monitored EPSPs and dendritic spines, using combined patch-clamp recording and two-photon time-lapse imaging in the same CA1 pyramidal neurons in acute hippocampal slices. We found that theta burst stimulation paired with postsynaptic spiking, which reliably induced LTP, also induced a rapid and persistent expansion of dendritic spines. Like LTP, this expansion was NMDA receptor dependent. Spine expansion occurred even when LTP was inhibited by postsynaptic inhibition of exocytosis or PKA (protein kinase A); however, under these conditions, the spine expansion was unstable and collapsed spontaneously. Furthermore, similar changes in LTP and spine expansion were observed when hippocampal neurons were treated with protein synthesis inhibitors. Like LTP, spine expansion was reversed by low-frequency stimulation (LFS) via a phosphatase-dependent mechanism, but only if the LFS was applied in a critical time window after induction. These results indicate that the initial expression of LTP and spine expansion is dissociable, but there is a high degree of mechanistic overlap between the stabilization of structural plasticity and LTP.

Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately

“…Further analyses showed substantial spine expansion in response to MMP-9 over the entire range of initial spine volumes (Fig. S3C), indicating that both small and large spines are capable of expansion in response to MMP-9, consistent with several recent studies (5,16). Together, these results demonstrate that local MMP-9 proteolysis is both necessary and sufficient for persistent spine enlargement and potentiation.…”

“…1B) and an immediate but small increase in EPSP slope, which gradually increased further until reaching a plateau by Ϸ30 min (Fig. 1C) as expected (5). In contrast, in the presence of an MMP-9 inhibitor (Inhibitor II), TBP produced a spine enlargement and synaptic potentiation that were transient ( Fig.…”

“…We blocked endogenous MMP proteolysis with bath-applied MMP inhibitors while applying a theta-burst pairing (TBP) protocol that induces rapid and persistent spine enlargement and LTP (5). Spine size and synaptic responses [excitatory postsynaptic potentials (EPSPs)] were monitored simultaneously in CA1 neurons by 2-photon time-lapse imaging and whole-cell patch clamp recording (Fig.…”

“…Spines were visualized by intracellular labeling with an inert fluorescent dye, calcein, contained in the recording patch pipette. A stimulating glass electrode was positioned Ϸ20 m from the imaged spines to elicit EPSPs and TBP, a configuration that maximizes the likelihood that synapses on the imaged spines are activated (5,14,15). In the absence of MMP inhibitors, TBP induced a rapid and persistent increase in spine volume (Fig.…”

“…Studies show that dendritic spines undergo significant morphological remodeling in association with long-lasting plasticity (3). Spine growth, for example, is associated with the induction of LTP and is thought to be important for supporting persistent changes in synaptic strength (4)(5)(6). However, little is known about signals that instruct and coordinate persistent modifications in synapse structure and function during LTP.…”