Cell biology in neuroscience: the interplay between Hebbian and homeostatic synaptic plasticity

Abstract

Synaptic plasticity, a change in the efficacy of synaptic signaling, is a key property of synaptic communication that is vital to many brain functions. Hebbian forms of long-lasting synaptic plasticity-long-term potentiation (LTP) and long-term depression (LTD)-have been well studied and are considered to be the cellular basis for particular types of memory. Recently, homeostatic synaptic plasticity, a compensatory form of synaptic strength change, has attracted attention as a cellular mechanism that counteracts changes brought about by LTP and LTD to help stabilize neuronal network activity. New findings on the cellular mechanisms and molecular players of the two forms of plasticity are uncovering the interplay between them in individual neurons.

Figure 1.

Compensation of Hebbian plasticity at neighboring synapses. A synapse undergoing LTP (middle) is adjoined by weaker synapses (left and right). Compensatory depression of synaptic strength of synapses adjacent to a potentiated synapse could be a form of homeostatic compensation to help maintain local dendritic activity (see text).

Figure 2.

Homeostatic regulation of synaptic strength. (Left) RIM proteins are central organizers of the active zone. Under basal conditions, these proteins are essential for synaptic vesicle docking and priming and for the recruitment of Ca²⁺ channels to the active zone. RIM proteins interact with both Ca²⁺ channels (VGCC) and Rab3. (Right) Adaptation to inactivity is mediated by (a) an enhancement of presynaptic Ca²⁺ influx, probably due to a RIM-dependent increase in presynaptic voltage gated Ca²⁺ channel density at the active zone, and (b) by a RIM/Rab3-dependent regulation of synaptic vesicle docking/priming step that increases the readily releasable pool of synaptic vesicles and a Rab3-dependent control of the synaptic vesicle cycle. Postsynaptically, chronic activity blockage increases postsynaptic strength by recruiting additional AMPA-type glutamate receptors (AMPARs). CaMKIIβ controls accumulation of the scaffolding molecule GKAP at synapses, which in turn regulates the synaptic levels of the scaffolding molecules PSD-95 and Shank to anchor AMPARs, thereby controlling homeostatic scaling.

Figure 3.

Molecular players and mechanisms involved in AMPAR trafficking during Hebbian plasticity. AMPAR lateral diffusion allows for a rapid increase in postsynaptic efficacy. (Right) For long-term potentiation (LTP) to occur, activation of NMDAR promotes Ca²⁺ influx, which is followed by activation of kinases (PKC, PKA, and CaMKII), phosphorylation of GluA1-containing AMPARs, and triggering of their exocytosis from intracellular pools. Palmitoylation (Palm) of AKAP79/150 promotes AMPAR trafficking and surface delivery. The specific location where AMPARs are incorporated at the surface is under debate; this could occur extrasynaptically or in spine heads. AMPAR exocytosis is mediated by members of the SNARE complex that differ from the ones that regulate presynaptic release. (Left) Long-term depression (LTD) is induced by a moderate level of Ca²⁺ influx and is characterized by the endocytosis of AMPAR from synapses. AMPAR are linked to clathrin via AP2. AKAP79/150 is depalmitoylated and removed from dendritic spines.

Figure 4.

Basal and activity-dependent regulation of synaptic strength by N-cadherin. (Left) Under basal conditions, postsynaptic N-cadherin controls presynaptic strength by modulating synaptic vesicle recycling. Notably, the retrograde role of postsynaptic N-cadherin (purple) appears independent of the homophilic interaction with presynaptic N-cadherin (light purple). GluA2-containing AMPAR seems to be the postsynaptic effector; how these two molecules cooperate to regulate presynaptic strength is not clear (dashed arrows). A possible mechanism is the interaction of postsynaptic N-cadherin and/or GluA2 with a presynaptic partner, another postsynaptic adhesion protein, and/or the release of a soluble effector molecule to target synaptic vesicle recycling. (Right) Although N-cadherin homophilic adhesion is not required for the homeostatic up-regulation of p_r (right half), it plays a critical role in LTP (left half). During potentiation associated with LTP, N-cadherin proteins levels are enhanced as a consequence of PKA activity and protein synthesis.