Multiple cellular cascades participate in long-term potentiation and in hippocampus-dependent learning

Abstract

Since its discovery by Bliss and Lomo, the phenomenon of long-term potentiation (LTP) has been extensively studied, as it was viewed as a potential cellular mechanism of learning and memory. Over the years, many signaling cascades have been implicated in its induction, consolidation and maintenance, raising questions regarding its real significance. Here, we review several of the most commonly studie signaling cascades and discuss how they converge on a common set of mechanisms likely to be involved in the maintenance of LTP. We further argue that the existence of cross-talks between these different signaling cascades can not only account for several discrepancies in the literature, but also account for the existence of different forms of LTP, which can be engaged by different types of stimulus parameters under different experimental conditions. Finally, we discuss how the understanding of the diversity of LTP mechanisms can help us understand the diversity of the types of learning and memory. This article is part of a Special Issue entitled SI: Brain and Memory.

Keywords: Actin polymerization; Calpain; CamKII; PKA; PTEN.

Fig. 1

The calpain cascades. Calpain-1 is rapidly activated as a result of increased calcium concentration produced by stimulation of NMDA receptors. It cleaves RhoA, producing rapid changes in cytoskeleton, as well as SCOP, a negative regulator of ERK. ERK has been involved in the regulation of AMPA receptor trafficking. These steps are necessary for triggering the cascades leading to LTP. On the other hand, calpain-2 is activated after a few minutes as a result of BDNF-mediated ERK activation and phosphorylation. Calpain-2 cleaves PTEN, resulting in mTOR activation and stimulation of local protein synthesis. In particular, SCOP is synthesized, reestablishing ERK inhibition. mTOR also phosphorylates p70S6kinase, which phosphorylates/activates PAK, thus also participating in actin polymerization. Finally, calpain-2 cleaves the phosphatase, STEP, which has been involved in AMPA receptor trafficking. GluAs: Glutamateric AMPA receptors; GluNs: Glutamateric NMDA receptors; VDCC: voltage-dependent calcium channel; TARP: transmembrane AMPA receptor regulatory proteins; STEP: Striatal-Enriched protein phosphatase; SCOP: SCN circadian oscillatory protein; ROCK: Rho-associated coiled-coil containing protein kinase; PAK: p21activated kinase.

Fig. 2

The CamKII cascade. CamKII is rapidly activated by calcium influx through the NMDA receptor-channel. It is released from actin filaments and binds to (1) and phosphorylates (2) the NMDA receptors, regulating their functions. It also regulates the association of stagazin/TARP to AMPA receptor and PSD-95 (3), thereby participating in the regulation of changes in AMPA receptors. Finally, CamKII is redistributed from dendritic shafts to the spines, where it can bundle and enlarge actin filaments (4). A2Ar: Adenosine 2A receptor.

Fig. 3

The PKA cascade. PKA is activated by a variety of upstream signals, including calcium, adenosine A2 receptors, as well as catecholaminergi receptors (not shown in the diagram). It can phosphorylate AMPA receptors and regulate their functions (1), as well as phosphorylate a variety of downstream signaling cascades linked to regulation of transcription and translation (2). It can also phosphorylate NMDA receptors and regulate their functions as well (3). Finally, it can also participate in the regulation of actin filaments through phosphorylation of various actin-binding proteins (4).

Fig. 4

Convergence of the 3 cascades on a common set of mechanisms. The three cascades discussed in the review converge on a common set of mechanisms: (1) post-translational protein modifications, (2) translational regulation and (3) regulation of gene expression. In turn these mechanisms are linked to 2 of the common events responsible for LTP: increased number of postsynaptic AMPA receptors, and increased filamentous actin, resulting in enlarged dendritic spines. Moreover, the existence of multiple cross-talks between calpains, PKA and CamKII suggest that depending on the conditions, various forms of LTP can be triggered with different features. It also suggest that genetic alterations of some elements of these cascades might be overcome by activating the intact elements of the cascades to elicit normal LTP and therefore normal learning.