Metaplastic protein phosphatases.

Activity-dependent synaptic plasticity is widely considered to be one of the cellular mechanisms that underlie learning and memory. Long-term potentiation (LTP) is the most intensely studied form of synaptic plasticity, in part because it can be induced at glutamatergic synapses in the mammalian brain, including the hippocampus, a structure known for its involvement in memory function. LTP can be divided into at least two phases, an early phase (E-LTP) and a late phase (L-LTP). There is a great deal known about the biochemical signal transduction cascades that underlie both E-LTP and L-LTP. However, comparatively little is known about the mechanisms by which prior activity may modulate synaptic plasticity, a phenomenon termed metaplasticity (Abraham and Bear 1996). In addition, it is not known whether there are differences in the metaplasticity of E-LTP and L-LTP. In this issue of Learning & Memory, Woo and Nguyen (2002) present the results of an elegant series of experiments that begin to address these questions. E-LTP is typically induced with one train of highfrequency stimulation (HFS) of 100 Hz and lasts 1–3 h, whereas L-LTP can be induced with multiple, spaced trains of 100 Hz HFS and persists for at least 24 h (for reviews, see Huang et al. 1996; Kandel 2001). The biochemical mechanisms supporting E-LTP and L-LTP have been extensively characterized. In hippocampal area CA1, both E-LTP and L-LTP are dependent on N-methyl-D-aspartate (NMDA) receptor activation, calcium influx into the postsynaptic neuron, and the activation of a number of protein kinase cascades. However, E-LTP and L-LTP can be distinguished from one another by several important criteria. The expression of L-LTP, but not E-LTP, requires activation of a cAMP-dependent protein kinase (PKA)/extracellular signal-regulated kinase (ERK) signaling cascade, transcription, and new protein synthesis (Huang et al. 1996; Kandel 2001). The delineation of the molecular mechanisms necessary for L-LTP has generated much excitement because very similar mechanisms appear to be necessary for the long-term storage of implicit memories (Kandel 2001). Metaplasticity is neither appreciated nor studied as intensely as LTP, but several forms of metaplasticity have been identified and described. For example, the induction of long-term depression (LTD) can be facilitated by previous periods of HFS (Christie and Abraham 1992), and the induction of LTP can be inhibited by previous periods of low-frequency stimulation (LFS; Christie and Abraham 1992; Huang et al. 1992). However, little is known about the biochemical signal transduction mechanisms that are involved in these forms of metaplasticity. The first question Woo and Nguyen (2002) addressed was whether an LFS protocol (5 Hz for 3 min), which had no effect on naive synapses, could affect subsequently induced E-LTP and L-LTP. To address this question, they delivered LFS, waited 7 min, and then induced either E-LTP or L-LTP. They observed that prior LFS had no effect on subsequently induced E-LTP. Surprisingly, they found that the same LFS protocol was able to completely block the expression of L-LTP. The inhibition of L-LTP by prior LFS was temporally limited because LFS could block subsequently induced L-LTP if the delay between LFS and the first train of HFS was 20 min, but not if the delay was 40 min. In addition, the authors also found that the LFS protocol could not reverse already established L-LTP. Taken together, these results indicate that prior synaptic activity differentially affects E-LTP and L-LTP and that the anterograde inhibition of L-LTP by prior synaptic activity is temporally restricted. The second critical question that Woo and Nguyen (2002) addressed was the biochemical signaling mechanisms responsible for this novel form of metaplasticity. It was previously shown that LFS-induced LTD, paired-pulse stimulation-induced LTD in vivo, and depotentiation of LTP all require NMDA receptor activation and protein phosphatase 1 (PP1) and/or protein phosphatase 2A (PP2A) activity (Mulkey et al. 1993; O’Dell and Kandel 1994; Thiels et al. 2000). Therefore, they asked whether the anterograde inhibition of L-LTP by prior LFS required NMDA receptor activation and/or PP1/PP2A activity. The authors found that NMDA receptor blockade prevented LFS from inhibiting the subsequent induction of L-LTP. In addition, Woo and Nguyen found that both okadaic acid and calyculin A, inhibitors of PP1/PP2A, also prevented LFS from inhibiting the subsequent induction of L-LTP. Collectively, these findings indicate that NMDA receptor activation during LFS is required to trigger a signaling cascade that includes PP1/ PP2A, which can subsequently prevent the expression of L-LTP. The findings of Woo and Nguyen indicate that protein phosphatases, which have been shown to play critical roles in the regulation of both LTP and LTD (Winder and Sweatt 2001), also play a critical role in a novel form of metaplasE-MAIL [email protected]; FAX (713) 798-3475. Article and publication are at http://www.learnmem.org/cgi/doi/ 10.1101/lm.52802.