A critical period of protein kinase activity after tetanic stimulation is required for the induction of long-term potentiation.

Abstract

A critical period of protein kinase activity required for the induction of long-term potentiation (LTP) was determined in area CA1 of hippocampal slices using the broad-range and potent protein kinase inhibitors K-252a and staurosporine. As reported previously, K-252a and staurosporine blocked LTP induction when applied before, during, and after high-frequency stimulation (HFS). In contrast, K-252a did not block LTP when applied only before and during HFS and washed out immediately after HFS. K-252a and staurosporine both attenuated LTP magnitude when applied immediately after or as late as 5 min after HFS. However, K-252a applications beginning 30-45 rain after HFS did not affect LTP expression significantly. K-252a had no detectable effect on isolated N-methyl-v-aspartate (NMDA) receptor-mediated EPSPs but significantly inhibited the in situ phosphorylation of specific hippocampal proteins (synapsin I, MARCKS, and B-50). In addition, K-252a attenuated 4~-phorbol-12,13-dibutyrate (PDBu)-enhanced synaptic transmission. Our results indicate that there is a critical period of protein kinase activity required for LTP induction that extends for ---20 min after HFS. In addition, our results suggest that protein kinase activity during and immediately after HFS is not sufficient for LTP induction. These results provide new information about the mechanisms that underlie LTP induction and expression and aCorresponding author.provide evidence for persistent and/or Ca2+-independent protein kinase activity involvement in LTP

Bidirectional Regulation of Protein Kinase Mζ in the Maintenance of Long-Term Potentiation and Long-Term Depression

“…This suggests that the molecular mechanisms bidirectionally regulating synaptic transmission involve a constitutively active PKC, perhaps PKM, although there may be other forms of autonomous PKC to be characterized in future studies. In addition, however, staurosporine and its analog K252a, inhibitors acting on the catalytic domain of many kinases, including conventional PKCs and CaM-kinase II (Ward and O'Brian, 1992;Huber et al, 1995), have been reported not to reverse LTP maintenance (Denny et al, 1990b;Muller et al, 1992; Huber et al, 1995) (but see Matthies et al, 1991). These results appear to contradict the experiments with H7 and chelerythrine.…”

“…PKC␥ was decreased only in LTD slices (57.1 Ϯ 4.1, p Ͻ 0.05), but not in slices receiving 3 and 100 Hz (108.9 Ϯ 7.0). several protein kinases, CaM-kinase II (Lisman, 1994), full-length PKCs , cGMP-dependent kinase (Zhuo et al, 1994), cAMP-dependent kinase (Huang and Kandel, 1994;Blitzer et al, 1995), and tyrosine kinases (O'Dell et al, 1991), all appear to act interdependently (Huber et al, 1995;Wang and Kelly, 1995), so that the inhibition of any single pathway prevents LTP. On the other hand, calcineurin has been implicated in the induction mechanisms of LTD (Mulkey et al, 1994).…”

Postsynaptic Calcineurin Activity Downregulates Synaptic Transmission by Weakening Intracellular Ca2+Signaling Mechanisms in Hippocampal CA1 Neurons

“…One could argue that CaN-inhibited synaptic potentiation only results from basal CaM-KII / PKC activities (Ocorr and Schulman, 1991;Huber, 1995) instead of from an absolute increase in their activities by positive feedback. Because inhibiting postsynaptic CaM-KII / PKC activities does not significantly alter basal synaptic transmission (Tsien et al, 1990;Feng and Wang, 1992;Wang and Kelly, 1996), basal CaM-KII / PKC activities are not high enough to strengthen synaptic transmission.…”

“…It may be simply understood as shifting the balance between protein kinase and phosphatase activities toward enhancing the phosphorylation of protein substrates responsible for synaptic transmission without increasing the absolute activity of protein kinases. In other words, after CaN is inhibited, the action of basal kinase activities on synaptic substrates becomes dominant, because Ca 2ϩ -dependent protein kinases are active under basal conditions in hippocampal slices (Ocorr and Schulman, 1991;Huber, 1995). However, the inhibition of postsynaptic CaM-KII and PKC activities do not significantly alter basal synaptic transmission (Tsien et al, 1990;Feng and Wang, 1992;Wang and Kelly, 1996a), implying that basal CaM-KII and PKC activities are below a threshold for strengthening synaptic transmission.…”

Tianeptine induces GluA1 phosphorylation and subsequent alteration of the firing properties of CA1 neurons

“…Hippocampal LTP consists of several, partly overlapping phases involving different molecular pathways. Besides being sensitive to kinase inhibitors (Huber et al, 1995), the initial phase is dependent on GluA1 function, as genetically modified mice lacking the GluA1 subunit (Gria1 À/À mice) show impairment of the initial phase of LTP (Romberg et al, 2009). Moreover, an allosteric positive AMPA receptor modulator was reported to enhance approximately the first 10 min of LTP in vivo (Bernard et al, 2010), similar to our results with 10 lM Tianeptine.…”