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Departments of 1Physiology and 2Pharmacology and Therapeutics, Trinity College, Dublin, Ireland
Submitted 30 November 2005; accepted in final form 1 March 2006
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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; Malenka and Nicoll 1999). The induction of N-methyl-D-aspartate receptor (NMDAR)–dependent LTP in adult CA1 is well known to depend on activation of Ca/calmodulin-dependent protein kinase II (CaMKII) (reviewed in Colbran et al. 2004; Lisman et al. 2002). CaMKII is a serine/threonine holoenzyme that is abundant in the postsynaptic density (PSD) and has catalytic and regulatory domains (for review see Hudmon and Schulman 2002). During LTP induction, Ca influx activates calmodulin, which binds to CaMKII subunits, resulting in Thr286 autophosphorylation in the CaMKIIa isoform. Such autophosphorylation renders CaMKII independent of Ca/CaM and constitutively active. The induction of LTP in adult CA1 is inhibited by intracellular application of CaMKII peptide inhibitors (Chen et al. 2001; Malinow et al. 1989; Otmakov et al. 1997) or extracellular application of the CaMKII inhibitors KN62 or KN93 (Bortolotto and Collingridge 1998; Ito et al. 1991). LTP induction was absent in CaMKII (T286A) mutant mice (Giese et al. 1998) and strongly reduced in mutant mice null in 
-CaMKII (Silva et al. 1992), whereas constitutively active CaMKII mimics and occludes LTP when introduced by a viral expression sytem (Pettit et al. 1994) or by direct injection postsynaptically (Lledo et al. 1995). CaMKII was also persistently activated by LTP-inducing stimuli (Barria et al. 1997; Fukanaga et al. 1993). Recent studies have shown that the dependency of LTP on CaMKII is developmentally regulated. LTP induction in very young CA1 is dependent entirely on PKA and independent of CaMKII (Yasuda et al. 2003), or dependent on multiple kinases, specifically CaMKII or PKA, with a switch to a dependency solely on CaMKII in juvenile animals (Wikstrom et al. 2003).
The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway is also known to be important for synaptic plasticity and a number of studies have demonstrated the essential role of PKA in LTP in CA1. Thus PKA inhibitors prevented induction of both early- (Blitzer et al. 1995, 1998) and late-phase LTP (Huang and Kandel 1994; Matthies and Reymann 1993), although only when induced by spaced trains of high-frequency stimulation (HFS) (Blitzer et al. 1995; Nguyen and Kandel 1996). The p42/44 mitogen-activated protein kinase (MAPK) also has a role in synaptic plasticity (reviewed in Sweatt 2001; Thiels and Klann 2001). MAPK has been found to be phosphorylated after LTP-inducing HFS in an NMDAR-dependent manner in the hippocampus (Atkins et al. 1998; Davis et al. 2000; De Cristo et al. 2001; Dudek and Fields 2001; English and Sweatt 1996, 1997; Giovanni et al. 2001). In addition, selective MAPK cascade inhibitors substantially attenuated the induction of LTP in the hippocampus (Atkins et al. 1998; Davis et al. 2000; De Cristo et al. 2001; Dudek and Fields 2001; English and Sweatt 1996, 1997; Giovanni et al. 2001; Rosenblum et al. 2000, 2002; Watabe et al. 2000).
The involvement of kinases in NMDAR-dependent LTP induction in the dentate gyrus has not been subject to the same intense investigation as in CA1. The dentate gyrus is an area that displays neurogenesis, and therefore LTP may have properties different from those in CA1. In the present study, we have investigated the involvement of several kinases in LTP in the dentate gyrus in young adult rats aged 6–8 wk. We show that LTP is mediated by multiple kinases, including CaMKII, PKA, and p42/44 MAPK. An abstract of this work was previously published (Wu et al. 2004).
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The control media contained the following (in mM): 120 NaCl, 2.5 KCl, 1.25 NaH2PO4, 26 NaHCO3, 2.0 MgSO4, 2.0 CaCl2, and 10 D-glucose. All solutions contained 100 µM picrotoxin (Sigma, St. Louis, MO) to block 
-aminobutyric acid type A (GABAA)–mediated activity.
The following drugs were used: KN62, KN92, KN93, KT5720, Rp-8-cAMP (from Calbiochem), PD98059, U0126, and U0124 (from Tocris Cookson), all dissolved in dimethylsulfoxide to give a maximal final concentration of 0.1%. Control experiments were carried out using the same vehicle.
Standard electrophysiological techniques were used to record field potential excitatory presynaptic potentials (EPSPs). Presynaptic stimulation was applied to the medial perforant pathway of the dentate gyrus using a bipolar insulated tungsten wire electrode, and field EPSPs were recorded at a control test frequency of 0.033 Hz from the middle one third of the molecular layer of the dentate gyrus with a glass microelectrode. The inner blade of the dentate gyrus was used in all studies. Field potential EPSPs recorded in CA1 were made in the stratum radiatum in response to stimulation of the Schaffer collateral/commissural fibers. In each experiment, an input–output curve (presynaptic stimulus intensity vs. EPSP amplitude) was plotted at the test frequency, and the amplitude of the test EPSP was adjusted to one quarter to one third of the maximum. LTP was evoked by high-frequency stimulation (HFS) consisting of eight trains, each of eight stimuli at 200 Hz, and an intertrain interval of 2 s, with the stimulation voltage increased during the HFS to elicit an initial EPSP of the train of double the normal test EPSP amplitude. Measurements of LTP were made at 60 min post-HFS unless otherwise stated. In experiments involving kinase inhibitors, the agents were preperfused over the slices for 60 min before HFS.
Recordings were analyzed using pClamp software (Axon Instruments, Foster City, CA). Values are the means ± SE for n slices. A two-tailed Student's t-test was used for statistical comparison.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Previous studies have shown that extracellular application of membrane-permeable CaMKII inhibitors such as KN62 and KN93 inhibited LTP induction in the CA1 region of slices of young adult or adult rats (Bortolotto et al. 1998; Ito et al. 1991; Wilkstrom et al. 2003; Yasuda et al. 2003). However, in the present experiments in the dentate gyrus of young adult rats, LTP was not blocked by the CaMKII inhibitors KN62 or KN93 applied alone. HFS induced LTP in control slices measuring 151 ± 11% at 60 min post-HFS (P < 0.005; n = 6) (Fig. 1 A). In the presence of either the CaMKII inhibitor KN62 (10 µM) or KN93 (10 µM) perfused throughout the experiment from 1 h before HFS, the induction of LTP was unchanged, measuring 143 ± 5% (P > 0.05; n = 5) in KN62 and 156 ± 11% in KN93 (P > 0.05; n = 5) (Fig. 1, B and C).
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; Huang and Kandel 1994). In the present experiments, inhibition of PKA with the inhibitor KT5720 (5 µM) did not block LTP induction, which measured 137 ± 9% (P > 0.05; n = 5) (Fig. 1D). Induction of LTP was also not blocked by a second PKA inhibitor, Rp-8-cAMP (100 mM), which measured 142 ± 5% (P > 0.05; n = 6) (Fig. 1E). Inhibitors of MEK, and therefore of the p42/44 MAPK cascade, such as PD98059 or U0126, have also been shown to block LTP induction in CA1 of mature rats in previous studies (English and Sweatt 1996; Sweatt 2001). In the present studies, LTP was not blocked by p42/44 MAPK cascade inhibition. Thus in the presence of the MEK inhibitor PD98059 (50 mM), the induction of LTP was unchanged, measuring 143 ± 7% (P > 0.05; n = 5) (Fig. 2 A). Similarly, the MEK inhibitor U0126 (10 µM) did not inhibit LTP induction, which measured 138 ± 6% (P > 0.05, n = 6) (Fig. 2B).
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; Ito et al. 1991; Yasuda et al. 2003). To verify such a difference between the dentate gyrus and CA1, the involvement of CaMKII was investigated in CA1 in rats the same age (6–8 wk) as that of rats used in the experiments on the dentate gyrus. Application of the CaMKII inhibitor KN62 (10 mM), perfused throughout the experiment from 1 h before HFS, strongly inhibited induction of LTP, which measured 144 ± 9% in control and 106 ± 5% in the presence of KN62 (P < 0.05; n = 5) (Fig. 2C). Induction of LTP is blocked by coapplication of inhibitors of CaMKII and MEK or PKA
The inability of inhibitors of CaMKII, MAPK, or PKC to block LTP when the inhibitors were applied alone could be attributable to the use of an alternative kinase pathway when one kinase pathway is blocked. To investigate this possibility, we coapplied inhibitors of these kinases.
The coapplication of a CaMKII and PKA inhibitor was found to strongly inhibit LTP. Thus the coapplication of KN62 plus KT5720, applied continuously from 1 h before HFS, was found to strongly inhibit LTP, which measured 101 ± 3% (P < 0.01; n = 6) (Fig. 3 A). KN62 plus KT5720 did not alter baseline test EPSPs, which measured 98 ± 3% at 1 h after perfusion of KN62 plus KT5720 (Fig. 3B) A further CaMKII inhibitor, KN93, when coapplied with KT5720, had a similar inhibitory action on LTP induction, LTP measuring 112 ± 6% (P < 0.01; n = 5) (Fig. 3C). In contrast, the inactive analog KN92 (10 mM) did not inhibit LTP when coapplied with KT5720, LTP measuring 147 ± 7% (P > 0.05; n = 5) (Fig. 3D). Coapplication of KN62 and a further PKA inhibitor, Rp-8 cAMP, strongly inhibited LTP, which measured 98% ± 7% (P < 0.01; n = 6) (Fig. 3E). The baseline was not significantly altered by KN62 and Rp-8-cAMPs after 60 min application (98 ± 3%, n = 4) (not shown).
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These experiments demonstrate that LTP is mediated by either of two parallel cascades, one involving CaMKII and the other PKA or MAPK.
LTP is blocked by coapplication of inhibitors of CaMKII and PKA, or CaMKII and MEK, after HFS
To determine the time window for the inhibition of LTP by the kinase inhibitors, inhibitors of these kinases were immediately after HFS or 30 min post-HFS. The fast perfusion system resulted in the inhibitors reaching the surface of the slice in 1–2 min, but the inhibitors would take at least several minutes to reach equilibrium concentrations within the slice.
The coapplication of KN62 plus KT5720 immediately after HFS still resulted in an inhibition of LTP and, moreover, the inhibition was as large at 90 min post-HFS as when these inhibitors were applied continuously from 1 h before HFS. LTP was inhibited from 20 min post-HFS, and measured 123 ± 8 and 103 ± 6% at 60 and 90 min post-HFS (P < 0.01; n = 5) (Fig. 5 A). Washout of KN62 plus KT5720 after 30 min of perfusion did not result in recovery of the LTP, which measured 115 ± 7% at 90 min post-HFS (Fig. 5B). Coapplication of KN62 and KT5720 commencing at 30 min post-HFS also inhibited LTP, which measured 112 ± 6% at 60 min after the start of coapplication of the agents (P < 0.01; n = 5) (Fig. 5C). However, coapplication of KN62 and KT5720 commencing at 1 h after the induction of LTP did not inhibit LTP, which measured 143 ± 5% at 40 min after the start of the coapplication of the agents (Fig. 5D).
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Because the CaMKII inhibitor KN62 alone was found to block LTP induction in CA1, we determined whether LTP was blocked by application of KN62 after HFS. No inhibition of LTP expression occurred when KN62 was applied immediately after HFS, with LTP measuring 155 ± 6% (P < 0.05; n = 5) (not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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The involvement of kinases in LTP induction in CA1 is developmentally regulated. LTP induction is initially dependent on PKA in very young animals but switches to a dependency on CaMKII over the first 2–3 wk of age. Thus in P7–P8, LTP induction is solely dependent on activation of PKA and independent of CaMKII (Yasuda et al. 2003). In P12–P16, LTP induction is dependent on CaMKII and either PKA or PKC (Wikstrom 2003). LTP induction becomes solely dependent on CaMKII by P20–P24 (Yasuda et al. 2003), and many studies have shown that LTP induction in young adults/adult CA1 is prevented by inhibitors of CaMKII (Bortolotto et al. 1998; Chen et al. 2001; Ito et al. 1991; Malinow et al. 1989; Otmakov et al. 1997; Wikstrom et al. 2003). The delayed developmental dependency of LTP on CaMKII activation in CA1 occurred in parallel with the slow developmental expression of -CaMKII in the hippocampus, which is very low on postnatal day 1 and then increases fivefold to the high adult levels by 3 wk of age (Burgin et al. 1990). In contrast to CA1, our studies in the medial perforant path of the dentate gyrus have found that multiple kinases are required for LTP induction in the adult animal. CaMKII inhibitors applied alone did not prevent induction of LTP. Moreover, two MEK inhibitors (PD98059 and UO126) and two PKA inhibitors (KT5720 and Rp-8-cAMPS) also did not inhibit LTP induction when applied alone. Inhibition of LTP induction was achieved only by coapplying -CaMKII and a PKA or MEK inhibitor.
The possibility that the PKA and MEK inhibitors used in the study have nonspecific effects and partially inhibit CaMKII, summating with the inhibition of CaMKII by KN62 or KN93, can be discounted. First, the concentration of KN62 used in the study, 10 mM, would by itself give a strong block of CaMKII and therefore of induction of LTP, and both previous studies and the present study have shown that 10 mM KN62 blocks LTP in CA1. In addition, if KT5720 and UO126 were each partially blocking CaMKII, then the coapplication of KT5720 and UO126 would be expected to block LTP, although no such block was observed. Such involvement of multiple kinases in LTP induction in the adult dentate gyrus closely resembles that shown previously in P12–P16 CA1 (Wikstrom et al. 2003). Our studies show that LTP in the adult dentate gyrus, at least 
8 wk of age, does not fully switch over to a full dependency on CaMKII as in adult CA1, but remains partially dependent on other kinases as in P12–P16 CA1. Such developmental freezing of the kinase dependency of LTP in the dentate gyrus could be explained by the occurrence of neurogenesis in the dentate gyrus, with newly formed cells generated by neurogenesis keeping other cells in a developmental young state for induction of LTP.
MAPK activation alone was not found to be required for the induction of LTP in the dentate gyrus because MAPK inhibitors did not inhibit LTP induction when applied alone throughout the experiment. The coapplication of the MEK and CAMKII inhibitors was required to block LTP. This is in contrast to the in vivo studies in the dentate gyrus by Davis et al. (2000), who showed a MEK inhibitor applied alone blocked LTP in vivo. It is possible that the induction of LTP in vivo is strongly dependent on modulatory neurotransmitters such as acetylcholine and amines whose action is solely dependent on MAPK. Alternatively, the study of Davis et al. (2000) used rats much older than those used in the present study (several months of age vs. 6–8 wk in the present study) and it is possible that LTP becomes more dependent on MAPK with increased age. The results of the present study also differ from adult CA1 in which ERK inhibitors were shown to block LTP (Atkins et al 1998; Giovanni et al. 2001; Sweatt 2001; Watabe et al. 2000; Winder et al. 1999). However, these studies used either spaced or more prolonged stimuli that may recruit MAPK more strongly. MAPK activation can be elicited by PKA (Roberson et al. 1999), and therefore we cannot completely eliminate the possibility that the use of the PKA inhibitors will block downstream MAPK activity.
The ability of coinhibition of CaMKII and PKA, or coinhibition of CaMKII and MAPK, to inhibit LTP when applied after HFS demonstrates the existence of persistent activation of CaMKII/PKA/MAPK for an extended duration after HFS. This extended time window when the kinase inhibitors are active could be termed an extended period of induction of LTP or an early maintenance period of LTP. The presence of such CaMKII/PKA/MAPK kinase activity in an extended induction period/early maintenance period of LTP in the dentate gyrus is in contrast to CA1, where application of selective CaMKII inhibitors after the induction of LTP have failed to block LTP, although CaMKII inhibitors applied before induction block LTP (Chen et al. 2001; Lisman et al. 2002; Malinow 1989; Otmakhov et al. 1997), and confirmed in the present studies. It should be noted that a constitutively active form of PKC, protein kinase M zeta, has been shown to block LTP when applied after the induction stimulation (Ling et al. 2002). The failure of CaMKII inhibitors to block LTP in CA1 when applied after the induction stimulation is surprising because LTP induction produces a constitutive activation of CaMKII, with autophosphorylated CaMKII activity elevated for >1 h after LTP induction (Barria et al. 1997; Fukunaga et al. 1993, 1995; Lengyel et al. 2004; Ouyang et al. 1997, 1999). Perhaps multiple kinase pathways are involved in an extended induction period/early maintenance period of LTP in the adult CA1, and that inhibition of both CaMKII and a further kinase such as PKA or MAPK is required to observe inhibition of LTP when the inhibitors are applied after the induction stimulus.
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. Anwyl, Department of Physiology, Trinity College, Dublin 2, Ireland (E-mail: ranwyl{at}tcd.ie)
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