Review: Protein Kinase Signal Transduction Cascades in Mammalian Associative Conditioning

Abstract

One of the most intriguing and intensely studied questions facing contemporary neuroscientists involves the elucidation of the physiological mechanisms that underlie learning and memory. Recent advances have given us a much more detailed understanding of the signal transduction mechanisms subserving learning in the intact animal. One fact that has become clear is that activation of protein kinases and phosphorylation of their downstream effectors play a critical role. Four protein kinase cascades have garnered considerable attention in the study of information storage at both the synaptic and behavioral levels: Ca⁺⁺/phospholipid-dependent protein kinase (PKC), Ca⁺⁺/calmodulin-dependent protein kinase II (CaMKII), cAMP-dependent protein kinase (PKA), and extracellular signal-regulated kinase (ERK). This review will concentrate on studies of two behavioral tasks, conditioned fear and conditioned taste aversion, that provide evidence for the involvement of these kinase systems in associative learning. The authors will also examine a number of potential kinase substrates and how each could participate in the formation of long-term memories.

Keywords

Learning Memory MAP kinase PKC PKA CaMKII ERK Kv4.2 Acetyltransferase CREB Fear conditioning Conditioned taste aversion

Get full access to this article

View all access options for this article.

References

Abel T , Nguyen PV , Barad M , Deuel TA , Kandel ER , Bourtchouladze R . 1997. Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Cell 88:615-626.

Abeliovich A , Paylor R , Chen C , Kim JJ , Wehner JM , Tonegawa S . 1993. PKCγ mutant mice exhibit mild deficits in spatial and contextual learning. Cell 75:1263-1271.

Adams JP , Anderson AE , Varga AW , Dineley KT , Cook RG , Pfaffinger PJ , and others . 2000. The A-type potassium channel Kv4.2 is a substrate for the mitogen-activated protein kinase ERK. J Neurochem 75:2277-2287.

Alessi DR , Cuenda A , Cohen P , Dudley DT , Saltiel AR . 1995. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 270:27489-27494.

Alonso G , Widmer H . 1997. Clustering of KV4.2 potassium channels in postsynaptic membrane of rat supraoptic neurons: an ultrastructural study. Neuroscience 77:617-621.

Anderson AE , Adams JP , Qian Y , Cook RG , Pfaffinger PJ , Sweatt JD . 2000. Kv4.2 phosphorylation by cyclic AMP-dependent protein kinase. J Biol Chem 275:5337-5346.

Atkins CM , Selcher JC , Petraitis JJ , Trzaskos JM , Sweatt JD . 1998. The MAPK cascade is required for mammalian associative learning. Nat Neurosci 1:602-609.

Bach ME , Hawkins RD , Osman M , Kandel ER , Mayford M . 1995. Impairment of spatial but not contextual memory in CaMKII mutant mice with a selective loss of hippocampal LTP in the range of the theta frequency. Cell 81:905-915.

Berman DE , Hazvi S , Rosenblum K , Seger R , Dudai Y . 1998. Specific and differential activation of mitogen-activated protein kinase cascades by unfamiliar taste in the insular cortex of the behaving rat. J Neurosci 18:10037-10044.

10.

Bliss TVP , Lomo T . 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232:331-356.

11.

Bourtchouladze R , Abel T , Berman N , Gordon R , Lapidus K , Kandel ER . 1998. Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. Learn Mem 5:365-374.

12.

Colbran RJ , Fong YL , Schworer CM , Soderling TR . 1988. Regulatory interactions of the calmodulin-binding, inhibitory, and autophosphorylation domains of Ca2+/calmodulin-dependent protein kinase II. J Biol Chem 263:18145-18151.

13.

de Rooij J , Zwartkruis FJ , Verheijen MH , Cool RH , Nijman SM , Wittinghofer A , and others . 1998. Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396:474-477.

14.

DeSilva DR , Jones EA , Favata MF , Jaffee BD , Magolda RL , Trzaskos JM , and others . 1998. Inhibition of mitogen-activated protein kinase kinase blocks T cell proliferation but does not induce or prevent anergy. J Immunol 160:4175-4181.

15.

Ebinu JO , Bottorff DA , Chan EY , Stang SL , Dunn RJ , Stone JC . 1998. RasGRP, a Ras guanyl nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs. Science 280:1082-1086.

16.

Frankland PW , Cestari V , Filipkowski RK , McDonald RJ , Silva AJ . 1998. The dorsal hippocampus is essential for context discrimination but not for contextual conditioning. Behav Neurosci 112:863-874.

17.

Goosens KA , Holt W , Maren S . 2000. A role for amygdaloid PKA and PKC in the acquisition of long-term conditional fear memories in rats. Behav Brain Res 114:145-152.

18.

Grewal SS , York RD , Stork PJ . 1999. Extracellular-signal-regulated kinase signalling in neurons. Curr Opin Neurobiol 9:544-553.

19.

Hanson PI , Kapiloff MS , Lou LL , Rosenfeld MG , Schulman H . 1989. Expression of a multifunctional Ca2+/calmodulin-dependent protein kinase and mutational analysis of its autoregulation. Neuron 3:59-70.

20.

Hoffman D , Magee JC , Gray R , Johnston D . 1997. Modulation of transient, A-type K+ channels in dendrites of hippocampal CA1 pyramidal neurons. Soc Neurosci Abstr 23:1394.

21.

Hoffman DA , Johnston D . 1998. Downregulation of transient K+ channels in dendrites of hippocampal CA1 pyramidal neurons by activation of PKA and PKC. J Neurosci 18:3521-3528.

22.

Huang YY , Kandel ER , Varshavsky L , Brandon EP , Qi M , Idzerda RL , and others . 1995. A genetic test of the effects of mutations in PKA on mossy fiber LTP and its relation to spatial and contextual learning. Cell 83:1211-1222.

23.

Impey S , Obrietan K , Wong ST , Poser S , Yano S , Wayman G , and others . 1998a. Cross talk between ERK and PKA is required for Ca2+ stimulation of CREB-dependent transcription and ERK nuclear translocation. Neuron 21:869-883.

24.

Impey S , Smith DM , Obrietan K , Donahue R , Wade C , Storm DR . 1998b. Stimulation of the cAMP response element (CRE)-mediated transcription during contextual learning. Nat Neurosci 1:595-601.

25.

Jerusalinsky D , Quillfeldt JA , Walz R , Da Silva RC , Medina JH , Izquierdo I . 1994. Post-training intrahippocampal infusion of protein kinase C inhibitors causes amnesia in rats. Behav Neural Biol 61:107-109.

26.

Jiang Y-H , Armstrong D , Albrecht U , Atkins CM , Noebels JL , Eichele G , and others . 1998. Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. Neuron 21:799-811.

27.

Kawasaki H , Springett GM , Toki S , Canales JJ , Harlan P , Blumenstiel JP , and others . 1998. A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia. Proc Natl Acad Sci U S A 95:13278-13283.

28.

Kim JJ , Rison RA , Fanselow MS . 1993. Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear. Behav Neurosci 107:1093-1098.

29.

Kogan JH , Frankland PW , Blendy JA , Coblentz J , Marowitz Z , Schutz G , and others . 1997. Spaced training induces normal long-term memory in CREB mutant mice. Curr Biol 7:1-11.

30.

Lu YF , Kandel ER , Hawkins RD . 1999. Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. J Neurosci 19:10250-10261.

31.

Malenka RC , Kauer JA , Perkel DJ , Mauk MD , Kelly PT , Nicoll RA , and others . 1989. An essential role for postsynaptic calmodulin and protein kinase activity in long-term potentiation. Nature 340:554-557.

32.

Malinow R , Madison DV , Tsien RW . 1988. Persistent protein kinase activity underlying long-term potentiation. Nature 335:820-824.

33.

Mayford M , Bach ME , Huang YY , Wang L , Hawkins RD , Kandel ER . 1996. Control of memory formation through regulated expression of a CaMKII transgene. Science 274:1678-1683.

34.

Miller SG , Kennedy MB . 1986. Regulation of brain type II Ca2+/calmodulin-dependent protein kinase by autophosphorylation: a Ca2+-triggered molecular switch. Cell 44:861-870.

35.

Phillips RG , LeDoux JE . 1992. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci 106:274-285.

36.

Roberson ED , English JD , Adams JP , Selcher JC , Kondratick C , Sweatt JD . 1999. The mitogen-activated protein kinase cascade couples PKA and PKC to cAMP response element binding protein phosphorylation in area CA1 of hippocampus. J Neurosci 19:4337-4348.

37.

Rosenblum K , Berman DE , Hazvi S , Lamprecht R , Dudai Y . 1997. NMDA receptor and the tyrosine phosphorylation of its 2B subunit in taste learning in the rat insular cortex. J Neurosci 17:5129-5135.

38.

Rosenblum K , Schul R , Meiri N , Hadari YR , Zick Y , Dudai Y . 1995. Modulation of protein tyrosine phosphorylation in rat insular cortex after conditioned taste aversion training. Proc Natl Acad Sci U S A 92:1157-1161.

39.

Schafe GE , LeDoux JE . 2000. Memory consolidation of auditory Pavlovian fear conditioning requires protein synthesis and protein kinase A in the amygdala. J Neurosci 20:RC96.

40.

Schafe GE , Nadel NV , Sullivan GM , Harris A , LeDoux JE . 1999. Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. Learn Mem 6:97-110.

41.

Selcher JC , Atkins CM , Trzaskos JM , Paylor R , Sweatt JD . 1999. A necessity for MAP kinase activation in mammalian spatial learning. Learn Mem 6:478-490.

42.

Serrano PA , Rodriguez WA , Pope B , Bennett EL , Rosenzweig MR . 1995. Protein kinase C inhibitor chelerythrine disrupts memory formation in chicks. Behav Neurosci 109:278-284.

43.

Sheng M , Thompson MA , Greenberg ME . 1991. CREB: a Ca(2+)-regulated transcription factor phosphorylated by calmodulin-dependent kinases. Science 252:1427-1430.

44.

Sheng M , Tsaur M-L , Jan YN , Jan LY . 1992. Subcellular segregation of two A-type K+ channel proteins in rat central neurons. Neuron 9:271-284.

45.

Swank MW . 2000. Phosphorylation of MAP kinase and CREB in mouse cortex and amygdala during taste aversion learning. Neuroreport 11:1625-1630.

46.

Swank MW , Sweatt JD . 2001. Increased histone acetyltransferase and lysine acetyltransferase activity and biphasic activation of the ERK/RSK cascade in insular cortex during novel taste learning. J Neurosci 21:3383-3391.

47.

Varga AW , Anderson AE , Adams JP , Vogel H , Sweatt JD . 2000. Input-specific immunolocalization of differentially phosphorylated Kv4.2 in the mouse brain. Learn Mem 7:321-332.

48.

Vossler MR , Yao H , York RD , Pan M-G , Rim CS , Stork PJ . 1997. cAMP activates MAP Kinase and Elk-1 through a B-Raf- and Rap- 1-dependent pathway. Cell 89:73-82.

49.

Weeber EJ , Atkins CM , Selcher JC , Varga AW , Mirnikjoo B , Paylor R , and others . 2000. A role for the beta isoform of protein kinase C in fear conditioning. J Neurosci 20:5906-5914.