Elsevier

Neuroscience Research

Volume 38, Issue 1, 1 September 2000, Pages 3-17
Neuroscience Research

Review article
A working model of CaM kinase II activity in hippocampal long-term potentiation and memory

https://doi.org/10.1016/S0168-0102(00)00139-5Get rights and content

Abstract

Recent advances in molecular genetics provide strong evidence for a relationship between hippocampal long-term potentiation (LTP) and hippocampus-dependent memory. The α-CaM kinase II knock-out mouse and transgenic mice expressing a mutant form of CaM kinase II clearly demonstrate that CaM kinase II plays a prominent role in hippocampal LTP and hippocampus-dependent memory. Furthermore, the observation that there is a diversity of silent as well as functional synapses has shed light on the molecular basis of learning and memory during development as well as in adult brain. Here we present a working model of CaM kinase II activity as a memory molecule in hippocampal LTP and describe molecular targets of CaM kinase II involved in the establishment of functional synapses following LTP induction.

Introduction

Hippocampal long-term potentiation (LTP), a long-lasting increase in synaptic efficacy, is the molecular basis for learning and memory. During the past 10 years, molecular genetic approaches have not only provided insight into the mechanisms of LTP in the hippocampus but have also demonstrated a link between LTP and learning/memory. Spatial learning has been known to be a hippocampus-dependent task and has been extensively studied in animals. However, in electrophysiological studies, demonstration of an increase in hippocampal synaptic strength such as LTP during spatial learning has remained elusive. In contrast, a fear conditioning task, which is an amygdala-dependent implicit memory task, is associated with LTP. In fear conditioning, a conditioned stimulus (CS) such as a tone is followed by an unconditioned stimulus (US) such as foot shock, which causes stereotypic behavior, i.e. freezing. After one or several pairings of the stimuli, the CS alone elicits freezing behavior. In such cases the lateral amygdala is the critical region combining information from both the CS and US. This connection between the auditory thalamus and lateral amygdala is responsible for LTP (McKernan and Shinnick-Gallagher, 1997, Rogan et al., 1997). For example, the extracellular field potential in the lateral amygdala in response to the CS has been monitored in trained rats. With pairing of the CS and US, the auditory CS-evoked field potential increases as well as CS-evoked freezing behavior (Rogan et al., 1997). In future, analysis of learning behavior and electrophysiological properties in transgenic animals provides a molecular basis of the amygdala-dependent implicit memory.

Table 1 summarizes the electrophysiological and behavioral properties observed in transgenic or mutant mice with alterations in specific signal transduction molecules. Using the transgenic mice, the extensive work aimed at understanding the mechanisms of LTP has been performed on the synapses between the Schaffer collateral and commissural axons and the apical dendrites of CA1 pyramidal neurons. Silva et al., 1992a, Silva et al., 1992b first demonstrated that mice lacking α-CaM kinase II are deficient in spatial learning as well as LTP induction in the hippocampal CA1 region. Similarly, mice lacking Fyn, a non-receptor tyrosine kinase, are deficient in LTP induction and spatial learning (Grant et al., 1992). The defect is possibly due to interference with NMDA receptor function associated with lack of tyrosine phosphorylation. In contrast, the effects protein kinase C (PKC) and nitric oxide synthases (NOS) loss are not simple as to induction of LTP as well as learning behavior. For example, mice lacking PKCγ show deficits in LTP with conventional stimulation, along with a small impairment of contextual memory (Abeliovich et al., 1993a, Abeliovich et al., 1993b). However, a priming stimulation at 1 Hz can restore stable LTP. NOS knock-outs show a small defect in LTP, especially the endothelial NOS (eNOS) knockout mice. Mice lacking neuronal NOS (nNOS) or eNOS alone exhibit normal or nearly normal LTP (Huang et al., 1993, O'Dell et al., 1994), but mice lacking both nNOS and eNOS show reduced LTP in the CA1 region (Son et al., 1996). However, a submaximal stimulation does not elicit LTP in the eNOS knockout mice, in which strong tetanic stimulation induces a robust LTP (Wilson et al., 1999). In addition, LTP induced by strong tetanus is not blocked by treatment with a NOS inhibitor. Because effects of nNOS and/or eNOS deficits have not been tested in behavioral learning tasks, we cannot evaluate the role of the retrograde messenger, NO, in spatial and contextual memory. Taken together, CaM kinase II plays a key role in promoting changes in synaptic efficiency during LTP induction. While PKC, eNOS/nNOS and the Fyn tyrosine kinase modulate LTP induction.

Like CaM kinase II, an essential role for cAMP-dependent protein kinase (PKA) in LTP maintenance as well as in long-term memory has been demonstrated using PKA and calcium-stimulated adenylyl cyclase knock-out mice. In addition, the cAMP signaling may also underlie gating the CaM kinase II activation in LTP through protein phosphatase 1 (PP-1). Tetanic stimulation induced LTP triggered cAMP-dependent phosphorylation of inhibitor 1 and thereby caused decrease in PP-1 activity. Since PP-1 is a major phosphatase to dephosphorylate CaM kinase II in the postsynaptic density (PSD), the decreased PP-1 activity accounts for the increased autophosphorylation of CaM kinase II in LTP (Iyenger, 1996, Blitzer et al., 1998). The PKA holoenzyme is composed of regulatory (R) and catalytic (C) subunits. There are two C subunit genes in mice, Calpha and Cbeta. Like wild type mice, mice lacking the Cbeta1-subunit can produce synaptic potentiation by high frequency stimulation of the Schaffer collateral-CA1 pathways. However, the mice are unable to maintain the synaptic potentiation. Similarly, long-term depression produced by low frequency stimulation also failed to maintain (Qi et al., 1996). Furthermore, transgenic mice expressing an inhibitory form of the regulatory subunit of PKA do not maintain the late phase of LTP without deficit in the early phase of LTP (Abel et al., 1997). The late phase deficit is associated with behavioral deficits in spatial and long-term memory but not with short-term memory for a contextual fear conditioning task (Abel et al., 1997). The important role of PKA has been confirmed in mice lacking both types 1 and 8 calcium-activated adenylyl cyclases, which account for most of the calcium-stimulated adenylyl cyclase activity in the hippocampus (Wong et al., 1999). Deficits in the late phase of LTP as well as in long-term memory are also evident in these knockout mice. Taken together, cAMP and PKA are important mediators of the late phase of LTP as well as of long-term memory.

Like LTP in the CA1 regions, the molecular basis underlying LTP at the synapses between mossy fibers and CA3 pyramidal neurons has been well documented. The mossy fiber LTP requires presynaptic activation which is not blocked by NMDA receptor antagonists. The tetanic stimulation of the mossy fibers induces rise in presynaptic Ca2+ and results in activation of Ca2+/calmodulin-dependent adenylyl cyclase. This in turn causes activation of PKA and elicits a long-lasting increase in transmitter release. In support of the idea, the mutant mice lacking the Ca2+-stimulated type 1 adenylyl cyclase failed to induce the mossy fiber LTP (Villacres et al., 1998). Likewise, ablation of gene targeting of a catalytic subunit isoform (Cbeta1) or a regulatory subunit isoform (RIbeta) of PKA produced a selective defect in mossy fiber LTP (Huang et al., 1995). Furthermore, the observation that the mossy fiber LTP is absent in knockout mice lacking the synaptic vesicle protein Rab3A (Castillo et al., 1997) suggests that Rab3A or proteins interacted with Rab3A such as rabphillin or Rim (Shirataki et al., 1993, Li et al., 1994, Wang et al., 1997, Lonart et al., 1998) is a possible target molecule for PKA and underlies increase in neurotransmitter release.

In this review, we focus on how CaM kinase II encodes the frequency of synaptic usage as a memory molecule and what presynaptic and postsynaptic molecular targets of CaM kinase II underlie that mechanism during LTP. Furthermore, we will discuss whether CaM kinase II serves as a transient trigger or a sustained mediator of the late phase of LTP and long-term memory.

Section snippets

CaM kinase II encodes Ca2+ pulse frequency

CaM kinase II is highly expressed in brain and enriched at synaptic structures, particularly in the postsynaptic density (PSD). The enzyme forms a homo- or hetero-oligomeric structure composed of 8–10 subunits of the α or β isoform (Brocke et al., 1999). An interesting feature of the enzyme is that autophosphorylation of Thr-286 converts CaM kinase II from a Ca2+-dependent form to a Ca2+-independent (constitutively active) form (Schworer et al., 1988, Miller et al., 1988, Thiel et al., 1988,

Involvement of CaM kinase II autophosphorylation in explicit and implicit memory

Targeted mutation of the α-CaM kinase II gene provides strong evidence for involvement of the enzyme in LTP, as well as in spatial learning, an explicit memory (Silva et al., 1992a, Silva et al., 1992b). Also, infection of hippocampal slices with a vaccinia virus carrying a truncated, Ca2+-independent CaM kinase II gene potentiates synaptic transmission and blocks LTP induction (Pettit et al., 1994). To further test the role of CaM kinase II autophosphorylation in LTP and memory, Mayford et al.

Molecular targets of CaM kinase II involved in LTP/LTD induction

Although CaM kinase II is established as a memory molecule encoding the frequency of synaptic usage, the molecular mechanisms underlying LTP and LTD are still unclear. It is evident that mechanisms of LTP/LTD are not uniform in different regions of the hippocampus. For example, LTP induction of the Schaffer collateral/commissural synapses in CA1 regions of the hippocampus involves a postsynaptic mechanism and that of the mossy fiber synapses in the CA3 region is presynaptic (Nicoll and Malenka,

Involvement of CaM kinase II in maintenance and consolidation mechanisms of LTP

In contrast to LTP induction, the mechanism of maintenance and consolidation is poorly understood. Because CaM kinase II inhibitors fail to block maintenance of LTP, once LTP is established, CaM kinase II acts as a transient trigger in hippocampal LTP. Similarly, protein kinase C activation is required for the initial phase (5–60 min after LTP) of LTP. Despite the requirement for CaM kinase II activity in only the early phase of LTP, constitutively active CaM kinase II was relatively stable for

Conclusion and future prospects

As summarized in Fig. 4, a large increase in [Ca2+]i, resulting from influx through NMDA receptors, leads to the generation of constitutively active CaM kinase II through autophosphorylation of Thr-286. Molecular targets for CaM kinase II during LTP induction include the AMPA receptor (GluR1), MAP2 in postsynaptic sites and synapsin I in presynaptic sites. Due to the requirement for CaM kinase II in recruitment and/or clustering of AMPA receptors in the spines, phosphorylation is possibly

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