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phosphorylate the NMDA receptor (4, 5), increasing calcium flux through the receptor. Tyrosine phosphorylation of the NMDA receptor increases current flow1 through the ion channel by reducing a tonic, Zinc-dependent inhibition (6).

Protein tyrosine kinase phosphorylation of the NMDA receptor may be required for LTP induction and at a minimum serves an important modulatory role controlling the likelihood of LTP induction (7). The activities of src and fyn in Area CA1 are controlled by a number of upstream signal transduction cascades. One important regulator of src is the focal adhesion kinase (FAK) CAKbeta, also known as pyk2, and this cascade has been shown to be involved, through src, in regulating LTP induction (8). In addition, the Extracellular Signal Regulated Kinase (ERK) MAP kinase cascade and the PKC cascades, which we will return to later, also can activate src-family kinases, and these pathways may also modulate NMDA receptor function and LTP induction via Src (9). Dephosphorylation of the src/fyn sites on NMDA receptors likely occurs through the action of the tyrosine phosphatase STEP.

A number of interesting cell surface receptors modulate NMDA receptor function, and thus potentially LTP induction, acting through the src cascade (see Figure 2).

1There are a number of different mechanisms that can cause "increased current flow" through a ligand-gated ion channel: (1) The probability that the channel will open can be increased, which is referred to as increased "channel open probability". (2) The conductance, that is, the rate at which ions flow through the channel, can be increased.

(3) The number of channels in the membrane can increase.

(4) The affinity of the channel for its ligand can increase— a mechanism that, of course, can only operate at subsatu-rating ligand concentrations. By and large, throughout the book, I will not go into detail on which of these mechanisms is involved in channel modulation, except where the mechanism is directly relevant to the molecular mechanisms that are involved (e.g., increased membrane insertion of a channel implies the involvement of specific molecular processes). In addition, in many cases, the specifics are not known or the channel modulation involves multiple mechanisms. For your reference, src modulation of the NMDA receptor at a minimum involves increased channel open probability.

The Ephrins, which have been mostly studied in the context of nervous system development, modulate NMDA receptors in cultured neurons (10). EphrinB2, acting through its receptor EphB2, activates src and modulates NMDA receptors via this mechanism. Genetic deletion of EphB2 leads to an attenuation of LTP in area CA1 (11, 12). Recent data from Ed Weeber in my laboratory has implicated the Apolipoprotein E receptors in hippocampus as modulating LTP induction via a src/NMDA receptor pathway—we will return to this system in Chapter 11 on mechanisms contributing to Alzheimer's disease. Finally, the obese gene product leptin acts through its cell surface receptor and a PI3-Kinase/MAPK/src pathway to modulate NMDA receptors and LTP induction in the hippocampus (13). Thus, the src/fyn pathways serve an important role in funneling cell surface signals to the NMDA receptor itself, modulating its activity and regulating LTP induction.

Src tyrosine kinase potentiation of NMDA receptors is also subject to a variety of other influences. RACK1 (Receptor for Activated C Kinase 1) promotes formation of a fyn/RACK1 /NR2B complex that actually inhibits fyn phosphorylation of the NMDA receptor and diminishes current through the receptor (14). Also, the Postsynaptic Density core protein PDS-95 modulates src phosphorylation of NMDARs, and src potentiation of NMDAR currents appears to require the presence of PSD-95 (15).

Protein kinase C not only can act indirectly through src to modulate the NMDAR but also can directly phosphory-late the receptor on serine/threonine residues and affect its function (16, 17). Phosphorylation of the NMDAR by PKC causes increased calcium flow through the receptor (18). The potential import of this is quite straightforward—any cell surface receptor coupled to a phospholipase C cascade can modulate the likelihood of LTP induction through direct regulation of the NMDA receptor complex (see Figure 2).

Kv4 And Nmda
FIGURE 2 Receptor modulation of the NMDA receptor by the src, PKA, and PKC cascade. These kinase cascades are represented here in relation to modulation of NMDA receptors, which could potentially lead to regulating LTP induction. See text for discussion and definitions.

The cAMP-dependent protein kinase (PKA) also can augment NMDA receptor function, although the mechanism is complex and not entirely worked out (19). PKA binds to the NMDA receptor via an associated protein, Yotiao (Yotiao is a specific isoform of A Kinase Anchoring Protein, which we will discuss again in a later section of this chapter). Yotiao binds both PKA and Protein Phosphatase 1 (PP1) to the NMDA receptor, and when all three are bound together the PP1 activity predominates and keeps the NMDA receptor phosphorylation (and activation) low. PKA activation by cAMP leads to enhancement of NMDA currents, although it is not entirely clear whether this is the result of PKA phosphorylation of the NMDA receptor, loss of tonic dephosphorylation by PP1, or both. Again, in the context of the hippocampal pyramidal neuron, this mecha nism represents a basis for any neurotrans-mitter receptor coupled to adenylyl cyclase to be able to modulate NMDA receptor function and the induction of LTP.

The cyclin-dependent kinases (CDKs) are key regulators of cell division, controlling progression through the cell cycle. However, this role is, of course, not germane to understanding the function of non-dividing neurons in the adult CNS. However, one CDK isoform, CDK-5, is selectively expressed in postmitotic neurons and functions in regulating neuronal migration and neurite outgrowth in development. Moreover, recent work has shown that this kinase is involved in synaptic plasticity and learning in adult animals (20). Specifically, inhibition of CDK-5 blocks NMDA receptor-dependent LTP in area CA1 and blocks contextual fear conditioning. One possible mechanism for this effect is CDK-5 regulation of NMDA receptor function because CDK-5 phospho-rylates the NR2A subunit and CDK-5 inhibitors reduce NMDA-induced currents in hippocampal neurons (21). Thus, CDK-5 may modulate NMDA receptor function in a manner reminiscent of src, PKC, etc. The mechanisms controlling CDK-5 regulation in hippocampal pyramidal neurons have yet to be worked out.

C. Redox Regulation of the NMDA Receptor

Modulation of the NMDA receptor is, of course, not restricted to post-translational modifications involving phosphorylation. An interesting and novel type of regulation that is starting to gather increased attention in general in the signal transduction world is redox modulation of protein function. In the context of NMDA receptor function there are two specific examples of this type of regulation, both of which elicit inhibition of NMDA receptor function. The reactive nitrogen species nitric oxide (NO), a free radical, can react with sulfhydryl moieties in cysteine side chains, a reaction leading to S-nitrosylation of the side chain. This reaction occurs in NR2A subunits at reasonably low levels of free NO and leads to decreased channel opening (22). A second example of redox regulation of NMDA receptors involves reactive oxygen species (ROS) such as superoxide and peroxynitrite, the product of the reaction of superoxide plus NO (23). ROS inhibition of the NMDA receptor likely occurs via cysteine oxidation in a fashion reminiscent of the effects of NO, although the mechanisms of this effect are not clear at present. Likewise, the physiologic role of NO and ROS inhibition of NMDA receptor function is also not clear. One interesting speculation is that oxidative inhibition of NMDA receptors might serve to "lock" the synapse in a particular state after plasticity had been triggered, or the mechanism might serve as a basis for inhibitory cross-talk limiting the capacity of a synapse to undergo LTP.

D. Polyamine Regulation of the NMDA Receptor

Finally, polyamine compounds with unsavory names like spermine, spermidine, and putrescine can modulate NMDA receptor function. Polyamines are synthesized normally in cells and are basically long aliphatic chains with several amino groups hanging off them. Polyamines have diverse modulatory effects on NMDA receptors in vitro and in vivo, but one effect that they have is augmentation of NMDA receptor function. This effect is through the unusual mechanism of relief of tonic proton inhibition of the channel (24, 25). Polyamine co-application with NMDA leads to an enhancement of NMDA-induced synaptic potentiation in area CA1. Casein Kinase II (CKII), a calcium-independent protein kinase whose function has not been widely investigated in the CNS, augments NMDA receptor function by acting in concert with polyamine binding to the receptor intra-cellular domain (26). The role of this mechanism in LTP induction in the intact cell is unknown. However, CKII is activated by LTP-inducing stimulation (27) and evidence exists suggesting activity-dependent increased polyamine synthesis in the hippocampus (28). These mechanisms might serve a role in temporal integration with repeated stimulation or in setting a baseline likelihood of LTP induction.

III. LTP INDUCTION COMPONENT 2—MECHANISMS UPSTREAM OF THE NMDA RECEPTOR THAT CONTROL MEMBRANE DEPOLARIZATION

As we discussed in the last chapter, recent discoveries have highlighted the importance of mechanisms for controlling membrane depolarization in LTP induction, membrane depolarization necessary for NMDA receptor activation. One important factor is the discovery of back-propagating action potentials and of their involvement in providing the depolarization of the synaptic membrane necessary for LTP induction (29-31). A second relevant consideration is the "silent synapse" model of LTP induction, wherein there are synapses that contain NMDA receptors but no AMPA receptors. Obviously, in the second scenario, the membrane depolarization necessary for NMDA receptor activation cannot come from local AMPA receptors but must be propagated via the membrane from a distal site. Taken together, these two considerations bring into focus the necessity of understanding the mechanisms that control the electrical properties of the dendrite and dendritic spines.

Table 2 lists a number of the important molecules contributing to regulation of membrane depolarization in pyramidal neuron dendrites. Progress in this area has been greatly facilitated by relatively recent technical advances that allow direct cell-attached-patch recording from the distal dendritic regions of CA1 pyramidal neurons. These studies have identified a number of relevant membrane currents that control dendritic membrane depolarization and excitability, and in most cases there are reasonable hypotheses about the molecules underlying these currents. However, keep in mind that as is the case in most of neurobiology right now, linking a specific molecule with a specific ionic current involves some degree of speculation.

In the next section, wherever possible I will use the term "current" to refer to an entity identified in physiology experiments, and use the term "channel" to refer to specific molecules. Also, in some cases the molecules can be referred to by their own names (e.g., Kv4.2).

A. Dendritic Potassium Channels A-Type Currents

"A-type", or voltage-dependent, rapidly inactivating K+ channels localized to the den-drites of hippocampal pyramidal neurons play a critical role in shaping the local electrical responses of the dendritic membrane and dendritic tree. The functions of A-type channels in general are to repolarize the membrane after an action potential, contribute to the resting membrane potential (modestly), and regulate firing frequency. My colleague Dan Johnston and his co-workers have proposed a model in which A-type channels in distal den-drites of the hippocampus are critical

Table 2 Mechanisms Upstream of the NMDA Receptor Involved in Membrane Depolarization

Ionic Current

Molecules Involved

Role

Mechanisms of Modulation

K currents Voltage-dependent

"A" currents

"H" currents

Na currents AMPA receptors

Voltage-dependent Na+ currents Ca currents

Cl currents

GABA receptors

NCN channels (HCN)

All GABA-A receptor subunits

Limit bpAPs

Limit EPSP magnitude

Regulate excitability

Depolarize membrane

AP propagation

AP propagation (hypothetical)

AP firing, excitability

ERK, PKA, CaMKII Cyclic nucleotides (direct)

PKA, CaMKII, PKC

PKC (decreased inactivation)

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