Functional Roles

EPILEPSY

There is much evidence that both the initiation and maintenance of epileptic seizures involves the release of glutamate even though there is clear evidence that reduced GABA function may be equally impaired. Drugs that block NMDA receptors are anticonvulsant experimentally whereas the clinically effective antiepileptic drug lamotrigine reduces glutamate release as part of its action (see Chapter 16). As yet no NMDA receptor antagonists have been tested clinically.

PAIN

The excitatory amino acids are found in most sensory fibres of both large- and small-diameter fibres and, in the latter, they are co-localised with peptides such as substance P. The co-existence of these two transmitters suggests that they are released together in response to a noxious stimulus and hence contribute to the transmission of pain. While AMPA receptors are activated in response to brief acute stimuli and are involved in the fast events of pain transmission, NMDA receptors are only activated following repetitive noxious inputs, under conditions where the stimulus is maintained (for more details see Chapter 21). NMDA receptors have been implicated in the spinal events underlying 'wind-up', whereby the responses of dorsal horn neurons are significantly increased after repetitive C-fibre stimulation despite the constant input. Thus the activation of this class of receptors brings about a marked increase in neuronal excitability and is responsible for the amplification and prolongation of neuronal responses in the spinal cord. Substantial evidence exists for the involvement of NMDA receptors in various pathological pain states. Studies have demonstrated the effectiveness of NMDA receptor antagonists in animal models of inflammation, neuropathic pain, allodynia and ischemia. Both pre- and postsurgical administration of antagonists were shown to be effective, suggesting that the induction and maintenance of these ongoing pain states are dependent on NMDA receptor-mediated events.

Neuropathy may produce a prolonged activation of NMDA receptors, due to a sustained afferent input to the spinal cord, and this may result in a relatively small but continuous increase in the extracellular level of glutamate. As ketamine is a licensed drug which use-dependently blocks the NMDA receptor channel, the positive effects of this drug in patients with neuropathic pain (although not without side-effects) would strongly suggest that the NMDA receptor is as important in sensory processing of painful events in humans as suggested by the animal work.

MEMORY

It is generally accepted that long-term potentiation (LTP) is a key event in the processes that lead to the laying down of memories in the brain. LTP is a long-lasting enhancement of synaptic effectiveness that follows certain types of tetanic electrical stimulation to input pathways into the hippocampus. Although much of the work has been based on the hippocampus, where it was first documented, LTP has also been described in areas such as cortex, amygdala and spinal cord. The consensus would be that synaptic activation during high-frequency stimulation triggers a series of intracellular events that lead to the expression of synaptic potentiation with the release of glutamate being the first step. This persistent increase in synaptic efficacy is thought then to be critical for memory, presumably the acquisition. Much of the vast literature is based on electrophysiology, mainly in vitro, and so despite the conceptual appeal of LTP, the functional studies find it much harder to link LTP with memory. From a large clinical literature, the hippocampus appears to be a key structure in memory, and blocking glutamate receptors causes reduced memory-like behaviour in animals. Also the more recent description of activity-dependent long-term depression (LTD) could be associated with the processes of forgetting. However, this may be overly simple since LTD also occurs in the cerebellar cortex and might contribute to the motor aspects of learning in animals. LTD is reversibly blocked by NMDA receptor antagonists which suggests that postsynaptic Ca2+ entry through the NMDA receptor channel is critical for LTD induction.

Nearly all mechanistic studies of LTP have been carried out in the CA1 region of hippocampal slices, where Schaffer collateral/commissural fibres make monosynaptic contacts with the dendrites of CA1 pyramidal cells. It is generally accepted that the

Table 10.1 Classification of NMDA receptors

Metabotropic Ionotrophic

Metabotropic Ionotrophic

Table 10.1 Classification of NMDA receptors

NMDA

AMPA

Kainate

Channel

Sodium calcium

Sodium*

Sodium*

Endogenous

Glutamate

Glutamate

Glutamate

Glutamate

agonist

Other

Quisqualate

NMDA

AMPA

Kainate

agonists

Kainate

Antagonists

L-AP3

MK-801

CNQX

LY382884

Memantine

NBQX

Ketamine

Dextrophan

CPP

7-CK (glycine site)

Abbreviations: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), L(+)-2 amino-3-phosphonopropionic acid (L-AP3), 6-cyano-7-nitroquinoxaline (CNQX), 2,3-dihydroxy-6-nitro-7-sulfamyl-benzo-f-quinoxaline (NBQX), 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), 7 Chlorokynureic acid (7-CK).

*Some AMPA and kainate receptors are calcium permeable. Some of the antagonist structures are shown in Fig. 10.4.

Abbreviations: N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA), L(+)-2 amino-3-phosphonopropionic acid (L-AP3), 6-cyano-7-nitroquinoxaline (CNQX), 2,3-dihydroxy-6-nitro-7-sulfamyl-benzo-f-quinoxaline (NBQX), 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), 7 Chlorokynureic acid (7-CK).

*Some AMPA and kainate receptors are calcium permeable. Some of the antagonist structures are shown in Fig. 10.4.

induction of LTP at this synapse requires activation of postsynaptic NMDA receptors by synaptically released glutamate during adequate postsynaptic depolarisation. This results in the relief of the voltage-dependent block of the NMDA receptor channel by Mg2+. Ca2+ then enters the postsynaptic neurons or dendrite as a necessary and perhaps sufficient trigger for LTP. Although the NMDA receptor channel may be the critical entry point for the Ca2+ involved in triggering LTP, activating voltage-dependent calcium channels during NMDA receptor blockade can also cause an increase in synaptic efficacy. Once induction of LTP has occurred, the maintenance of LTP is then non-NMDA receptor dependent, favouring the idea of intracellular mechanisms as key factors.

It has also been suggested that activation of mGluRs enhances NMDA receptor-mediated LTP and there is also good evidence that switching off GABA mechanisms is also a prerequisite. One of the most controversial areas in the study of the mechanisms of LTP has been the search for a so-called retrograde messenger, a factor that is released from the postsynaptic neuron and diffuses back across the synapse to modify neurotransmitter release from the presynaptic terminal. The necessity for the existence of such a messenger was first suggested by the finding that LTP was associated with an increase in the concentration of glutamate in perfusates. Although there is data that the candidate retrograde messenger could be arachidonic acid, most recent work indicates the gas NO (nitric oxide), although there is almost as much evidence against as for this molecule (see Chapter 13). Postsynaptic NMDA receptors are involved in the induction of both LTP and both forms of plasticity appear to need retrograde messengers, and use common intracellular events—what occurs when these mechanisms converge will then determine whether neurons become potentiated or depressed.

On the basis of the events that occur in pain and LTP, it is easy to see how the actions of glutamate relate to the excessive firing of neurons — as yet no NMDA receptor antagonist has been tested in human epilepsy.

Figure 10.4 Structures of some antagonists at the various receptors for glutamate. CNQX is an AMPA antagonist but NQQX has greater selectivity. AP-5 is an NMDA receptor antagonist while MK-801 blocks the NMDA receptor channel (non-competitive)

EXCITOTOXICITY

The final issue relating to the function of the NMDA receptor is excitotoxicity. Briefly, the depolarisation may drive neurons into a state where large quantities of calcium enter the neuron. For this to occur, the release of glutamate would have to be excessive and in this context, cerebral ischaemic episodes are thought to disrupte the reuptake of glutamate into neurons and glia. The consequent influx of calcium, if excessive, can bring water into the neuron as a result of the cation entry. These osmotic changes can then lead to swelling and damage to the cell, although if the neuronal activity is reduced, then the osmotic stress is reversible. A second delayed phase of neuronal damage then occurs in that intracellular signalling is driven by the high calcium levels leading to permanent destruction of the neuron. A number of culprits have been identified, including activation of kinases, phospholipases leading to the generation of arachidonic acid and free radicals, nitric oxide synthase and also lipases and proteases.

The overactivation of glutamate receptors is therefore thought to be a key initial step in the neuronal and glial cell loss following cerebral vascular accidents. Despite this, the trials of NMDA receptor antagonists in patients with brain ischemia had so far been disappointing with poor efficacy and marked side-effects. Both factors could be improved by targeting NMDA receptor subtypes but it may be that AMPA and kainate receptors also have key roles in excitotoxicity. Another issue is that even when NMDA receptors are blocked the influx of calcium through voltage-gated calcium channels may induce neuronal damage.

It is unclear as to what extent events such as these are responsible for the cell death seen in neurological disorders like Parkinson's, Huntington's and Alzheimer's diseases. However, a combination of motoneuron disease, dementia and a Parkinson-like syndrome was possibly triggered by a constituent of the cyclad seed, used in Guam in times of famine for which the most likely candidate appears to be an excitatory amino-acid agonist. Certainly, there is evidence for a defect in mitochondrial energy metabolism in PD which may lead to neuronal depolarisation and an easier removal of the voltage-dependent Mg2+ block of the NMDA receptor. The resulting excessive neuronal excitation may contribute to nigrostriatal cell death. Whatever the case, once PD is established, the corticostriatal and subthalamofugal pathways, that use glutamate, are overactive. In MPTP-treated monkeys both NMDA and non-NMDA antagonists have efficacy. In rats, NR2B antagonists stimulate motor function.

Finally, AIDS dementia has parallels with cerebral ischemia or stroke and again the key mechanism appears to involve overactivation of glutamate receptors, in particular the NMDA receptor, followed by excessive influx of calcium and the generation of free radicals.

Clearly there is much therapeutic potential for drugs acting on glutamate systems but much more progress is needed.

DEVELOPMENT

Glutamate receptor expression is developmentally regulated and glutamate-mediated neurotransmission is generally enhanced in the immature brain at ages when certain glutamate receptors are transiently overexpressed. Furthermore, receptor subunit composition differs compared to the adult. Glutamate receptors play a critical role in neuronal plasticity and activity-mediated growth during brain development and yet the immature brain is more vulnerable than the adult to excitotoxic neuronal injury, suggesting that the functional state of glutamate receptors modifies the response of the brain to injury. In view of the general role of glutamate in the development and plasticity of connections in the immature CNS it is perhaps surprising that as yet we know little of its function apart from a pivotal role in the organisation of sensory pathways. In the CNS, NMDA receptor binding is much more restricted in the adult than in young animals although in broad terms, affinity appears the same as in the adult. In the immature hippocampus, NMDA EPSPs are much greater in amplitude and significantly less sensitive to Mg2+ although glycine modulation appears the same as in the adult. In the spinal cord, during the first postnatal week, NMDA and NMDA induced elevations of [Ca2+]i are markedly elevated, gradually declining to adult levels although the AMPA response or resting [Ca2+]i do not show these developmental changes. The neonatal brain represents a unique problem because any therapy based on glutamate receptors will somehow have to avoid adverse effects on the physiological roles of these receptors in plasticity and synaptic development.

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