l-glutamate is present in the mammalian brain at remarkably high concentrations. For a while this observation, coupled with the ability of glutamate to excite neurons all over the brain, cast doubt on its role in neurotransmission; for how can such a 'non-specific' agent mediate specific information? The case for glutamate as a neurotransmitter in the invertebrate neuromuscular junction was easier to establish (Usherwood 1994; "criterion). But with time it became clear that not only is glutamate a transmitter in mammalian brain—it is the major excitatory transmitter, and as such is critical for ongoing activity in the central nervous system. Furthermore, it is now known to play a key part in neuronal "plasticity and learning.
Glutamate belongs to the family of amino acid neurotransmitters. The closely related amino acids l-aspartate and l-homocysteine possibly play a part in excitatory neurotransmission as well. Other amino acids that serve as neurotransmitters are the inhibitory neurotransmitter y-aminobutyric acid (GABA), and glycine, which serves as an inhibitory neurotransmitter and also as a modulator of glutamatergic transmission (Cooper et al. 1996). In neurons, l-glutamate is synthesized from glucose via the Krebs' cycle and transamination of a-oxoglutarate, and from glutamine (imported from glia cells1), by glutaminase. Glutamate released from presynaptic vesicles interacts with several types and subtypes of glutamate "receptors, depending on the neuronal circuit, synaptic target, and physiological context. Two major types of glutamate receptors are known: ionotropic and metabotropic. The ionotropic receptors are ligand-gated "ionic channels, permeable to cations. There are at least three subtypes of ionotropic receptors, which differ in their ligand binding as well as in channel properties. These receptor subtypes are each named after the glutamate analogue that activates the receptor preferentially: a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, N-methyl-o-aspartate (NMDA) receptors, and kainate receptors (Seeburg 1993; Hollman and Heinemann 1994). The metabotropic receptors (mGlu) are coupled to "intracellular signal-transduction cascades, which, again, exist in multiple subtypes (Hollman and Heinemann 1994; Riedel 1996). Additional proteins interact with glutamate in the brain, among them high-affinity glutamate transporters that swiftly terminate the glutamatergic synap-tic signal (Auger and Attwell 2000). The glutamate transporters fulfil another function as well. Excess extracellular glutamate is neurotoxic and responsible for neurodegeneration under certain pathological conditions (Meldrum and Garthwaite 1990; Michaelis 1998). The transporters maintain extracellular glutamate levels below those that cause excitotoxic damage. In doing so they contribute to the compart-mentalization of glutamate in the brain, without which our brain cells get excessively excited and die.
Glutamate, and multiple types of its neuronal receptors, have been implicated in multiple facets of cellular, "developmental and behavioural plasticity in many species, "paradigms and brain regions (e.g. Morris et al. 1986; Bannerman et al. 1995; Aamodt et al. 1996; Riedel 1996; Riedel et al. 1999; Catalano et al. 1997; Rosenblum et al. 1997; Bortolotto et al. 1999; Hayashi et al. 2000). Glutamate is also critical for "long-term potenti-ation, the "zeitgeist cellular "model of learning in the mammalian brain. Three points concerning the role of glutamate in plasticity are noteworthy.
1. Glutamate is a prime candidate for a synaptic "stimulus that triggers *acquisition and *retrieval.
It possibly subserves cellular and circuit operations in other "phases of learning and memory as well.
2. Glutamate plays a part in *coincidence detection in "synapses that detect and encode "associations. A prominent coincidence detector is the NMDA receptor, which associates glutamate, depolarization, and probably additional molecular stimuli, such as glycine. The NMDA receptor is assumed to be instrumental in implementing elementary types of synaptic "algorithms of associative learning.
3. The plasticity at glutamatergic synapses could be expressed not only in use-dependent alterations in the availability of glutamate in the synapse, but also in use-dependent availability of the glutamatergic receptors (Shi et al. 1999). Further, these receptors interact with other proteins in the membrane, the cytoplasm and the nucleus. This is achieved via soluble second messengers, and also via mechanical links in a protein-protein network that extends from the membrane deep into the cytoplasm (Ottersen and Landsend 1997; Wyszynski et al. 1997). The role of glutamate in plasticity must therefore be considered in the context the spatiotemporal state of the multi"dimensional "system of the transmitter molecules, their receptor sites, and the intracellular macromolecular web that is regulated by the interaction of the transmitter with the receptor. The same argument for complexity holds for other transmitters as well (e.g. Shoop et al. 2000), only that at this stage we know more about the complexity of the glutamatergic signalling network because of its universal role in transmission and plasticity. This complexity turns the life of the investigator more interesting (or miserable, depending on the personalities involved), but clearly adds dimensions to the processes and mechanisms that implement neuronal plasticity.
Being such a ubiquitous molecular mediator of behav-iourally meaningful stimuli, glutamate is an appealing candidate for perturbation experiments, in which learning and memory are blocked by applying receptor antagonists to the postulated site(s) of the "engram (e.g. Morris et al. 1986; Bannerman et al. 1995; Reidel 1996; Rosenblum et al. 1997). The glutamatergic synapse could also become the focus of mimicry experiments, in which the behavioural stimulus is simulated by molecular or cellular manipulations ("method). This type of approach is illustrated by studies of'pregnancy blocking' in the "mouse (Kaba et al. 1994). In the female mouse, post-mating exposure to pheromones of a strange male, but not to those of the mate, blocks pregnancy. The mate is recognized because the female forms olfactory memory of his pheromones during mating ("flashbulb memory?). This memory is subserved by the accessory olfactory system, and involves reduction of GABAergic inhibition by "noradrenaline released in mating. Infusion of agonists of one of the mGlu receptors, which in this system reduce GABAergic inhibition, into the female's accessory olfactory bulb during an exposure to a male pheromone, mimics the effect of mating by establishing a memory for that pheromone without mating.
The strong evidence that glutamate is involved in plasticity and learning marks the components of the glutamate system as targets for candidate mnemonic drugs. Indeed, compounds that bind to the AMPA receptor-channel complex are already under clinical trial as memory boosters ("nootropics).
Selected associations: Acquisition, Long-term potentiation, Neurotransmitter, Receptor, Synapse
1Glia cells do much more than supplying nerve cells with glutamine and other *nutrients; see *synapse.
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