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A complementary explanation as to why motoneurones die is

that these injured motoneurones become excessively

inputs they would normally receive within the maturing

nervous system.

Olney (1971) suggested the hypothesis that endogenous

excitatory amino acids, particularly glutamate and

aspartate can cause excessive excitation and neuronal

death. The discovery that exogenous glutamate was

excitotoxic was first made by Lucas and Newhouse (1957)

when they reported that injection of glutamate could

destroy the inner neural layer of mouse retina.

The amino acid glutamate, one of the main excitatory

neurotransmitters found in the mammalian central nervous

system, is released when specific neural pathways are

activated (Nadler et. al., 1976). Uptake systems are

present to remove glutamate from the extracellular space.

Enzymes necessary for the synthesis of glutamate and its

receptors have been identified in both the pre- and

post synaptic membranes (Greenamyre, 1986) . In the monkey,

glutamate serves as the excitatory transmitter of spinal

cord intemeurones and the cortico-spinal pathways (Young

et. al., 1983). The sensitivity to glutamate was apparently

modulated by the presence of intemeurones since it was

Rossier, 1993). GluRl-4 have a higher affinity for AMPA

than for kainate while GluR5-7 have a higher affinity for

kainate than GluRl-4 do (see Wisden and Seeburg, 1993).

Glutamatergic neurotransmission is also mediated by

metabotrophic receptors (mGluR) which are linked to

intracellular second messenger systems. Of the

metabotrophic receptors, mGluRl and mGluRB are coupled to

phosphoinositide metabolism while mGluR2-4 regulate cAMP

than in those composed exclusively of motoneurones (O'Brien

and Fischbach, 1986a).

Glutamate receptors are activated during excitatory

transmission between intemeurones and motoneurones

(O'Brien and Fischbach, 1986b; Ziskind-Conhaim, 1990). On

the basis of their pharmacological, physiological and

agonist binding properties, the ionotrophic receptors

which mediate their effects through cation-selective

channels, are classified into the NMDA, AMPA and kainate

receptor subtypes (for reviev see Wisden and Seeburg,

1993).

The receptor subunits for NMDA receptors are subunits NRl

and NR2A-D. The NMDA receptor have been shown to be an

important determinant of neuronal survival and this

influence is likely to be calcium mediated (Brenneman et.

al., 1990) . The following NMDA receptor subunits are

expressed in spinal motoneurones: the NRl, 2B and 2D

subunits (Monyer et. al., 1994; Toile et. al., 1994). The

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Excitotoxicity may also result when the uptake mechanism

for glutamate is not able to cope and thus motoneurones are

exposed to increased levels of glutamate (Rothstein et.

al., 1992). Excess glutamate has been found after traumatic

lesions (Liu et, al., 1991). This excess glutamate or the

lethal for some neurones both in vivo (Coyle et. al, 1981)

and in vitro (Choi, 1991).

It has been suggested that glutamate is involved in the

pathogenesis of ALS (Choi, 1988; Plaitakis at. a l ., 1988;

Young, 1990). The abnormal glutamate metabolism observed in

patients with ALS (Plaitakis and Constantakakis, 1993) may

result in abnormal potentiation of excitatory transmission

mediated by glutamate receptors and thus, to

neurodegeneration. Exposure of cultured neurones to

cerebrospinal fluid from ALS patients which have been shown

to contain abnormally high levels of glutamate (Rothstein

et. al., 1990) result in a significant death of the

neurones in culture (Couratier et. al., 1993).

The mechanisms of excitotoxicity that result in death of

neurones are not fully established (for review see Choi,

1992). The first possibility is that osmotic swelling which

follows exposure to glutamate can result in immediate

necrosis. Secondly, increased concentrations of calcium in

the cell due to Ca"""^ influx when the NMDA receptor

associated channel is open (As cher and Nowak, 1986;

Dingledine, 1983), may activate proteases which will result

The excitotoxic hypothesis also implies that the neurotoxic

properties of the excitatory amino acid neurotransmitter,

glutamate can be attenuated by blocking the NMDA receptor.

Drugs that block NMDA receptors, including 2-amino-5-

phosphonovalerate (APV), 2-amino-7-phosphonoheptanoate

(APH) and kynurenate have been shown to attenuate the

cytotoxicity of NMDA (Choi et. al., 1988). Other

noncompetitive antagonists of the NMDA receptors, in

particular MK-801 (Foster et.al., 1987) which specifically

act on the associated ion channel, also reduce the

neurotoxicity of NMDA.

The excitatory amino acids (EAAs) plays a crucial role in

the activation of the locomotor CPGs of vertebrates (Dale

and Roberts, 1984; Brodin and Grillner, 1985). Excitatory

amino acids are known to be released by primary afferent

inputs and interneurones (Ziskin-Conhaim, 1990). Silar and

Roberts (1988) have shown that cutaneous afferents release

EAAs onto interneurones at the central synapses. O'Donovan

and Landmesser (1987) found that during locomotion,

glutamate receptors are activated. Recently, Cazalets et.

al. (1992) also showed that NMDA receptors participate in

Bath application of N-methyl-D; L-aspartate could evoke

locomotor activity in hindlimb muscles (Kudo and Yamada,

1987) . The endogenous EAAs, glutamate and aspartate have

been shown to trigger an alternating rhythmic pattern in

isolated brainstem-spinal cord preparation from the newborn

rat, and this activity could be prevented by blocking the

NMDA receptor with AP-5 (Cazalets et. al., 1992). This

supports the proposal that NMDA receptors and glutamate are

involved in the central pattern generation of locomotion.

Therefore, it may be possible that when motoneurones are

deprived of functional interaction with their target during

a critical period during the early development, they become

susceptible to the excitotoxic effects of glutamate.

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