Excitatory amino acids in neurological and neurodegenerative disorders.

Field: Neuroscience (Life Sciences)

Excitatory amino acids (glutamate and aspartate) form the mainstay of synaptic transmission in the central nervous system. By the same token, dysfunctional, excitotoxic activity of excitatory amino acids can lead to and/or become instrumental in the progression of a number of neurological and neurodegenerative conditions. Dementia due to Alzheimer's disease (AD) is characterized by extracellular plaques containing amyloid (Aβ peptide) which, together with its disruption of dendritic morphology, affects glutamate (AMPA and NMDA) receptor function to alter glutamatergic transmission. The progressive neurodegeneration of nigrostriatal neurons in Parkinson's disease (PD) may in part arise as a result of overactivity of glutamatergic inputs from the cortex and subthalamic nuclei, presenting the utility of respective antagonism and agonism of stimulatory and inhibitory metabotropic glutamate receptors (mGluR) in PD therapeutics. Huntington's disease (HD) manifests as atrophy of the corpus striatum and cortex, with neurons containing the mutant huntingtin protein perhaps being more susceptible to excitotoxicity from corticostriatal inputs, as reflected by the NMDA receptor loss and interactions of huntingtin with facilitatory Group I mGluR. In schizophrenia, abnormalities in brain (dendritic) development and synaptic plasticity may precipitate the dysfunction of mesolimbic and mesocortical dopaminergic pathways. Here again, aberrations in glutamatergic transmission in the form of NMDA receptor hypofunction may underpin the pathophysiology, with inhibitory mGluR2/3 agonism presenting potential as a therapeutic recourse. Depression is classically attributed to defects in monoaminergic neurotransmission, but long-term changes in dendritic architecture in limbic areas arising from chronic stress may be subject to some influence of glucocorticoids on the glutamatergic input to hypothalamic neurons, and thus affect the hypothalamic/pituitary/adrenal axis and glucocorticoid secretion itself. Epilepsy is the perhaps the most clear example of excitatory transmission gone awry, with the manifest increases in cortical network activity during seizures. Increased glutamatergic activity is instrumental in the pathology, particularly given evidence of the convulsant associations of the kainate type glutamate receptors (KAR). Glutamatergic hyperactivity ultimately leads to excessive Ca2+ influx which can initiate the sequelae of events leading to neuronal damage and death. Thus the Ca2+-permeable NMDA plays a villain's role in excitotoxic culling of motor neurons seen in amytrophic lateral sclerosis (ALS) and indeed the necrotic death of neurons following stroke and cerebral ischaemia. However, it is now increasingly evident that AMPA receptors and KAR, with subunit compositions that permit Ca2+-permeability, may contribute significantly to neurodegenerative chaos when overactivated. Addressing the excitotoxic aspects of excitatory amino acids therefore represents a major challenge in any potential therapeutic intervention with a number of neuropathologies.