HETEROGENEITY OF NMDA RECEPTORS IN BRAIN

The N-methyl-D-aspartate (NMDA) class of excitatory amino acid receptors
have rapidly become an important, major area of research in neuroscience.
NMDA receptors not only mediate and modulate neurotransmission at a vast
number of CNS synapses, but also play a pivotal role in linking neuronal
activity to synaptic plasticity during development and learning. NMDA
receptors have also been shown to be a critical factor in a variety of
pathological processes and have been suggested to be causal in Huntington's
and Alzheimer's diseases, schizophrenia, autism, cerebral palsy, and
epilepsy development. It is now becoming increasingly apparent that there are multiple
populations of NMDA receptors. At physiological, toxicological, and
biochemical levels of analysis, there is evidence that there are at least
two distinct populations of NMDA receptors that differ in their anatomy,
pharmacology, molecular composition, and development. In addition,
radioligand binding studies indicate that there are at least two
anatomically and pharmacologically-distinct binding site populations of
NMDA recognition sites. Thus, NMDA receptors appear to be homologous to
the other, genetically-related (Myers et al., 1989) ion-channel receptors
(nicotinic, GABA-A, and glycine) in having multiple, genetically-related
forms (isoforms or isoreceptors) which display differing distributions in
the brain, differing developmental patterns of expression, and variations
in agonist and antagonist sensitivities. NMDA receptor subtypes may have
significant clinical implications, because the receptor form with the
greater agonist sensitivity would be expected to be primarily responsible
for the cell death resulting from modest elevations of extracellular
glutamate following ischemia and hypoglycemia. The focus of this proposal is to identify the distinguishing properties of
NMDA receptor subtypes and to determine how the differing measures of
heterogeneity are inter-related. Quantitative autoradiography will be used
to evaluate how the anatomically-distinct NMDA binding site populations
differ in their physio-chemical ligand binding properties, their
pharmacological properties, and their anatomical and ontological patterns
of expression. These data are necessary for evaluating the correspondence
between heterogeneity observed in physiological/toxicological studies and
in radioligand binding studies. Anatomical and pharmacological properties
of NMDA receptor proteins labelled by the photoaffinity ligand azido[3H]-
MK801 will permit correlating NMDA receptor heterogeneity to that seen at
the molecular level. Together these studies should provide a unifying
classification and description of NMDA receptor subtypes. The identification of distinct receptor subpopulations is necessary not
only for the understanding of NMDA receptor action but is also of
fundamental relevance to the general area of NMDA-receptor mediated seizure
activity and neurotoxicity. Only with the resolution of subtypes and their
distinguishing properties, it is possible to determine their relative
contributions to various aspects of normal and abnormal brain function and
to develop subtype-specific antagonists that maximize protection while not
interfering with normal functions.