LTP and excitotoxicity

Mark Mattson mpm at seqanal.mi.uky.edu
Thu Oct 20 08:53:24 EST 1994


Kanning2 (kanning2 at aol.com) wrote:
: There seems to be a fragile balance among NMDA receptors and there ability
: to either potentiate synaptic efficacy (LTP), possibly by a mechanism
: invoking Nitric Oxide or some sort of other Ca++ related event, and the
: excitotoxic effect brought about as a possible overstimulation of these
: receptors by Glutamate.  I'd be interested in hearing anyone's ideas about
: how the various components of NMDA activation (such as MG++ block, glycine
: modulation, NO, CO, Ca++ second messengers, etc.) may lead to the chronic
: cell death in many neurodegenerative disorders, and also why this might
: have an evolutionary partnership with LTP (memory).  

Of course, many models of neurodegenerative disease have included excito-
toxicity, and very often these models suppose potentiation of RESPONSES
to glutamate (contrasted with elevation of ambient excitatory neurotrans-
mitters).  For instance, beta-amyloid peptide, a protein fragment that
almost certainly plays an early (causative?) role in Alzheimer's magnifies
the responses of NMDA receptors to glutamate.  In my reading, there is very
little conjecture about the MECHANISTIC explanation (i.e., whether there
is enhanced affinity for glycine, a more responsive NO synthase, etc.).
However, the recent discovery of modulation of NMDA receptor conductance
by phosphorylation (Wang and Salter, Nature 369:223; and adjacent Letters)
suggests that there may be some abnormalities of kinase or phosphatase
activities in neurodegenerative disease.

A somewhat different slant is taken by those who propose abnormalities in
neuronal physiology less directly related to glutamate receptors.  For 
instance a general reduction in the cells' ability to handle calcium could
feed into a toxicity associated with NMDA receptors.  The plethora of 
processes involved in cellular calcium homeostasis makes it very difficult
to get a handle on which one(s) are compromised.  However, the relationship
of neurodegenerative disease to aspects of normal aging suggests that 
things we know to happen in aging could contribute.  For instance, it is
now appreciated that mitochondria have a finite lifetime that depends
upon (among other things) the formation of permanent calcium phosphate
precipitates in the matrix.  A couple of studies have suggested that 
mitochondrial calcium sinks play a significant role in buffering synaptic
calcium.

Just some thoughts,
Steven W. Barger, Ph.D.
Sanders-Brown Center on Aging
  




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