Edith Graef McGeer - Society for Neuroscience

348 Patrick L. McGeer and Edith GraefMcGeer
Analysis of the voluminous data was a challenge in those pre-home
computer days: It involved learning Fortran, writing a suitable program,
having a few thousand punch cards prepared, and, finally, feeding them
through the university's mainframe computer—better than the old-fashioned
calculator of our earliest years but rather different than the ease of
such analysis on a modern Macintosh computer.
One of the unanticipated outcomes was a substantial decline in the
regional level of many of these enzymes with age. This was particularly
true of tyrosine hydroxylase in the striatum. The results were treated with
skepticism since the younger cases were accident victims, whereas the
older cases died from various fatal illnesses. Therefore, Lucien Cote and
Stanley Fahn repeated the study using only people dying of knife or gun
shot wounds to the heart—needless to say, they worked in New York City.
Their curve was almost identical to that which we reported.
We also found declines in cortical choline acetyltransferase. Were
these declines due to losses of the cell bodies of origin, or did they
merely represent less dynamic enzyme synthesis? To answer this question,
we did cell counts of dopaminergic nigral neurons and cholinergic basal
forebrain neurons in patients dying at various ages. In both cases,
cell counts decreased to almost half by age 65-75. Therefore, the decline
was largely accounted for by cell loss. It is still not understood why there
is such selective neuronal loss with aging, but it is not restricted to
humans. Similar decreases in aged rodents and other species have been
recorded.
One of the exciting findings in our biochemical studies on postmortem
brains was the dramatic decline in glutamic acid decarboxylase and
choline acetyltransferase, but not tyrosine hydroxylase, in the striatum of
Huntington's disease cases. This was evidence of GABAergic and cholinergic
cell loss in the striatum, with no loss of dopamine nerve endings.
Was there some way this could be duplicated in an animal model? The
idea of how this might be done came from following up on the excitotoxic
discovery of John Olney.
Excitotoxicity
John Olney's discovery of excitotoxicity opened the door for many branches
in neuroscience. Excitotoxic agents are now used to define anatomical
pathways and to create animal models of disease. The excitotoxic phenomenon
has also generated theories regarding the causation of such diverse
neurological diseases as Huntington's disease, epilepsy, Alzheimer's
disease, amyotrophic lateral sclerosis, Parkinson's disease, and, in Olney's
continuing work, developmental abnormalities. Glutamate is the most
ubiquitous neurotransmitter in brain, and almost all neurons have large
numbers of glutamate receptors on their surface. Therefore, neurons