Chris Burford requested my response to the article "Beyond the neuron doctrine" by R. Douglas Field ( Scientific American Mind June/July 2006). I am not sure why the author uses the term "doctrine" because every neuroscientist knows that we are continuously updating our knowledge of the brain and neuron, e.g., Dale's Law that states each neuron releases one neurotransmitter was displaced once colocalization with neuropeptides and other neurotransmitters was discovered. For a good review of this, but one slightly outdated, see "The Molecular Foundations of Psychiatry" by Steven Hyman & Eric Nestler (1993) published by the American Psychiatric Press, Inc. Glial cells have traditionally been viewed as supportive to neurons, yet recent research grants them more significant functions involving glutamatergic neurotransmission, glucose metabolism and neurotrophic support (Cotter 2005). Volume transmission is another mode of neurotransmission which uses gases (e.g., nitric oxide-NO). Field summarizes the newly emerging research data on neurotransmission, e.g., supplementing the neuron "doctrine," with a glial cell "doctrine." Field's article is a good introduction to some of the recent developments in the field, e.g., ephaptic transmission, gap junctions, neuromodulators and glia, which behave outside of what he terms the "neuron doctrine."

In terms of clinical applications of neuroscience, many of us knew it was only a matter of time before the simplistic dopamine theory of schizophrenia would be replaced by more sophisticated models. The original view of a hyperdopaminergic state was displaced by a more nuanced view of hyperdopaminergic neurotransmission in the Mesolimbic pathways and a hypodopaminergic state in the mesocortical pathways, accounting for the positive symptomatology and negative symptomatology, respectively. Now we have glutamatergic, GABAergic, etc., neurochemical models as well as emergent epigenetic models involving DNA methylation (e.g., environmental regulation of gene expression). All of these models, from my perspective, must be viewed within the context of the neuron and synaptic biochemistry as dynamic processes exquisitely responsive to the social and psychological environment.

For those interested in a fairly recent overview of what we have learned about synaptic plasticity and the neuron, I would highly recommend "The Dynamic Neuron" by John Smythies (2002) and published by The MIT Press. Smythies is a leading researcher on the neurochemistry of schizophrenia. In this relatively brief (150 pages) volume, he integrates research material from neuroscience and cell biology to provide a more comprehensive rendering of current knowledge of the neurochemistry of synaptic plasticity. Additional subjects include volume transmission (nonsynaptic signaling in the brain) which is especially important during neurogenesis and synaptic plasticity. Dopamine and glutamate can interact through nonsynaptic processes. Smythies also briefly addresses the role of psychological stress in synaptic plasticity.

Recent research has demonstrated how dynamic and plastic are the neuron and synapses. Most synapses are subject to continuous pruning and replacement by new synapses. Receptors, and indeed the whole external membrane of the neuron, are subject to a continual dynamic process of rapid internalization into the postsynaptic neuron, where they are processed by the endosome system. Some are recycled to the surface and reused. The rest are catabolized by proteosomes and lysosomes.

There is a virtual staggering complexity that underlies cellular signaling events in the CNS. This enormous complexity underlying synaptic complexity is vividly evident in three recent discoveries. First, Hevroni et al 1998 stimulated glutamate receptors in the dentate gyrus (in the hippocampus-an area subserving contextual and long-term learning/memory) and measured the resulting changes in mRNA levels: there was an increase in 362 mRNA levels and a decrease in 41. They identified 71 of these mRNAs as involved in a variety of signal transduction processes, trophic factors, receptors and channels, protease inhibitors, retrograde messenger systems, kinases, neurotransmitters and their enzymes, etc. Secondly, Husi et al (2000) identified many of the proteins in the postsynaptic density associated with glutamate receptors (NMDA). They identified 71 proteins (more than double the previously known numbers). Thirdly, Craig and Boudin (2001), demonstrated that every synapse is biochemically unique and different from every other synapse-depending on presynaptic and postsynaptic cell types, environmental factors, developmental status, and history of activity.

Many authors have asserted that our brains are uniquely custom made--no two brains are alike. John Strauss pointed out that DSM diagnostic categories are like static lumps which could never capture the dynamic complexity of the human brain (or person). I was once treated to a computer simulation of neuronal activity in our brains by Gerald Edelman ( see his Wider than the Sky: The phenomenal gift of consciousness published by Yale University Press in 2004), Nobel Laureate for Physiology and Medicine and chair of the Department of Neurobiology at the Scripps Research Institute. I and the audience were awed by the dazzling complexity (and beauty) of our neurons at work.

Brian Koehler PhD
Postdoctoral Faculty
New York University
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brian_koehler@psychoanalysis.net