Pruning Key to Schizophrenia Model

What is schizophrenia? Any number of researchers have described its symptoms and variants, theorized about causes, or studied the involvement of neurotransmitters. But the underlying pathophysiology of this heterogenous disorder is like the tale of the blind men and the elephant—many people have a piece of it, but they don't get the entire picture.

And that's what Thomas McGlashan, M.D., and colleague Ralph Hoffman, M.D., sought to provide in a report in the May 2000 Archives of General Psychiatry describing a remarkable computer simulation of brain dysfunction in schizophrenia. (For more information on McGlashan's work, see Original article: “Schizophrenia Scientist Comes Full Circle.”)

What they described was a model of “developmentally reduced synaptic connectivity.” Essentially, a diminished number of synapses in the prefrontal cortex and other crucial parts of the brain, they said, is the“ final common pathway to the symptoms and course of schizophrenia and, perhaps, to other psychotic disorders.”

According to the model, the diminished synaptic density results from a variable combination of disturbances in brain development in utero or early infancy and disturbances in synaptic “pruning” during adolescence.

The adolescent period of accelerated synaptic pruning is critical and provides a neurobiological window into the developmental nature of schizophrenia. Just as one “prunes” a bush by cutting away excess branches to shape it more accurately to its purpose, synaptic“ pruning” refers to the natural elimination of unnecessary synapses that occurs normally in adolescence, making the brain more organized and efficient.

It is the neurobiological counterpart to the way children and adolescents normally learn skills, from walking to navigating the social environment: with practice and refinement they gain mastery over all manner of habits of living. As they do so the superabundance of neuronal synapses provided them by nature early in life are “pruned”: necessary connections are made more efficient, while unnecessary ones are eliminated.

“The neuron stays alive and healthy,” McGlashan explained,“ it simply has fewer synaptic connections with other neurons, like a sentence with fewer dependent clauses.”

But in the person with schizophrenia, the process of pruning goes too far, diminishing a network of synapses that is often deficient from birth to begin with.

The result is that as the pruning progresses, the world is increasingly experienced as series of incomplete or redundant sentences. Like McGlashan's unmedicated patients who grew disorganized under the silence and relative disengagement of analysis , the schizophrenic brain fills in the gaps of its incomplete sentences with “all manner of disorganized thinking.”

More remarkably, the article describes a computer simulation of synaptic elimination created by Hoffman that models normal cognitive development and psychotic symptom formation.

In the paper, McGlashan and Hoffman describe how the model accounts for“ important aspects of schizophrenia, including its unique symptoms, short- and long-term course, typical age of onset, neurodevelopmental deficits, limited neurodegenerative progression, sex differences, and more.”

“Schizophrenia as a Disorder of Developmentally Reduced Synaptic Connectivity” is posted at<http://archpsyc.ama-assn.org/cgi/reprint/57/7/637.pdf>.