John Lisman, Ph.D.
Professor of Biology and
Volen National Center for
Understanding Schizophrenia as a Dynamical System:
What Happens at the Schizophrenic Break?
While many of the previous talks focused on how network disruptions or network malformations can lead to a variety of disease-states, Dr. Lisman’s presentation explored how even a healthy network can produce aberrant signals. In particular, the Lisman lab studies how positive reinforcement within a structurally sound network can lead to overstimulation of specific groups of cells, resulting in psychosis.
Schizophrenia affects a significant number of individuals in our society, but the cellular and molecular basis of the disease remains unclear. One important hint comes from the fact that antagonists of the NMDA-type of glutamate receptor can induce many of the positive and negative symptoms of the disease. There has therefore been considerable effort to determine how such antagonists produce disturbances of neuronal function. Indeed, it is not at all clear why an antagonist of a neurotransmitter that is excitatory should produce (rather than quiet) mental activity.
There have been previous indications that NMDA antagonists can strongly affect the thalamus. For this reason, the Lisman lab investigated this at the cellular level, particularly in the nucleus reticularis, which is a group of inhibitory neurons that surround the thalamus. Researchers in the lab have found that an NMDA antagonist produces bursting of these inhibitory cells, and have determined the underlying mechanisms: an unusual type of NMDA receptor (NR2C) affects resting potential, and block of these channels hyperpolarizes these cells, de-inactivating T-type Ca channels, which then produce the observed bursting. Dopamine has been shown to enhance this bursting.
Together with other results in the literature, these findings suggest the first model that explains the sudden onset of the disease, often during stress in late adolescence. The evidence points to a dynamical system with the potential for positive feedback. This system involves the thalamus (notably the nucleus reuniens), the excitation of the hippocampus by this nucleus and the resulting hippocampal-dependent excitation of the dopaminergic cells of the VTA. The release of dopamine closes the loop by promoting bursting of the thalamus. Dr. Lisman suggested that various genetic mutations or developmental problems can push this system closer to the threshold for bursting, creating a predisposition for schizophrenia. Stress, which leads to additional dopamine release, can push the system into a persistent bursting mode maintained by positive feedback, thereby resulting in a psychotic state.
We thank the speakers who came to the Brandeis campus this past year to share with us their research and to engage in many hours of stimulating discussion and exchange of data and ideas with Volen Center faculty, graduate students and postdoctoral fellows. We are also grateful to our visitors for forwarding us their lecture summaries, which form the basis of this report.
We also thank two outstanding graduate students in the life sciences at Brandeis, Sara Wasserman and Justin Slawson, for their editorial contributions in the preparation of this annual report.