Neuroreceptor antibodies cause psychosis

Rita Balice-Gordon, a guest lecturer from the University of Pennsylvania School of Medicine, presented two unpublished stories last Wednesday at DHMC. She described a novel factor regulating synapse formation, and also explained the surprising cause of a rare form of psychosis experienced by some women with ovarian cancer.

Image of an astrocyte courtesy of Ivey and MacLean, Tulane National Primate Research Center

The first story began inadvertently with a virus outbreak among the laboratory’s mice, which forced Balice-Gordon and colleagues to default to in vitro experiments with cultured neurons. Some cultures were grown with “support” cells known as astrocytes and some without. The researchers noted that the presence of astrocytes seemed to increase the synaptic density of the neurons.

The lab has since shown that this effect is strangely skewed towards GABAergic inhibitory neurons, which display a six-fold increase in synaptic number when cultured with astrocytes, compared to a two-fold increase for excitatory glutamatergic neurons. Additionally, axon length and branching were increased only for inhibitory neurons.

Historically, little importance has been placed on astrocytes, but Balice-Gordon et al.’s work reveals their true importance, perhaps as regulators of neural growth during development. The lab is currently hunting for the exact factors that mediate this synaptic proliferation effect, and has two likely protein candidates in mind.

The second story transitioned from cell cultures to humans. Balice-Gordon’s lab is investigating a rare phenomenon in which ovarian cancer cells produce an autoimmune response in the brain, leading to sudden and potentially lethal psychosis.

The researchers applied cerebral spinal fluid from patients to neurons in the lab and are currently developing an animal model. Results indicate that the psychosis is caused by antibodies specifically targets to NMDA receptors, a glutamatergic receptor essential for learning and memory. The antibodies bind to NMDA receptors and cross-link together, resulting in internalization of the receptors into the cell.

The findings are surprising because it was previously thought that the brain was isolated from the body’s immune system by the blood brain barrier, a tight seal around blood vessels blocking the passage of all but the smallest molecules.

“I hope that this will lead to a renewed appreciation that the brain is not an immune privileged compartment,” said Balice-Gordon.

Though only 220 cases have been identified thus far, correct diagnosis and early treatment have already prevented deaths. In addition to its clinical importance, continued research in this area, especially with the mouse model in development, promises to reveal more about how specific receptors are linked to complex behaviors.

“We are trying to flush out the biological roles of these receptors, and that is really the goal of using animal models,” said Balice-Gordon.