Rita Balice-Gordon, Ph.D.

Professor
School of Medicine
Department of Neuroscience
University of Pennsylvania
Jan. 25, 2010

Cellular and Synaptic Mechanisms Underlying Autoimmune Anti-Glutamate Receptor Disorders of Memory and Cognition

Dr. Rita Balice-Gordon is also interested in the mechanisms underlying synaptic dysfunction, which often lead to cognitive pathologies. In particular, the Balice-Gordon lab is interested in disorders stemming from glutamate neurotransmission, which has a well-known role in facilitating learning and memory. One such class of disorders is autoimmune in nature, where an organism’s own antibodies mistakenly attack its glutamate receptors, leading to severe cognitive difficulties. Dr. Balice-Gordon’s lab utilizes two different model organisms, the mouse and the zebrafish, to study this problem from the cellular, electrophysiological and behavioral perspectives, in hopes of producing a broader understanding of this complex type of disorder.

Synaptic plasticity is thought to underlie mechanisms of memory, learning and cognition. Central to these neurological functions is the proper synaptic localization and trafficking of neurotransmitter receptors, including excitatory glutamate NMDARs and AMPARs. The roles of these receptors at the synaptic and cellular level have been established through animal models in which the receptors have been genetically or pharmacologically altered. In humans, the role of these receptors in memory, learning and cognition comes from more indirect approaches such as pharmacological drug trials (e.g., NMDAR antagonists in schizophrenia) and analysis of brain tissue from patients with disorders such as Alzheimer’s disease or schizophrenia, in which multiple genetic or molecular pathways are affected.

Dr. Balice-Gordon’s presentation focused on two recently discovered human autoimmune disorders of memory, learning and cognition, and psychosis, in which the function of NMDA receptors and AMPA receptors is directly affected by a patient’s antibodies. These disorders are naturally occurring models of human memory dysfunction that are characterized by several unique phenomena: they are relatively frequent, cause severe memory loss, can be lethal but are potentially treatable, often affect children, and patients’ antibodies bind preferentially to hippocampus, cerebellum and striatum. The presence of highly specific serum and cerebrospinal fluid antibodies to extracellular domains of NMDA receptor and AMPA receptor subunits have been used to develop diagnostic tests. Recently, the Balice-Gordon lab has established that the cellular and synaptic mechanisms underlying these novel and life-threatening anti-glutamate receptor encephalopathies, as well as mechanisms of recovery, provide insights into cellular and circuit dysfunction caused by patients’ antibodies. Importantly, they begin to connect synaptic and circuit dysfunction with the behavioral abnormalities that are hallmarks of these disorders.