Moscato, Emilia Harrington
Now showing 1 - 1 of 1
PublicationCellular and Synaptic Homeostatic Plasticity in Response to Loss of Glutamatergic Transmission: Insights From Anti-Glutamate Receptor Encephalitides(2014-01-01) Moscato, Emilia HarringtonAnti-NMDA receptor and anti-AMPA receptor (NMDAR and AMPAR) encephalitides are debilitating but reversible autoimmune diseases of glutamatergic synapses of the central nervous system. Consistent with disruption of the major excitatory neurotransmitter in the central nervous system, symptoms of these newly characterized diseases are severe and include psychosis, memory loss, confusion, seizures, and autonomic instability. Previous work has shown that patients produce antibodies that can be detected in serum and cerebrospinal fluid that bind to NMDARs or AMPARs, causing their internalization and depletion from neuronal membranes and synapses. The goal of my thesis was to determine the mechanisms of patient antibody-mediated pathology and the compensatory responses of neurons upon antibody exposure. I used dissociated hippocampal neurons and organotypic hippocampal slice cultures for molecular (immunostaining, Western blotting, and quantitative PCR) and electrophysiological (whole-cell and extracellular recordings) studies. I found that antibodies from patients with anti-NMDAR or anti-AMPAR encephalitis caused internalization of their respective receptors. This internalization was stimulated by receptor cross-linking by patient immunoglobulins. Antibody-bound, internalized receptors trafficked through both recycling and lysosomal intracellular compartments. The loss of receptors was specific, time-dependent, reversible upon antibody removal, and did not result in neuronal death or structural dismantling of excitatory synapses. No acute effects on receptor function were detected. In response to the decreased glutamate signaling, neurons engage homeostatic plasticity mechanisms to maintain action potential firing rate, including down-regulating inhibitory synapses and increasing intrinsic excitability. Additionally, treatment with anti-AMPAR antibodies altered patterns of spontaneous action potential firing. Finally, a hippocampal slice culture model of anti-NMDAR antibody exposure was developed and validated for use in future studies. My work demonstrates that the hypoglutamatergic state created by anti-glutamate receptor antibodies leads to both direct and compensatory cellular and synaptic changes. Homeostatic plasticity of inhibition and intrinsic excitability opposes the declining excitatory synaptic transmission, but without the preservation of action potential firing pattern. Together, the direct and compensatory plasticity caused by patient antibodies may change the activity and thus the function of key brain circuits, contributing to patients' cognitive and behavioral symptoms.