Cellular and Synaptic Mechanisms of Anti-NMDA Receptor Encephalitis

• DOI: 10.1523/jneurosci.0167-10.2010
• Publication Date: 2010-04-28T16:53:04Z
• Authors: Ethan G. Hughes; Xiaoyu Peng; Amy J. Gleichman; Meizan Lai; Lei Zhou; Ryan Tsou; Thomas D. Parsons; David R. Lynch; Josep Dalmau; Rita J. Balice-Go...
• Keywords: Internalization; Anti-NMDA Receptor Encephalitis

We recently described a severe, potentially lethal, but treatment-responsive encephalitis that associates with autoantibodies to the NMDA receptor (NMDAR) and results in behavioral symptoms similar those obtained models of genetic or pharmacologic attenuation NMDAR function. Here, we demonstrate patients' antibodies cause selective reversible decrease surface density synaptic localization correlates antibody titers. The mechanism this is antibody-mediated capping internalization NMDARs, as Fab fragments prepared from did not density, subsequent cross-linking anti-Fab recapitulated caused by intact patient antibodies. Moreover, whole-cell patch-clamp recordings miniature EPSCs cultured rat hippocampal neurons showed specifically decreased NMDAR-mediated currents, without affecting AMPA receptor-mediated currents. In contrast these profound effects on alter expression other glutamate receptors proteins, number synapses, dendritic spines, complexity, cell survival. addition, was dramatically reduced hippocampus female Lewis rats infused antibodies, observed autopsied patients. These studies establish cellular mechanisms through which patients anti-NMDAR specific, titer-dependent, loss NMDARs. subtype eliminates function, resulting learning, memory, deficits encephalitis.