In vitro neuronal network activity in NMDA receptor encephalitis

Abstract

BackgroundAnti-NMDA-encephalitis is caused by antibodies against the N-methyl-D-aspartate receptor (NMDAR) and characterized by a severe encephalopathy with psychosis, epileptic seizures and autonomic disturbances. It predominantly occurs in young women and is associated in 59% with an ovarian teratoma.ResultsWe describe effects of cerebrospinal fluid (CSF) from an anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis patient on in vitro neuronal network activity (ivNNA). In vitro NNA of dissociated primary rat cortical populations was recorded by the microelectrode array (MEA) system.The 23-year old patient was severely affected but showed an excellent recovery following multimodal immunomodulatory therapy and removal of an ovarian teratoma. Patient CSF (pCSF) taken during the initial weeks after disease onset suppressed global spike- and burst rates of ivNNA in contrast to pCSF sampled after clinical recovery and decrease of NMDAR antibody titers. The synchrony of pCSF-affected ivNNA remained unaltered during the course of the disease.ConclusionPatient CSF directly suppresses global activity of neuronal networks recorded by the MEA system. In contrast, pCSF did not regulate the synchrony of ivNNA suggesting that NMDAR antibodies selectively regulate distinct parameters of ivNNA while sparing their functional connectivity. Thus, assessing ivNNA could represent a new technique to evaluate functional consequences of autoimmune encephalitis-related CSF changes.

Interaction of electrically evoked activity with intrinsic dynamics of cultured cortical networks with and without functional fast GABAergic synaptic transmission

“…Once generated, cortical neurons grown on MEAs allow non-invasive, long-term measurements of the spontaneous activity ( Maeda et al, 1995 ; Morefield et al, 2000 ; Potter and DeMarse, 2001 ; Van Pelt et al, 2004 ; Wagenaar et al, 2005 , 2006a ; Baltz et al, 2010 ; Gramowski et al, 2010 ; Weir et al, 2014 ) and electrical stimulation of the same cells over extended periods of time ( Wagenaar et al, 2006b ; Brewer et al, 2009 ; Bologna et al, 2010 ; Ide et al, 2010 ; Weihberger et al, 2013 ; Keren and Marom, 2014 ). Consequently, such a preparation has a variety of applications as for example studying basic neuronal mechanisms such as information processing, neuronal plasticity, neurotoxicity screening, biocompatibility testing as well as understanding sources of human disorders ( Shahaf and Marom, 2001 ; Eytan et al, 2003 ; Wagenaar et al, 2005 ; Bakkum et al, 2008 ; Kermany et al, 2010 ; Wallach and Marom, 2012 ; Dranias et al, 2013 ; Jantzen et al, 2013 ; Charkhkar et al, 2014 ; Frega et al, 2014 ; Gullo et al, 2014a , b ; Hedrich et al, 2014 ; Mack et al, 2014 ).…”

Autoimmune encephalitis in psychiatric institutions: current perspectives

“…Detection of anti-NMDAR antibodies by immunohistochemistry on rodent brain slices indicates a high hippocampal staining, a moderate cortical staining and a limited cerebellar staining,10 correlating well with the symptomatology. Various studies performed using animal models and in vitro suggest that the antibody decreases the surface expression and total density17,41 of NMDARs, leading to an alteration in synaptic plasticity and synaptic transmission 41,42. These data point toward a direct pathogenic role of antibodies on the NMDAR itself.…”

Neuronal central nervous system syndromes probably mediated by autoantibodies

“…A decrease of the NMDAR-mediated current seems to be caused only by internalization of NMDAR and not by an antagonistic effect (Moscato et al, 2014). Acute application of patients' CSF also decreased neuronal network activity in neuronal cultures (Jantzen et al, 2013). Finally, two studies reported an alteration of NMDARmediated plasticity by patients' NMDAR antibodies as they prevented induction of chemical long-term potentiation (LTP) (Mikasova et al, 2012) and electrophysiologically induced LTP in neuronal cell cultures (Zhang et al, 2012).…”